Conditions: β Thalassemia
Keywords: Transfusion TDT NTDT
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 122
Healthy volunteers: no

Brief summary:
A Study to Evaluate the Safety and Tolerability of IMR-687 in Subjects with Beta Thalassemia

Detailed description:
A phase 2, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, PK, and PD of IMR-687 (phosphodiesterase (PDE) 9 inhibitor) administered once daily (qd) orally for 36 weeks in 2 populations of adult subjects with β-thalassemia: Population 1 (Transfusion Dependent Thalassemia (TDT) subjects) and Population 2 (Non-Transfusion Dependent Thalassemia (NTDT) subjects).

Arms:
arm 1: Oral administration of once daily IMR-687 arm 2: Oral administration of once daily IMR-687 arm 3: Oral administration of once daily placebo

Interventions: intervention 1: IMR-687 intervention 2: Placebo
Intervention descriptions: intervention 1: Oral administration of once daily IMR-687 intervention 2: Oral administration of once daily Placebo

Protocol document:
Prot_000.pdf: 
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1. 
 TITLE PAGE 
PROTOCOL 
IMR-BTL-201 
 
Study Title: 
A Phase 2 Study to Evaluate the Safety and Tolerability of IMR-687 in 
Subjects with Beta Thalassemia 
Protocol Number: 
IMR-BTL-201 
Study Phase: 
2 
Study Drug: 
IMR-687 
US IND: 
EudraCT: 
130549 
2019-002989-12 
Indication: 
Treatment of adults with either transfusion dependent or non-transfusion 
dependent β-thalassemia 
Sponsor: 
IMARA, Inc. 
116 Huntington Avenue, 6th Floor 
Boston, MA 02116 
Sponsor Representative: 
Kenneth M. Attie, MD 
Senior Vice President and Chief Medical Officer, IMARA 
+1 617 710 0560 
kattie@imaratx.com 
Version Number: 
5.0 
Release Date: 
15 Mar 2021 
Replaces Version: 
4.0 
Release Date: 
15 Jan 2020 
GCP Statement: 
This study is to be performed in compliance with International Council 
for Harmonisation (ICH), applicable Good Clinical Practice (GCP), and 
federal and local regulations. 
 
Confidentiality Statement 
This document is the property of IMARA. The information in this document contains trade secrets and commercial 
information that are privileged or confidential and may not be disclosed without the express written permission of 
IMARA unless required by federal or state law or regulations. Any person to whom the information is disclosed 
must be informed that the information is privileged or confidential and may not be further disclosed by them. These 
restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged 
or confidential. 




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INVESTIGATOR’S AGREEMENT 
I have read and reviewed this clinical study protocol (IMR-BTL-201), and I agree to conduct this 
study according to this protocol, to comply with its requirements subject to ethical and safety 
considerations, and to conduct this study in accordance with all Regulatory Authority 
requirements and International Council for Harmonisation (ICH) Guidelines on Good Clinical 
Practice (ICH E6[R2]). I further agree to comply with all other applicable national and local laws 
and regulations in connection with my conduct of this study, including, without limitation, all 
applicable medical information privacy rule requirements. I agree to maintain the confidentiality 
of all information received or developed in connection with this protocol. 
I understand that the sponsor may decide to suspend or terminate the study at any time for 
whatever reason; such a decision will be communicated to me in writing. Conversely, should I 
decide to withdraw from the execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 


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KEY ROLES AND RESPONSIBILITIES 
Emergency Contact Information 
 
Pharmacovigilance and Patient Safety (PVS)  
North America 
Phone: +1 800 772 2215 or +1 434 951 3489 
Fax: +1 888 772 6919 or +1 434 951 3482 
Email:  CHOSafety@prahs.com 
 
EMEA/APAC 
Phone: +49 621 878 2154  
Fax: +44 1792 525 720 
Email:  MHGSafety@prahs.com 
 
 
Role in Study 
Telephone Number 
Fax Number 
Email 
Medical Monitor 
Support Center - 
North America 
+1 866 326 5053 (toll free) 
+1 434 951 4082 (direct) 
+ 1 800 280 7035 (toll free) 
+1 913 307 5751 (direct) 
imarabtl201@prahs.
com 
Medical Monitor 
for Europe, 
Middle East, 
Africa, and 
Asia-Pacific 
(EMEA/APAC)  
+49 621 878 2850 
+44 203 365 6752 
imarabtl201@prahs.
com 


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2. 
SYNOPSIS 
Name of Sponsor/Company: IMARA, Inc. 
Name of Investigational Product: IMR-687 
Name of Active Ingredient:  
6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-
imidazo[1,5-a]pyrazin-8-one 
Title of Study:  
A Phase 2 Study to Evaluate the Safety and Tolerability of IMR-687 in Subjects with Beta 
Thalassemia 
Indication: Treatment of adults with either transfusion-dependent (TDT) or non-transfusion-
dependent (NTDT) β-thalassemia 
Study Centers: This study will be conducted at approximately 50 study sites in North America, 
United Kingdom, European Union, Middle East, Asia-Pacific, and Africa. 
Phase of Development: 2 
Planned Number of Subjects:  
A total of approximately 120 adult subjects with β-thalassemia are expected to enroll: 
• 
Population 1 (TDT subjects): approximately 60 subjects 
• 
Population 2 (NTDT subjects): approximately 60 subjects 
Objectives: 
Primary Objective 
The primary objective of this study in both Population 1 (TDT) and Population 2 (NTDT) is to assess 
the safety and tolerability of IMR-687 in adult subjects with β-thalassemia. 
Secondary Objectives 
The secondary objectives in Population 1 (TDT) subjects are:  
• 
To evaluate the effect of IMR-687 versus placebo on reduction in red blood cell (RBC) 
transfusion burden. 
• 
To evaluate the effect of IMR-687 versus placebo on the change in iron overload. 
• 
To characterize the pharmacokinetic (PK) profile of IMR-687 and collect data for 
population PK analysis 
The secondary objectives in Population 2 (NTDT) subjects are:  
• 
To evaluate the effect of IMR-687 versus placebo on anemia (as defined by total 
hemoglobin [Hb]).  
• 
To evaluate the effect of IMR-687 versus placebo on fetal hemoglobin (HbF).  
• 
To evaluate the effect of IMR-687 versus placebo on the change in iron overload. 
• 
To characterize the PK profile of IMR-687 and collect data for population PK analysis 


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Exploratory Objectives 
The exploratory objectives in Population 1 (TDT) subjects are:  
• 
To characterize the pharmacodynamic (PD) profile of IMR-687 versus placebo with 
respect to erythropoiesis, iron metabolism, and hemolysis. 
• 
To evaluate the effect of IMR-687 versus placebo on the proportion of subjects who are 
transfusion independent. 
• 
To evaluate the effect of IMR-687 versus placebo on time to and duration of reduction in 
RBC transfusion burden.  
• 
To evaluate the effect of IMR-687 versus placebo on functional and health-related quality 
of life (QoL). 
• 
To evaluate responses to IMR-687 per genotypes in subjects with TDT. 
The exploratory objectives in Population 2 (NTDT) subjects are:  
• 
To characterize the PD profile of IMR-687 versus placebo with respect to erythropoiesis, 
iron metabolism, and hemolysis. 
• 
To evaluate the effect of IMR-687 versus placebo on functional and health-related QoL. 
• 
To evaluate the effect of IMR-687 versus placebo on β-thalassemia-related symptoms and 
severity. 
• 
To evaluate responses to IMR-687 per genotypes in subjects with NTDT. 
The objectives will be assessed by the endpoints described in Table 1 of the protocol. 
Study Design (Methodology): 
This is a phase 2, randomized, double-blind, placebo-controlled study to evaluate the safety, 
tolerability, PK, and PD of IMR-687 (phosphodiesterase (PDE) 9 inhibitor) administered once daily 
(qd) for 36 weeks in 2 populations of adult subjects with β-thalassemia: Population 1 (TDT subjects) 
and Population 2 (NTDT subjects). A schematic of the study is provided in Section 7 of the protocol.  
This study will enroll approximately 120 subjects with β-thalassemia (60 subjects with TDT and 
60 subjects with NTDT), aged 18 through 65 years. This study consists of a retrospective data 
collection period, a screening period, a double-blind treatment period, and a safety follow-up period. 
During the screening period of up to 28 days, subjects will provide informed consent and be evaluated 
on eligibility criteria as stated below.  
Subjects will receive either IMR-687 (lower dose [≥3.0 to ≤5.0 mg/kg] or higher dose [>4.5 to 
≤6.7 mg/kg]; the precise exposure ranges for different groups of subjects are dependent on the weight 
gate for tablet strength as summarized under Study Rationale below) or placebo in a blinded fashion. 
Subjects will be randomly assigned in a 2:1 ratio to receive either IMR-687 lower dose or placebo. 
Prior to the introduction of IMR-687 higher dose, the Data Monitoring Committee (DMC) will review 
safety data for at least 5 subjects who received IMR-687. If the DMC recommends inclusion of the 
higher dose, randomization will then proceed in a 1:2:1 ratio (IMR-687 lower dose, IMR-687 higher 
dose, or placebo). The DMC may request additional data and/or meeting(s) in order to make the 
recommendation on whether to move forward with inclusion of the higher dose. During study conduct 
under Protocol Version 4.0, the DMC approved the opening of enrollment in the higher dose 
IMR-687 group, which went into effect on 01 February 2021. 


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Subjects will return to the investigational site at Week 1 for a safety assessment, and qualified site 
personnel will contact the subject by telephone at Week 2 to capture potential AEs and concomitant 
medications. Subjects will be seen at the investigational site approximately every 3 weeks (TDT 
subjects) or every 4 weeks (NTDT subjects) throughout the remainder of the study. Safety will be 
monitored throughout the study, and PK, PD, QoL, and clinical outcome measures will be performed 
at the visits shown in the schedule of assessments for the TDT and NTDT populations (Table 2 and 
Table 3, respectively, in the protocol). 
The informed consent will specifically indicate that data will be retrospectively collected on 
transfusion burden, defined as the dates of transfusion events and the number of packed red blood cell 
(pRBC) units per event during the 12 weeks preceding the Baseline (Day 1) visit. If available, the 
following data should also be collected for each transfusion event: volume and hematocrit of each 
pRBC unit, pre-transfusion Hb, and pre-transfusion weight. 
Study Rationale: 
This is a phase 2 study intended to explore the potential use of IMR-687 to treat subjects with 
β-thalassemia. This is the first study of IMR-687 in a β-thalassemia population, and, as such, is 
designed to examine the safety, tolerability, and PK, as well as the potential PD effects, of IMR-687 
administered qd for 36 weeks in adult subjects with β-thalassemia.  
Administration for 30 days of 30 mg/kg/day (human equivalent dose [HED] of 2.4 mg/kg/day) or 
60 mg/kg/day (HED of 4.9 mg/kg/day) of IMR-687 in a β-thalassemia intermedia animal model 
(Hbbth1/th1 mice) improves markers of β-thalassemia disease progression by increasing RBCs and Hb, 
and reducing reticulocytes. The degree of these changes was dose dependent, with significant 
improvement at the higher dose of 60 mg/kg. In addition, IMR-687 at 60 mg/kg improved 
erythroblast differentiation, suggesting a role for this compound in the improvement of ineffective 
erythropoiesis of β-thalassemia. 
Clinical safety and tolerability data are available from Study IMR-SCD-101 in healthy volunteers for 
IMR-687 administered at doses up to 6 mg/kg/day in a fasted single ascending dose (SAD) portion 
(Part A) and at doses up to 4.5 mg/kg/day for 7 days in a fed multiple ascending dose (MAD) portion 
(Part C), as well as from the phase 2a study in fed subjects with sickle cell disease (IMR-SCD-102). 
Based on these data, exposure ranges from 3 mg/kg to approximately 6 mg/kg is expected to be 
tolerable, especially if taken with food because administration with food appears to reduce both the 
incidence and severity of nausea and/or gastrointestinal (GI) pain. The onset of nausea in the healthy 
volunteer study was rapid (between 30 to 120 minutes) and generally lasted 2 to 8 hours and was mild 
nature at doses ≤4.5 mg/kg (lower dose). These potential AEs of nausea, upper GI pain, and emesis 
are easily monitorable and are self-limited if dosing is stopped. Furthermore, following qd dosing for 
7 days in fed healthy volunteers, steady state was achieved before Day 7. Exposure (area under the 
concentration-time curve [AUC]) in healthy volunteers increased in a near dose-proportional manner 
(a 4.1-fold increase for a 4.5-fold change in dose [see Section 4.1.3.1 of the protocol]), and the mean 
exposure (AUC from time 0 to 24 hours [AUC0-24]) at 4.5 mg/kg on Day 7 was 26.3 µg•h/mL, which 
is approximately 3.3-fold below the Week 39 exposure (AUC0-24) in the female dog (most 
conservative species/gender) at the respective no observed adverse effect level (NOAEL) in the 
repeat-dose toxicology study. Furthermore, the predicted Day 1 exposure in the higher dose arm of up 
to 6.7 mg/kg is 32.0 µg•h/mL, which remains approximately 2.7-fold below the Week 39 exposure 
(AUC0-24) in the female dog (most conservative species/gender). 
This study initially imposed a minimum weight threshold of 45 kg and a 67-kg weight gate for tablet 
strength to ensure that subjects in the lower dose IMR-687 group received a dose equating to no more 
than the 4.5 mg/kg evaluated in the MAD part of the healthy volunteer study. Subsequently, the DMC 
approved the opening of enrollment in the higher dose IMR-687 group (up to 6.7 mg/kg). Having 
established safety and tolerability of the lower dose, the DMC also approved a change in weight gate 


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to 60 kg and the resultant modified dose range of up to 5.0 mg/kg in the lower dose group (with the 
minimum weight threshold of 45 kg unchanged). Starting from Protocol Version 5.0, subjects in the 
IMR-687 lower dose group will receive ≥3.4 to ≤5.0 mg/kg and subjects in the higher dose group will 
receive >5.0 to ≤6.7 mg/kg; no subject will receive more than 6.7 mg/kg. Under Protocol Version 4.0, 
the exposure ranges were ≥3.0 to ≤4.5 mg/kg in the lower dose group and >4.5 to ≤6.7 mg/kg in the 
higher dose group. Therefore, the overall exposure ranges during the course of the study are ≥3.0 to 
≤5.0 mg/kg and >4.5 to ≤6.7 mg/kg. 
Inclusion Criteria:  
Subjects must meet all of the following inclusion criteria to be eligible for the study: 
1. Subjects must understand and voluntarily provide informed consent and sign an informed 
consent form (ICF) prior to any study-related assessments/procedures being conducted. 
Although RBC transfusions and associated Hb laboratory measurements prior to Screening 
are not study related, the ICF will specifically request subject consent to collect these data. 
2. Subjects must be ≥18 to ≤65 years of age at the time of signing the ICF. 
3. Subjects must have documented diagnosis of β-thalassemia or HbE/β-thalassemia in their 
medical history. Concomitant alpha gene deletion, duplication, or triplication is allowed. 
4. For TDT subjects only: Subjects must be regularly transfused, defined as >3 to 10 pRBC 
units1 in the 12 weeks prior to the Baseline (Day 1) visit and no transfusion-free period for 
>35 days during that period. 
For NTDT subjects only: Subjects must be transfusion independent, defined as 0 to ≤3 units1 
of pRBCs received during the 12-week period prior to the Baseline (Day 1) visit, must not be 
on a regular transfusion program, must be RBC transfusion-free for at least ≥ 4 weeks prior to 
randomization, and must not be scheduled to start a regular hematopoietic stem cell 
transplantation within 9 months.  
5. Subjects must have documentation of the dates of transfusion events and the number of pRBC 
units per event within the 12 weeks prior to the Baseline (Day 1) visit. 
6. Subjects must be willing and able to complete all study assessments and procedures, and to 
communicate effectively with the investigator and site staff. 
7. Subjects must have Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 
1 (Appendix 1). 
8. Female subjects must not be pregnant or breastfeeding and be highly unlikely to become 
pregnant. Male subjects must be unlikely to impregnate a partner. Male or female subjects 
must meet at least one of the following criteria: 
• 
A female subject who is not of reproductive potential is eligible without requiring the use 
of contraception. A female subject who is not of reproductive potential is defined as one 
                                                 
 
1One unit in this protocol refers to one bag of packed RBCs. The dates of transfusion events and the number of 
pRBC units per event during the 12 weeks preceding the Baseline (Day 1) visit will be collected. If available, the 
following data should also be collected for each transfusion event: volume and hematocrit of each pRBC unit, pre-
transfusion Hb, and pre-transfusion weight. Transfusion burden as expressed in mL/kg transfused RBC may be 
calculated. 
 


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who: (1) has reached natural menopause (defined as 12 months of spontaneous 
amenorrhea without an alternative medical cause, and can be confirmed with serum 
follicle-stimulating hormone levels in the postmenopausal range as determined by the 
central laboratory); (2) is 6 weeks post-surgical bilateral oophorectomy with or without 
hysterectomy; or (3) has undergone bilateral tubal ligation. Spontaneous amenorrhea does 
not include cases for which there is an underlying disease that causes amenorrhea 
(e.g., anorexia nervosa). 
• 
A female of reproductive potential must have 2 negative pregnancy tests as verified by 
the investigator prior to starting study therapy. She must agree to ongoing pregnancy 
testing during the course of the study, at the end of treatment visit, and at the end of study 
visit. This applies even if the subject practices true abstinence from heterosexual contact. 
• 
A male subject who is not of reproductive potential is eligible without requiring the use 
of contraception. A male subject who is not of reproductive potential is defined as one 
who has undergone a successful vasectomy. A successful vasectomy is defined as 
(1) microscopic documentation of azoospermia, or (2) a vasectomy more than 2 years ago 
with no resultant pregnancy despite sexual activity post-vasectomy. 
• 
A male or female subject who is of reproductive potential agrees to remain truly abstinent 
or use (or have their partner use) acceptable methods of highly effective contraception 
starting from the time of consent through 3 months after the completion of study therapy. 
True abstinence is defined as abstinence that is in line with the preferred and usual 
lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods), declaration of abstinence for the duration of the study, and 
withdrawal are not acceptable methods of contraception. Acceptable methods of highly 
effective birth control are combined or progesterone-only hormonal contraception that is 
associated with inhibition of ovulation, intrauterine device, and intrauterine 
hormone-releasing system.  
9. Subjects receiving hydroxyurea must have received it continuously for at least 6 months prior 
to signing the ICF, and must have been on a stable dose for at least 3 months prior to signing 
the ICF, with no anticipated need for dose adjustments during the study including the 
screening period, in the opinion of the investigator. 
10. For NTDT subjects only: Subjects must have Hb ≤10.0 g/dL at Screening; the screening Hb 
sample must be collected 7 to 28 days prior to randomization. Hb values within 21 days 
post-transfusion will be excluded. 
Exclusion Criteria: 
Subjects meeting any of the following criteria must be excluded from the study: 
1. Any significant medical condition, laboratory abnormality, or psychiatric illness that would 
prevent the subject from participating in the study, including the presence of laboratory 
abnormalities that may place the subject at unacceptable risk if he/she were to participate in 
the study. 
2. Any situation or condition that confounds the ability to interpret data from the study 
(e.g., subjects also receiving RBC transfusions at centers not able to obtain laboratory 
samples for central processing). 
3. Diagnosis of α-thalassemia (e.g., hemoglobin H [HbH]) or hemoglobin S (HbS)/ 
β-thalassemia. 
4. Body mass index (BMI) <17.0 kg/m2 or a total body weight <45 kg; or BMI >35 kg/m2.  


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5. Subjects with known active hepatitis A, hepatitis B, or hepatitis C, with active or acute event 
of malaria, or who are known to be positive for human immunodeficiency virus (HIV). 
6. Stroke requiring medical intervention ≤24 weeks prior to randomization. 
7. Subjects taking direct acting oral anti-coagulants (DOACs) apixaban, dabigatran, 
rivaroxaban, edoxaban, or ticagrelor, or taking warfarin, are excluded due to the possibility of 
a cytochrome P450 (CYP)3A-mediated drug interaction, unless they stopped the treatment at 
least 28 days prior to randomization (Day 1); other oral anti-coagulants and anti-platelet 
drugs are permitted. Anti-coagulant therapies for prophylaxis of venous thromboembolism, 
including pulmonary emboli including when undergoing surgery or high-risk procedures, are 
allowed if low molecular weight heparins are used in the peri-operative period. Aspirin use 
(<100 mg per day) is allowed before and during the study.  
8. Participated in another clinical study of an investigational agent (or medical device) within 
30 days or 5 half-lives of date of informed consent, whichever is longer, or is currently 
participating in another study of an investigational agent (or medical device). 
9. Platelet count >1000 × 109/L. 
10. For subjects on iron chelation therapy (ICT) at the time of ICF signing, initiation of ICT less 
than 24 weeks before the predicted randomization date. ICT can be initiated at any time 
during treatment and should be used according to the label.  
11. Subjects who have had treatment with erythropoietin-stimulating agents ≤24 weeks prior to 
randomization. 
12. Uncontrolled hypertension as defined by systolic BP ≥160 mm Hg or diastolic BP ≥100 mm 
Hg, medical intervention indicated, and more than one drug or more intensive therapy than 
previously used indicated. 
13. Poorly controlled diabetes mellitus, in the opinion of the investigator, for example 
1) Hb A1c >9.0% within 12 weeks prior to randomization (in the medical history); 
2) short-term hyperglycemia leading to hyperosmolar or ketoacidotic crisis; and/or 3) history 
of diabetic cardiovascular complications. 
14. Subjects who have major organ damage, including: 
a. Liver disease with ALT or AST >3× ULN; direct bilirubin >3× ULN with proportion of 
direct/total bilirubin >0.3; or history/evidence of cirrhosis, liver transplant, or presence of 
clinically significant mass/tumor. 
b. Heart disease, heart failure as classified by the New York Heart Association 
classification 3 or higher, or significant arrhythmia requiring treatment, or recent 
myocardial infarction within 6 months of randomization, or significant cardiac iron 
overload. 
c. Severe lung disease, including pulmonary fibrosis or pulmonary hypertension, 
i.e., ≥Grade 3 NCI CTCAE version 5.0. 
d. Significant kidney disease as indicated by, for example, estimated glomerular filtration 
rate <45 mL/min/1.73 m2 (per Modification of Diet in Renal Disease formula). 
15. Subjects who have received chronic systemic glucocorticoids ≤12 weeks prior to 
randomization (≥5 mg/day prednisone or equivalent). Physiologic replacement therapy for 
adrenal insufficiency is allowed. 
16. Major surgery ≤8 weeks prior to randomization. 


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17. A history of a clinically significant allergic reaction or hypersensitivity, as judged by the 
investigator, to any drug or any component of the study drug formulations used in the study 
(see Investigator’s Brochure). 
18. History or current malignancies (solid tumors and hematological malignancies) unless the 
subject has been free of the disease (including completion of any active or adjuvant treatment 
for prior malignancy) for ≥5 years. However, subjects with the following history/concurrent 
conditions are allowed if, in the opinion of the investigator, the condition has been adequately 
diagnosed and is determined to be clinically in remission, and the subject’s participation in 
the study would not represent a safety concern: 
a. Basal or squamous cell carcinoma of the skin 
b. Carcinoma in situ of the cervix 
c. Carcinoma in situ of the breast 
d. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, 
metastasis clinical staging system) 
19. Screening or Baseline (Day 1) electrocardiogram (ECG) demonstrating a QTcF >450 ms in 
men and >470 ms in women on 2 or more of the triplicate ECGs, or the presence of clinically 
significant ECG abnormalities as determined by the investigator. 
20. Consumption/use of the following drugs or other substances within the specified time periods 
before randomization or plans to consume/use at any time during the study. If there is any 
question as to whether a substance is permitted, please review the product labelling (if 
applicable) and consult the medical monitor and/or sponsor. 
a. PDE type 5 inhibitors (including but not limited to sildenafil, tadalafil, and vardenafil) 
within 7 days prior to randomization (Day 1) or plans to use during the study. 
b. Grapefruit, grapefruit juice, grapefruit products, or herbal supplements with CYP-altering 
abilities within 1 week prior to randomization (Day 1) or plans to consume during the 
study. 
c. CYP3A-sensitive substrates, including the synthetic opioid fentanyl and alfentanil, or 
moderate to strong CYP3A inhibitors or inducers within 28 days prior to randomization 
(Day 1) or plans to use during the study. 
d. Any drugs or substances known to be substrates or inhibitors of P-glycoprotein (P-gp) or 
breast cancer resistance protein (BCRP) within 28 days prior to randomization (Day 1) or 
plans to use during the study. 
21. Other prior or ongoing medical condition, physical findings, or laboratory abnormality that, 
in the investigator's opinion, could adversely affect the safety of the subject, make it unlikely 
that the course of treatment or follow-up would be completed, or impair the assessment of 
study results (e.g., a history of drug or alcohol abuse as judged by the investigator within the 
past 1 year). 
22. Any clinically significant bacterial, fungal, parasitic, or viral infection requiring antibiotic 
therapy should delay screening/randomization (Day 1) until the course of antibiotic therapy 
has been completed. This includes but is not limited to long-term tuberculosis treatment. 
23. Prior exposure to any of following: 
a. IMR-687 or gene therapy 
b. Sotatercept or luspatercept (Reblozyl®) within 6 months prior to randomization (Day 1) 
24. In the opinion of the investigator, the subject is unable to meet the requirements of the study. 


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Investigational Product, Dose, and Mode of Administration:  
IMR-687 will be supplied as 100, 150, or 200 mg white tablets to be taken orally. Subjects will be 
advised to take two IMR-687 tablets orally with food qd for 36 weeks. The different doses of 
IMR-687 are visually identical in tablet form.  
Reference Therapy, Dosage and Mode of Administration:  
Placebo will consist of tablets containing matrix absent IMR-687 and will be identical in appearance 
to the IMR-687 tablets. Subjects will be advised to take two placebo tablets orally with food qd for 
36 weeks. 
Duration of Treatment and Study Duration:  
The planned maximum duration of study participation is approximately 44 weeks. This consists of a 
screening period of up to 4 weeks, a treatment period of 36 weeks, and a 4-week safety follow-up 
assessment after the last dose of study drug is administered. In addition, there is retrospective data 
review undertaken at the start of subject participation that aims to collect information on transfusion 
activity during the 12 weeks preceding the Baseline (Day 1) visit (historical transfusion burden). 
Statistical Methods 
General Considerations 
Descriptive summary statistics will be provided for demographics, disposition, and IMR-687 
exposure. The number and percentage of subjects who discontinue from the study, along with reasons 
for discontinuations will be tabulated. 
Continuous data will be summarized using descriptive statistics (number of subjects, mean, SD, 
median, Q1, Q3, minimum, and maximum) and, where appropriate, coefficient of variation (%CV) 
and graphic representation. Categorical data will be summarized by sample size and proportions. Data 
will be summarized by population (TDT, NTDT) and dose cohort at each timepoint as appropriate. 
Graphs of actual values and changes over time may also be created as appropriate. 
Interim analyses will be conducted at each of the following milestones: 
• 
30 subjects in the TDT population have completed 24 weeks of treatment 
• 
30 subjects in the NTDT population have completed 24 weeks of treatment 
• 
60 subjects in the TDT population have completed 24 weeks of treatment 
• 
60 subjects in the NTDT population have completed 24 weeks of treatment 
Analysis Sets 
Note that each of the following populations are defined for TDT and NTDT populations separately. 
Combined TDT and NTDT populations may also be used as appropriate. 
The safety analysis set will include all subjects who have received any amount of study drug and from 
whom informed consent has been obtained and will be used to summarize all safety and tolerability 
data. In safety summaries, subjects will be analyzed according to the actual treatment they received. 
The per protocol set will include all subjects in the safety population who have provided sufficient 
data without major protocol deviations or events that would be expected to affect the analysis. The 
per protocol set will be identified based on blinded data prior to unblinding the final analysis dataset. 
The per protocol set will be used to generate PD and clinical outcomes data. 
The PK analysis set will be defined as a subset of the safety analysis set that includes all subjects who 
are enrolled in the study, have received at least 1 dose of IMR-687, and have sufficient IMR-687 
concentration data; this set will be used in the PK analyses. 
Safety Analyses 
Descriptive statistics will be used to summarize all safety endpoints, by population and treatment 


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group as appropriate. Data summaries will be displayed for incidence of AEs, clinical laboratory 
variables, vital signs, and ECG parameters. Safety data summaries will use the safety analysis set. All 
AEs will be coded using MedDRA. Data will be summarized using preferred term and primary 
system organ class. AE summaries will include AEs leading to study discontinuation and severity and 
frequency of AEs and SAEs. All safety data will be summarized in by-subject listings. 
Preliminary Efficacy Analyses 
Population 1 (TDT) 
Hematological improvement will be evaluated using a Cochran-Mantel-Haenzel (CMH) test to 
compare the proportion of subjects who achieved improvement between the placebo group to each of 
the 2 active treatment arms (IMR-687 lower dose and IMR-687 higher dose). Hematological 
improvement is defined as a ≥20% reduction in pRBC units transfused measured over 12 weeks (from 
Week 12 to Week 24 and from Week 24 to Week 36) as compared to the 12-week period prior to the 
Baseline (Day 1) visit. The safety and per protocol populations will be used, and no multiple 
comparisons adjustment will be made.  
The mean number of transfusion events from baseline to Week 36 will be summarized by treatment 
group. Comparisons between placebo and each of the 2 active treatment arms (IMR-687 lower dose 
and IMR-687 higher dose) will be made using a t-test.  
The mean change from baseline to Week 36 for ICT mean daily dose and serum ferritin will be 
analyzed using an analysis of covariance (ANCOVA) model with baseline value as a covariate and 
treatment as a factor.  
Population 2 (NTDT) 
The baseline value of Hb will be defined as the mean of non-missing Hb values from Screening (7 to 
28 days prior to randomization) and randomization (Day 1) measurements. The baseline value of HbF 
will be defined in an analogous manner. The proportion of subjects with increase from baseline of 
≥1.0 g/dL in mean Hb values (at Weeks 12 to 24 and Weeks 24 to 36) will be evaluated using a 
Cochran-Mantel-Haenzel (CMH) test to compare the proportion of subjects who achieved 
improvement between the placebo group and each of the 2 active treatment arms (IMR-687 lower 
dose and IMR-687 higher dose). 
The average Hb concentrations in the absence of transfusions over a continuous 12-week interval 
(from Week 12 to Week 24 and from Week 24 to Week 36) as well as the change from baseline will 
be summarized by treatment group and timepoint. The change from baseline in average Hb at 
Weeks 12 to 24 and Weeks 24 to 36 will be compared between the placebo group and each of the 
2 active treatment arms (IMR-687 lower dose and IMR-687 higher dose) using a mixed model for 
repeated measures (MMRM) with fixed effects for treatment group and timepoint and a random 
subject effect. The safety and per protocol populations will be used, and no multiple comparisons 
adjustment will be made. Mean change in HbF concentrations from baseline to Week 24 and to 
Week 36 will be analyzed in the same manner.  
The number and proportion of subjects with HbF response of ≥3% using the mean values at Weeks 12 
to 24 and Weeks 24 to 36 will be summarized by timeframe and treatment group. Comparisons of 
each of the 2 active treatment arms (IMR-687 lower dose and IMR-687 higher dose) to placebo will 
be made using a CMH test. 
The mean change from baseline to Week 36 for ICT mean daily dose and serum ferritin will be 
analyzed using an ANCOVA model with baseline value as a covariate and treatment as a factor. 
Pharmacokinetic Analyses 
Summary statistics for trough plasma concentration (Ctrough) data will be provided. Accumulation may 
be assessed. 
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clinical response, PD endpoints, or AEs, as data permit. These data will be analyzed together with PK 
data from other clinical studies for a population PK analysis, as appropriate. 
Analyses of Exploratory Endpoints 
Exploratory PD and clinical outcomes data for each timepoint will be listed by subject and 
summarized by treatment group separately for Population 1 (TDT) and Population 2 (NTDT) as 
appropriate. Correlations between PK and the exploratory endpoints may be assessed. Descriptive 
statistics will be computed as appropriate. 
Summary statistics for QoL scores from the prespecified domains will be calculated at each 
administration timepoint. Summary statistics will also be calculated for change from baseline in each 
score at each administration timepoint. 
Exploratory PD outcomes will be based on the PD analysis set, and QoL outcomes will be based on 
the safety and per protocol sets. 
Sample Size Calculations 
Both populations will have primary objectives of safety, and the sample sizes are not based on 
statistical assumptions. 
Population 1 (TDT) 
For the secondary efficacy endpoint of percentage of subjects with hematologic improvement 
(reduction in transfusion burden), 16 subjects in each treatment arm provide 80% power to detect a 
difference of 10% of subjects improving in the placebo arm versus 50% of subjects improving in 
either of the active treatment arms, using an alpha level of 0.05. No multiple comparisons adjustments 
will be made as these are secondary analyses. 
Population 2 (NTDT) 
For the secondary efficacy endpoint of proportion of subjects with increase from baseline of 
≥1.0 g/dL in mean Hb values at Weeks 12 to 24 and Weeks 24 to 36, 17 subjects in each treatment 
arm provide >90% power to detect a difference of 10% of subjects improving in the placebo arm 
versus 50% of subjects improving in either of the active treatment arms, using an alpha level of 0.05. 
No multiple comparisons adjustments will be made as these are secondary analyses. 
 


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TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
SPONSOR’S APPROVAL ..............................................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
KEY ROLES AND RESPONSIBILITIES ......................................................................................4 
2. 
SYNOPSIS ...................................................................................................................5 
TABLE OF CONTENTS ...............................................................................................................15 
LIST OF TABLES .........................................................................................................................20 
LIST OF FIGURES .......................................................................................................................20 
3. 
LIST OF ABBREVIATIONS .....................................................................................21 
4. 
INTRODUCTION ......................................................................................................24 
4.1. 
Overview of Disease Pathogenesis .............................................................................24 
4.2. 
Overview of IMR-687 Development ..........................................................................24 
4.2.1. 
IMR-687 .....................................................................................................................24 
4.2.2. 
Nonclinical Data .........................................................................................................24 
4.2.2.1. 
Nonclinical Data in β-Thalassemia .............................................................................25 
4.2.3. 
Clinical Data ...............................................................................................................26 
4.2.3.1. 
Phase 1a Study of IMR-687 in Healthy Adult Volunteers (IMR-SCD-101) ..............26 
4.2.3.2. 
Phase 2a Study of IMR-687 in Adult Subjects with Sickle Cell Anemia 
(IMR-SCD-102) ..........................................................................................................27 
5. 
RATIONALE .............................................................................................................28 
5.1. 
Study Rationale and IMR-687 Dose Rationale ..........................................................28 
5.2. 
Benefit/Risk Assessment ............................................................................................29 
5.2.1. 
Potential Benefits ........................................................................................................30 
5.2.2. 
Potential Risks ............................................................................................................30 
5.2.2.1. 
Gastrointestinal ...........................................................................................................30 
5.2.2.2. 
Central Nervous System .............................................................................................30 
5.2.2.3. 
Cardiovascular ............................................................................................................31 
5.2.3. 
Potential Interactions ..................................................................................................31 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................34 
6.1. 
Primary Objective .......................................................................................................34 
6.2. 
Secondary Objectives .................................................................................................34 


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6.2.1. 
Population 1: Transfusion-dependent β-Thalassemia .................................................34 
6.2.2. 
Population 2: Non-transfusion-dependent β-Thalassemia ..........................................34 
6.3. 
Exploratory Objectives ...............................................................................................34 
6.3.1. 
Population 1: Transfusion Dependent β-Thalassemia ................................................34 
6.3.2. 
Population 2: Non-transfusion Dependent β-Thalassemia .........................................35 
6.4. 
Endpoints ....................................................................................................................35 
7. 
INVESTIGATIONAL PLAN .....................................................................................38 
7.1. 
Overall Study Design ..................................................................................................38 
7.2. 
Data Monitoring Committee .......................................................................................46 
8. 
SELECTION OF STUDY POPULATION ................................................................47 
8.1. 
Inclusion Criteria ........................................................................................................47 
8.2. 
Exclusion Criteria .......................................................................................................48 
8.3. 
Screen Failures ............................................................................................................51 
8.4. 
Guidelines for Withdrawal of Subjects from Study Participation ..............................51 
8.5. 
Guidelines for Study Drug Dose Withholding or Discontinuation ............................52 
8.5.1. 
Safety Criteria for Study Dose Interruption or Discontinuation .................................52 
8.6. 
Replacement of Subjects .............................................................................................53 
8.7. 
Stopping Rules and Study Termination ......................................................................54 
9. 
STUDY TREATMENTS ............................................................................................55 
9.1. 
Storage Conditions ......................................................................................................55 
9.2. 
Study Drug ..................................................................................................................55 
9.3. 
Packaging and Labeling ..............................................................................................55 
9.4. 
Study Drug Preparation ..............................................................................................55 
9.5. 
Administration ............................................................................................................55 
9.6. 
Treatment Compliance ................................................................................................56 
9.7. 
Concomitant Medications ...........................................................................................56 
9.7.1. 
Non-investigational Medicinal Products ....................................................................56 
9.7.2. 
Prohibited Concomitant Medications/Therapies ........................................................56 
9.7.3. 
Prohibited Concomitant Procedures ...........................................................................57 
9.8. 
Handling and Disposal ................................................................................................57 
10. 
RANDOMIZATION AND BLINDING ....................................................................58 
10.1. 
Randomization ............................................................................................................58 


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10.2. 
Blinding ......................................................................................................................58 
10.3. 
Unblinding for Interim Analysis .................................................................................58 
10.4. 
Emergency Unblinding ...............................................................................................58 
11. 
ASSESSMENTS .........................................................................................................60 
11.1. 
Screening and Baseline Activities ..............................................................................60 
11.1.1. 
Informed Consent .......................................................................................................60 
11.1.2. 
Demographic Information and Medical/Disease History ...........................................60 
11.1.3. 
Inclusion/Exclusion Criteria Evaluation .....................................................................61 
11.1.4. 
Eastern Cooperative Oncology Group Performance Score ........................................61 
11.1.5. 
Historical Transfusion Burden ....................................................................................61 
11.1.6. 
Height .........................................................................................................................61 
11.1.7. 
Serum Virology ..........................................................................................................61 
11.1.8. 
Pharmacogenomic Evaluation (Optional) ...................................................................61 
11.2. 
Preliminary Efficacy and Pharmacodynamic Assessments ........................................62 
11.2.1. 
Transfusion Burden ....................................................................................................62 
11.2.2. 
Quality of Life ............................................................................................................62 
11.2.3. 
Specialty Hematology .................................................................................................63 
11.2.4. 
Pharmacodynamic Markers ........................................................................................63 
11.3. 
Safety Assessments .....................................................................................................63 
11.3.1. 
Telephone Visits .........................................................................................................63 
11.3.2. 
Vital Signs ..................................................................................................................64 
11.3.3. 
Weight .........................................................................................................................64 
11.3.4. 
Physical Examinations ................................................................................................64 
11.3.5. 
Electrocardiogram .......................................................................................................64 
11.3.6. 
Central Laboratory Assessments ................................................................................65 
11.3.6.1. 
Hematology .................................................................................................................65 
11.3.6.2. 
Coagulation .................................................................................................................65 
11.3.6.3. 
Serum Chemistry ........................................................................................................65 
11.3.6.4. 
Urinalysis ....................................................................................................................65 
11.3.6.5. 
Pregnancy Test ............................................................................................................65 
11.3.7. 
Adverse Event Collection ...........................................................................................66 
11.3.8. 
Concomitant Medications ...........................................................................................66 


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11.4. 
Pharmacokinetic Assessments ....................................................................................66 
11.4.1. 
Plasma Pharmacokinetics ...........................................................................................66 
12. 
SAFETY MONITORING AND REPORTING .........................................................67 
12.1.1. 
Adverse Event and Serious Adverse Event Collection ...............................................67 
12.1.1.1. 
Time Period Adverse Event Collection ......................................................................67 
12.1.1.2. 
Follow-up ....................................................................................................................67 
12.1.2. 
Adverse Event Recording and Reporting ...................................................................67 
12.1.2.1. 
Definitions ..................................................................................................................67 
12.1.2.2. 
Evaluation of Adverse Events/Serious Adverse Events .............................................69 
12.1.2.3. 
Recording and Reporting Adverse Events and Serious Adverse Events ....................70 
12.1.2.4. 
Regulatory Reporting Requirements ..........................................................................71 
12.1.2.5. 
Exposure During Pregnancy .......................................................................................72 
12.1.3. 
Medication Error and Reporting .................................................................................72 
13. 
STATISTICAL METHODS .......................................................................................73 
13.1. 
General Considerations ...............................................................................................73 
13.2. 
Analysis Sets ...............................................................................................................73 
13.3. 
Safety Analyses ..........................................................................................................73 
13.4. 
Preliminary Efficacy Analyses ...................................................................................74 
13.4.1. 
Population 1: Transfusion Dependent β-Thalassemia ................................................74 
13.4.2. 
Population 2: Non-Transfusion Dependent β-Thalassemia ........................................74 
13.5. 
Pharmacokinetic Analyses ..........................................................................................75 
13.6. 
Analyses of Exploratory Endpoints ............................................................................75 
13.7. 
Sample Size Calculations ...........................................................................................75 
13.7.1. 
Population 1: Transfusion Dependent β-Thalassemia ................................................75 
13.7.2. 
Population 2: Non-transfusion Dependent β-Thalassemia .........................................75 
14. 
DATA COLLECTION AND QUALITY CONTROL ...............................................76 
14.1. 
Database Management and Data Quality Control ......................................................76 
14.2. 
Study Site Monitoring .................................................................................................76 
14.3. 
Subject Data Protection and Confidentiality ..............................................................77 
15. 
ADMINISTRATIVE, ETHICAL, AND REGULATORY 
CONSIDERATIONS ..................................................................................................79 
15.1. 
Protocol .......................................................................................................................79 


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15.1.1. 
Protocol Amendments ................................................................................................79 
15.1.2. 
Protocol Adherence ....................................................................................................79 
15.1.3. 
Discontinuation of Site Participation ..........................................................................79 
15.1.4. 
Protocol Disclosure and Confidentiality .....................................................................79 
15.2. 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) ..............80 
15.3. 
Ethical Conduct of the Study ......................................................................................80 
15.4. 
Subject Informed Consent ..........................................................................................80 
15.5. 
Publication of Study Protocol and Results .................................................................81 
15.6. 
Correlative Studies ......................................................................................................81 
15.7. 
Investigators and Study Personnel ..............................................................................81 
15.8. 
Study Documentation, Record Keeping, and Retention of Documents .....................82 
15.9. 
Audits and Inspections ................................................................................................82 
16. 
REFERENCES ...........................................................................................................83 
17. 
APPENDICES ............................................................................................................85 
Appendix 1: Eastern Cooperative Oncology Group (ECOG) Performance Status .......................86 
Appendix 2: National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE, v5.0) ........................................................................................87 
Appendix 3: Lists of Potential In Vivo CYP3A Drug-Drug Interactions ......................................88 
 


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LIST OF TABLES 
Table 1: 
Study Endpoints ..........................................................................................................35 
Table 2: 
Schedule of Assessments: Population 1 (TDT β-Thalassemia) ..................................40 
Table 3: 
Schedule of Assessments: Population 2 (NTDT β-Thalassemia) ...............................43 
Table 4: 
Safety Guidelines for Study Dose Reduction, Interruption, or 
Discontinuation ...........................................................................................................53 
LIST OF FIGURES 
Figure 1:  Overview of Study Design and Dose Groups ...............................................................39 
 


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3. 
LIST OF ABBREVIATIONS 
Abbreviation  
Definition 
%CV 
coefficient of variation 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-24 
AUC from time 0 to 24 hours 
BCRP 
breast cancer resistance protein 
CFR 
Code of Federal Regulations 
cGMP 
cyclic guanosine monophosphate 
C24 
concentration at 24 hours after study drug administration 
Cmax  
maximum plasma concentration 
CMH 
Cochran-Mantel-Haenzel 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
CRO 
contract research organization 
CSR 
clinical study report  
Ctrough 
trough plasma concentration 
CYP 
cytochrome P450 
DMC 
Data Monitoring Committee 
DOAC 
direct-acting oral anti-coagulant 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOT 
end of treatment 
FE 
food effect 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 
Hb 
hemoglobin 
HbE 
hemoglobin E (abnormal variant) 
HbF 
fetal hemoglobin 
HbS 
hemoglobin S (abnormal variant) 


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Abbreviation  
Definition 
HED 
human equivalent dose 
HIV 
human immunodeficiency virus  
hsCRP 
highly sensitive C-reactive protein 
IB 
Investigator’s Brochure 
IC50 
half-maximal inhibitory concentration 
IC90 
concentration at which inhibition is 90% 
ICAM-1 
intercellular adhesion molecule 1 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICT 
iron chelation therapy 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IWRS 
interactive web response system 
LDH 
lactate dehydrogenase 
MAD 
multiple ascending dose 
NCI CTCAE 
National Cancer Institute Common Terminology for Adverse 
Events 
NOAEL 
No observed adverse effect level 
NT-proBNP 
N-terminal pro B-type natriuretic peptide 
NTDT 
non-transfusion-dependent (β)-thalassemia 
NTDT-PRO 
Non-transfusion Dependent β-thalassemia Patient Reported 
Outcome 
OECD 
Organization for Economic Cooperation and Development 
PD 
pharmacodynamic(s) 
PDE 
phosphodiesterase 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
pRBC 
packed red blood cells  
Q1 
first quartile 
Q3 
third quartile 
qd 
once daily 
QoL 
quality of life 
QTcF 
corrected QT interval using Fridericia’s formula 


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Abbreviation  
Definition 
RBC 
red blood cell 
SAD 
single ascending dose 
SAE 
serious adverse event 
SCD 
sickle cell disease 
SD 
standard deviation 
SF-36 
Short Form (36) Health Survey 
SUSAR 
suspected unexpected serious adverse reaction 
t½  
half-life 
tmax 
time to maximum plasma concentration 
TDT 
transfusion-dependent (β)-thalassemia 
TEAE 
treatment-emergent adverse event 
TIBC 
total iron binding capacity 
TranQoL 
Transfusion-dependent Quality of Life Questionnaire 
ULN 
upper limit of normal 
VCAM-1 
vascular cell adhesion molecule 1 
 


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4. 
INTRODUCTION 
4.1. 
Overview of Disease Pathogenesis 
The sponsor is developing IMR-687 for the treatment of adult subjects with β-thalassemia and 
sickle cell disease (SCD). 
With an incidence of symptomatic individuals estimated at 1 in 100,000 worldwide 
(Galenello 2010), β-thalassemia is a rare inherited blood disorder characterized by the reduced or 
absent synthesis of the β chain of hemoglobin (Hb) and is caused by mutations in the 
hemoglobin beta (HBB) gene. The most common manifestations of β-thalassemia include 
reduced Hb in red blood cells (RBCs), decreased RBC production, and anemia (Galanello 2010). 
Clinically significant β-thalassemia is typically classified by the need for blood transfusions: 
non-transfusion-dependent β-thalassemia (NTDT) or transfusion-dependent β-thalassemia 
(TDT). 
4.2. 
Overview of IMR-687 Development 
4.2.1. 
IMR-687 
IMR-687 (6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-
yl-7H-imidazo[1,5-a]pyrazin-8-one) is a potent, specific, and highly selective small molecule 
inhibitor of phosphodiesterase (PDE) 9; PDE9 mediates cellular signaling pathways by 
degrading cyclic guanosine monophosphate (cGMP) to its inactive or monophosphate form. 
By inhibiting PDE9, IMR-687 is intended to increase cGMP levels and in doing so, stimulate the 
production of fetal hemoglobin (HbF), which reduces the cellular concentration of abnormal Hb 
(HbS) within RBCs and its associated sequelae. The importance of increasing HbF in treating 
SCD is evidenced by results from large studies like the Cooperative Study of Sickle Cell Disease 
in the US and studies in a variety of patient cohorts outside of the US showing that HbF is 
among the most important modifiers of this disease (Platt 1991; Platt 1994; Alsultan 2013), as 
well as data showing that modifiers of HbF improve other hematological parameters of SCD 
(Akinsheye 2011; Alsultan 2013; Barbosa 2013; Sheehan 2013). 
PDE9 is highly expressed in hematopoietic cells and is also widely distributed in the brain 
(Fisher 1998; Matsumoto 2003; Nagasaki 2012), with the highest expression measured in 
cerebellar Purkinje cells of rodents (van Staveren 2002). A potential advantage of IMR-687 for 
the β-thalassemia indication is that it does not readily distribute to the brain and, therefore, is less 
likely to result in the central nervous system (CNS) effects observed with other, 
brain-penetrating PDE9 inhibitors (Schwam 2014; Hutson 2011; Van der Staay 2008). 
Moreover, due to its specificity for PDE9, and the absence of evidence of genotoxicity and 
hepatotoxicity in Good Laboratory Practice (GLP) toxicology studies, IMR-687 could contribute 
to a meaningful improvement in the standard of care for patients. 
4.2.2. 
Nonclinical Data 
The IMR-687 nonclinical program for SCD supports its potential utility for the treatment of 
β-thalassemia. 


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In vitro studies have demonstrated IMR-687’s ability to increase cGMP in K562 cells and 
increase HbF in both K562 and CD36+ RBCs cultured ex vivo from blood-derived CD34+ cells 
from SCD patients, supporting IMR-687’s proposed mechanism of action. These findings were 
confirmed and extended by in vivo studies demonstrating IMR-687’s ability to increase HbF and 
reduce RBC sickling in both Berkeley and Townes sickle cell transgenic mouse models and to 
reduce the degree of microvascular stasis observed following hypoxia and re-oxygenation in 
Townes mice. Administration of 10 or 30 mg/kg IMR-687 to C57Bl/6J mice for 5 days 
demonstrated low CNS exposure, with no effect on locomotor activity or memory.  
In a series of GLP/OECD-compliant safety pharmacology studies evaluating behavioral, 
respiratory, and cardiovascular functions, no untoward adverse effects were noted. In addition, 
repeat-dose toxicology studies in rats (up to 6 months) and dogs (up to 9 months) were well 
tolerated and provided no observed adverse effect levels (NOAELs) that were comfortably in 
excess of those to be administered to humans. 
IMR-687 had low-moderate plasma protein binding in the 5 species tested (<32%), and there was 
no notable partitioning into red blood cells (RBCs). IMR-687 has the potential for induction of 
CYP3A4 (half-maximal effective concentration [EC50]= 32.4 to 133 µM). IMR-687 was not a 
competitive inhibitor of CYPs 1A2, 2B6, 3A4/5, 2C9, 2C19, 2C8, and 2D6. IMR-687 is a 
substrate of P-glycoprotein (P-gp) (Km >500 µM) and breast cancer resistance protein (BCRP) 
(Km = 45.5 µM). IMR-687 is an inhibitor of BCRP (half-maximal inhibitory concentration 
[IC50] = 32.5 µM), OCT1 (IC50 = 834 µM), and MATE2-K (IC50 = 441 µM). 
Fifteen metabolites have been detected to date. Metabolic pathways included dehydrogenation, 
hydration, and oxidation. Both renal and biliary excretion of 14C-IMR-687-related radioactivity 
(as unchanged IMR-687 and metabolites) were observed in the rat. Metabolites found in rat 
hepatocytes were consistent with those observed in vivo. Metabolites in human hepatocytes were 
not unique relative to those observed in rat and dog hepatocytes. CYP phenotyping experiments 
have indicated that IMR-687 is primarily a substrate for CYP3A4 (Km ≅ 127 µM). Metabolites 
M1 and M4 result from N-dealkylation of IMR-687 and may be major circulating metabolites. 
4.2.2.1. 
Nonclinical Data in β-Thalassemia 
Preliminary pharmacology studies of IMR-687 were conducted in a β-thalassemia intermedia 
animal model (Hbbth1/th1 mice). This mouse model does not have functional Hbβ, leading to 
deficits in Hb and RBCs and defective RBC maturation. IMR-687 administration led to a 
dose-dependent increase in total Hb (increase of 1.3 g/dL compared to placebo at the highest 
dose tested of 60 mg/kg). Total RBCs increased in a similar fashion and differences from 
placebo administration were statistically significant for both measures. IMR-687 also showed 
enablement of RBC maturation, a key mechanistic component in reducing disease pathology. 
High-dose IMR-687 (60 mg/kg) produced a statistically significant difference in immature RBCs 
(polychromatic erythroblasts) and greater prevalence of mature RBCs (orthochromatic and 
reticulocytes) compared to placebo administration. 
Administration for 30 days of 30 mg/kg/day or 60 mg/kg/day of IMR-687 improves markers of 
β-thalassemia disease progression by increasing RBCs and Hb and reducing reticulocytes. The 
degree of these changes was dose dependent. In addition, IMR-687 at 60 mg/kg/day improved 


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erythroblast differentiation, suggesting a role for this compound in the improvement of 
ineffective erythropoiesis of β-thalassemia. 
Additional information on the nonclinical effects of IMR-687 is provided in the Investigator’s 
Brochure. 
4.2.3. 
Clinical Data 
4.2.3.1. 
Phase 1a Study of IMR-687 in Healthy Adult Volunteers (IMR-SCD-101) 
A first-in-human, randomized, double-blind, placebo-controlled study to evaluate the safety, 
tolerability, and pharmacokinetics (PK) of IMR-687 (capsule formulation) has been completed 
(IMR-SCD-101). The study enrolled 66 healthy male and female adults (aged 18 to 55 years, 
inclusive), of whom 16 subjects received placebo and 50 subjects received IMR-687. The study 
was divided into 3 parts: a single-ascending-dose (SAD) study (Part A), a food effect study 
(Part B), and a multiple-ascending-dose (MAD) study (Part C); all parts had oral dosing. In Part 
A, 20 subjects received single doses of IMR-687 in the fasted state. The initial planned doses 
were 0.3, 1, 3, 6, 9, and 12 mg/kg; a 4.5 mg/kg dose was added and the 9 and 12 mg/kg doses 
were removed after a dose-limiting toxicity of moderate emesis was observed at 6 mg/kg. In 
Part B, 12 subjects received 2 single doses of IMR-687 at 1 mg/kg under fed and fasting 
conditions. In Part C, 18 subjects received 7 doses of either 1, 3, or 4.5 mg/kg/day.  
IMR-687 was safe and well-tolerated at doses up to 4.5 mg/kg when administered as single and 
multiple once daily (qd) doses (up to 7 days) of oral capsules to healthy volunteers in a weight-
based dosing regimen. The most frequent drug-related adverse event (AE) was nausea. In Part A 
(SAD study in the fasted state), 35% of all IMR-687 subjects experienced nausea, compared to 
0% of placebo subjects. Nausea was mild, transient, and self-limited at doses ≤4.5 mg/kg; the 
incidence of nausea was sporadic at single doses ≤3 mg/kg IMR-687. Headaches were also a 
notable, likely drug-related treatment-emergent adverse event (TEAE), particularly in the fasted 
state (30% of all IMR-687 subjects in the SAD Part A, compared to 0% in the placebo group). 
Oral administration of IMR-687 with food significantly reduced both the incidence and severity 
of the nausea and headache TEAEs. Whereas single doses of 4.5 mg/kg IMR-687 in fasted 
subjects resulted in mild nausea in 75% of subjects, single doses of 4.5 mg/kg IMR-687 did not 
result in nausea when given after a high-fat meal. Only after at least 6 daily doses did mild 
nausea occur with 4.5 mg/kg IMR-687 given with a meal. The incidence of headaches when 
IMR-687 was given with food was similar between IMR-687-treated (11.1%) and 
placebo-treated (16.7%) groups. 
Nausea onset was between 30 and 120 minutes after the oral administration of IMR-687, and 
generally lasted 2 to 8 hours. Timing of nausea onset preceded/overlapped with the IMR-687 
time to maximum concentration (tmax). Together with the mitigating effects of food intake and 
the fact that IMR-687 is a P-gp substrate and unlikely to be CNS penetrant, these data are 
consistent with nausea/emesis resulting from a local effect of IMR-687 in the stomach or the 
gastrointestinal (GI) tract. 
IMR-687 administration was not associated with any clinically significant changes in laboratory 
values, physical examinations, or standard 12-lead electrocardiograms (ECGs). Of note, 


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IMR-687 did not demonstrate any significant changes in white blood cell (WBC), platelet, or 
absolute neutrophil counts. 
Exposure parameters following single or multiple qd doses of IMR-687 increased with dose in a 
near dose proportional manner (e.g., a 4.1-fold increase for a 4.5-fold change in dose). 
Administration with food slowed the rate of absorption of IMR-687 (median tmax delayed by 
approximately 3 hours), which resulted in an approximately 26% decrease in maximum plasma 
concentration (Cmax), but no change in overall exposure (area under the concentration-time curve 
[AUC]). Multiple dose PK demonstrated that IMR-687 did not accumulate to a significant extent 
in healthy volunteers (<13%). In addition, steady state was achieved prior to dosing on Day 3. 
4.2.3.2. 
Phase 2a Study of IMR-687 in Adult Subjects with Sickle Cell Anemia 
(IMR-SCD-102) 
Study IMR-SCD-102 was a phase 2a, randomized, double-blind, placebo-controlled study in 
adult subjects with homozygous HbSS or sickle-β0-thalassemia that was completed in 2020.  
The objectives of this study were to evaluate the safety, tolerability, PK, and pharmacodynamic 
(PD) effects of IMR-687 (tablet formulation) administered for 16 to 24 weeks in 2 subject 
populations: those not on HU (Population A) and those receiving a stable dose of HU according 
to standard of care (Population B). Eligible subjects in non-HU Population A were initially 
randomized 1:1:1 to receive 50 mg IMR-687, 100 mg IMR-687, or placebo for a total of 
24 weeks. A planned interim analysis suggested that the 50 mg dose would not provide the 
exposure and efficacy needed to meet clinical outcomes, and the protocol was amended for 
subjects to receive 100 mg IMR-687 or placebo in a 2:1 randomization for 4 weeks and, if well 
tolerated, to escalate from 100 mg to 200 mg for the remaining 20 weeks of the study. Similarly, 
in stable HU Population B, subjects were randomized 2:1 to receive 50 mg IMR-687 or placebo; 
following the planned interim analysis, subjects received 50 mg IMR-687 or placebo for 4 weeks 
and, if well tolerated, escalated from 50 mg to 100 mg for the remaining 20 weeks of the study.  
A total of 93 subjects with SCD were enrolled, randomized, and received study drug (IMR-687 
or placebo) in Study IMR-SCD-102 (58 subjects in Populations A/A1 and 35 subjects in 
Populations B/B1; 63 subjects received IMR-687 and 30 subjects received placebo). In summary, 
qd dosing of IMR-687 was generally safe and well tolerated. Additional information on the study 
results is provided in the Investigator’s Brochure. 


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5. 
RATIONALE 
5.1. 
Study Rationale and IMR-687 Dose Rationale 
This is a phase 2 study intended to explore the potential use of IMR-687 to treat subjects with 
β-thalassemia. This is the first study of IMR-687 in a β-thalassemia population, and, as such, is 
designed to examine the safety, tolerability, and PK, as well as the potential PD effects, of 
IMR-687 administered qd for 36 weeks in adult subjects with β-thalassemia. The dose rationale 
is based on three important considerations as described below. 
Nonclinical Safety and Efficacy 
The NOAELs identified in repeat-dose toxicology studies were 100 mg/kg/day (600 mg/m2/day) 
in male and female rats, 50 mg/kg/day (1000 mg/m2) in male dogs, and 25 mg/kg/day 
(500 mg/m2/day) in female dogs, which correspond to human equivalent doses (HEDs) of 16.2 
and 13.5 mg/kg/day, respectively. These HEDs provide approximately 2-fold exposure margins 
based on body weight for the highest possible dose in the proposed clinical study (up to 
6.7 mg/kg). Therefore, the dose exposure in this study is supported by the nonclinical program 
and considered safe for adult subjects. Additionally, administration for 30 days of 30 mg/kg/day 
(HED of 2.4 mg/kg/day) or 60 mg/kg/day (HED of 4.9 mg/kg/day) of IMR-687 in a 
β-thalassemia intermedia animal model (Hbbth1/th1 mice) improves markers of β-thalassemia 
disease progression by increasing RBCs and Hb, and reducing reticulocytes. The degree of these 
changes was dose dependent, with significant improvement at the higher dose of 60 mg/kg. In 
addition, IMR-687 at 60 mg/kg improved erythroblast differentiation, suggesting a role for this 
compound in the improvement of ineffective erythropoiesis of β-thalassemia. Testing a broader 
dose range in this program is justified by the nonclinical efficacy data observed. 
Actual and Predicted Human Safety Margins of IMR-687 Doses 
Clinical safety and tolerability data are available from Study IMR-SCD-101 in healthy 
volunteers for IMR-687 administered at doses up to 6 mg/kg/day in a fasted single ascending 
dose (SAD) portion (Part A) and at doses up to 4.5 mg/kg/day for 7 days in a fed multiple 
ascending dose (MAD) portion (Part C), as well as from the phase 2a study in fed SCD subjects 
(IMR-SCD-102). Based on these data, an exposure range from 3 mg/kg to approximately 
6 mg/kg is expected to be tolerable, especially if taken with food because administration with 
food appears to reduce both the incidence and severity of GI-related TEAEs, such as nausea and 
upper GI pain.  
The onset of nausea in the healthy volunteer study was rapid (between 30 to 120 minutes), 
generally lasted 2 to 8 hours, and was mild nature at doses ≤4.5 mg/kg (lower dose). These 
potential AEs of nausea, upper GI pain, and emesis are easily monitorable and are self-limited if 
dosing is stopped. Furthermore, following qd dosing for 7 days in fed healthy volunteers, steady 
state was achieved before Day 7. Exposure (AUC) in healthy volunteers increased in a near dose-
proportional manner (a 4.1-fold increase for a 4.5-fold change in dose [see Section 4.2.3.1]), and 
the mean exposure (AUC from time 0 to 24 hours [AUC0-24]) at 4.5 mg/kg on Day 7 was 
26.3 µg•h/mL, which is approximately 3.3-fold below the Week 39 exposure (AUC0-24) in the 
female dog (most conservative species/gender) at the respective NOAEL in the repeat-dose 
toxicology study. Even for the higher dose arm of up to 6.7 mg/kg (assumed to be equivalent to 
approximately a 400 mg dose), the predicted Day 1 exposure is 32.0 µg•h/mL, which is 


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approximately 2.7-fold below the Week 39 exposure (AUC0-24) in the female dog (most 
conservative species/gender). PK plotting (e.g., concentration at 24 hours after study drug 
administration [C24]) predicted that higher exposure to IMR-687 should result in drug 
concentration levels above the estimated concentration at which inhibition is 90% (IC90) for 
approximately 22 hours at a 300-mg dose and more than 24 hours at a 400-mg dose. This 
possible IC90 advantage with respect to inhibition of the target, PDE9, further supports 
evaluating both the lower and higher doses of IMR-687 and specifically doses of up to 
6.7 mg/kg, which can provide adequate target coverage to potentially improve clinical benefit. 
Independent Data Monitoring Committee Oversight 
This study initially imposed a minimum weight threshold of 45 kg and a 67-kg weight gate for 
tablet strength to ensure that subjects in the lower dose IMR-687 group received a dose equating 
to no more than the 4.5 mg/kg evaluated in the MAD part of the healthy volunteer study. 
Subsequently, the Data Monitoring Committee (DMC) approved the opening of enrollment in 
the higher dose IMR-687 group (up to 6.7 mg/kg). Having established safety and tolerability of 
the lower dose, the DMC also approved a change in weight gate to 60 kg and the resultant 
modified dose range of up to 5.0 mg/kg in the lower dose group (with the minimum weight 
threshold of 45 kg unchanged). Starting from Protocol Version 5.0, subjects in the IMR-687 
lower dose group will receive ≥3.4 to ≤5.0 mg/kg and subjects in the higher dose group will 
receive >5.0 to ≤6.7 mg/kg; no subject will receive more than 6.7 mg/kg. Under Protocol 
Version 4.0, the exposure ranges were ≥3.0 to ≤4.5 mg/kg in the lower dose group and >4.5 to 
≤6.7 mg/kg in the higher dose group. Therefore, the overall exposure ranges during the course of 
the study are ≥3.0 to ≤5.0 mg/kg and >4.5 to ≤6.7 mg/kg and are presented as such hereafter. 
For this first study evaluating IMR-687 in subjects with β-thalassemia, the DMC has noted some 
of the related pathology that is shared with patients who have SCD. The shared manifestations 
include chronic anemia, fatigue, delayed growth, cerebral ischemia, splenomegaly, gallstones, 
pulmonary hypertension, and leg ulcers. In the phase 2a study in adult subjects with SCD 
(IMR-SCD-102), IMR-687 has been shown to be well tolerated, with initial evidence of PD 
effects. The DMC has reviewed interim results from this study and is supportive of the dose 
exposure and duration of treatment in this first β-thalassemia study. 
5.2. 
Benefit/Risk Assessment 
IMR-687 is currently being investigated for the treatment of SCD as its primary indication. It is 
anticipated that it will differ from established therapy (i.e., HU) in maintaining a similar or 
improved efficacy profile, while having a much-improved safety profile, without 
myelosuppression or a mutagenicity/carcinogenicity risk.  
Consequently, the frequent monitoring of blood counts required for patients who use HU would 
not be required for IMR-687. The proposed exposure in this study is between ≥3.0 to ≤5.0 mg/kg 
(lower dose) daily and, following DMC approval, >4.5 to ≤6.7 mg/kg (higher dose) daily; these 
exposures are anticipated to be in the pharmacologically active range based on available 
nonclinical and clinical data (see Section 5.1 for dose selection rationale). Based on the observed 
safety and tolerability of IMR-687 in the first-in-human study (Section 4.2.3.1) and subsequent 
study in SCD subjects, these dose levels should be tolerable and may have a clinically beneficial 
PD effect in subjects with β-thalassemia.  


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Based on the data from healthy volunteers and SCD subjects to date, IMR-687 is considered to 
be safe and well tolerated with the most common side effects being sickle cell anemia with crisis, 
abdominal pain, nausea, headache, indigestion, diarrhea/loose stools, and influenza-like illness 
which are mild and easily managed. Newly emerging safety data will be updated in the 
Investigator Brochure’s (IB) and Informed Consent Form (ICF). The potential benefits and risks 
are summarized below. 
5.2.1. 
Potential Benefits 
This is the first study of IMR-687 in β-thalassemia subjects; therefore, the primary objective of 
this study is to determine the safety and tolerability of qd oral doses of IMR-687 across several 
doses anticipated to be pharmacologically active. As in SCD, potential benefits of IMR-687 
include addressing the missing or decreased presence of the beta globin subunit by 
pharmacologic induction of HbF production. In addition to resolving persistent anemia, HbF 
induction rectifies the missing or mutated beta globin subunit and thereby reduces the 
overabundance of free-floating alpha globin subunits. These benefits have the potential to result 
in increased functional RBC production, higher Hb levels, reduced hemolysis and the reduction 
of adhesion and inflammation. Like in SCD, infants with β-thalassemia major do not present 
clinical symptoms of their disorder until age 6 to 24 months, and sometimes later, when their 
HbF is replaced by mutated adult Hb. Natural history data show that patients with β-thalassemia 
who have high HbF levels, due to hereditary persistence of HbF, have less severe forms of the 
disorder. In addition, genetic variations associated with increased HbF production have been 
shown to correlate with reduced β-thalassemia severity (Borgna-Pignatti 2010). 
5.2.2. 
Potential Risks 
The potential risks of IMR-687 are inferred from the relevant nonclinical findings and the results 
of the first-in-human study in healthy volunteers (IMR-SCD-101) and the interim analysis from 
the phase 2a study (IMR-SCD-102). These potential risks are briefly summarized in the sections 
below. Further details are provided in the Investigator’s Brochure. 
5.2.2.1. 
Gastrointestinal 
Based on the observed incidence of nausea in healthy volunteers in the first-in-human study, oral 
administration of IMR-687 may result in nausea within the first several hours of dosing. Nausea 
observed thus far was transient and self-limited. A dose-limiting toxicity of emesis occurred at 
6 mg/kg when IMR-687 was administered in the fasted state. Oral administration of study drug 
with food significantly reduced the incidence and severity of the nausea TEAE. No correlated 
changes in liver function tests were observed in any healthy volunteers administered IMR-687, 
or specifically in those subjects with nausea, with or without emesis. 
5.2.2.2. 
Central Nervous System 
Mild headaches (self-limited or treatable with acetaminophen) were observed in the 
first-in-human study in healthy normal volunteers and appeared to occur with nausea. Headaches 
were also observed in the phase 2a study and as of the interim analysis, 21.4% of subjects had 
reported a TEAE of headache. Oral administration of study drug with food significantly reduced 
the incidence and severity of the headache TEAE. 


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5.2.2.3. 
Cardiovascular 
In nonclinical safety pharmacology and 14-day GLP toxicology studies in beagle dogs, IMR-687 
appeared to result in increases in heart rate that did not appear to be dose dependent. In the safety 
pharmacology study in dogs, at doses of 75 mg/kg, statistically significant changes in heart rates 
were observed. In the 14-day toxicology study in dogs, the highest heart rates were noted at the 
highest dose level of 75 mg/kg but did not reach statistical significance. In a subsequent 9-month 
study in dogs at doses up to and including 50 mg/kg/day, there was no evidence of any increases 
in heart rate and there were no histopathological abnormalities noted in cardiac tissue. In healthy 
volunteers in the first-in-human study, at doses between 0.3 to 6 mg/kg, sporadic observations of 
sinus tachycardia (i.e., heart rates >100 bpm) occurred in various subjects, including a subject in 
the MAD on placebo. The contribution of concomitant AEs such as headache to the rise in heart 
rate could not be excluded. No dose dependency or dose-duration dependency was noted for 
these heart rate observations. No signs of prolongation of corrected QT interval, Fridericia’s 
formula (QTcF) were noted in any cohort of healthy volunteers at any dose of IMR-687. In the 
interim safety analysis of Study IMR-SCD-102, with respect to vital signs, there were no 
observable changes in systolic, diastolic blood pressure and pulse, and there were no changes in 
respiratory rate. In the IMR-SCD-102 clinical study, the mean interim steady state AUC0-24 was 
16,300 ng•hr/mL for the 200 mg (~2.9 mg/kg) IMR-687 dose level. In the 39-week dog 
toxicology study mentioned above, mean AUC0-24 was ≥87,500 ng•hr/mL at the NOAEL in 
female dogs, resulting in safety margins of at least ~5.3-fold for the 200 mg clinical dose.  
Monitoring of vital signs is recommended for subjects in IMR-687 studies. In the event of noted 
persistent and/or clinically significant tachycardia, other causes of tachycardia, particularly pain 
and dehydration, should also be considered. 
5.2.3. 
Potential Interactions 
In vitro studies indicate that IMR-687 is not expected to competitively inhibit the major human 
cytochrome P450 (CYP) enzymes, including CYPs 3A4, 2D6, 2C9, 2C19, 2C8, 1A2, and 2B6. 
IMR-687 does have the potential for induction of CYP3A4/5 (in vitro EC50 = 32.4 to 133 µM) 
and other drug metabolizing enzymes whose expression levels are also controlled by the 
pregnane X receptor (PXR). In addition, IMR-687 has been shown to primarily be a CYP3A4 
substrate (Km = 127 µM); IMR-687 may be at least partially cleared as unchanged drug. 
After oral administration, concentrations of IMR-687 at the target exposure of ≥3.0 to 
≤5.0 mg/kg for the lower dose or >4.5 to ≤6.7 mg/kg for the higher dose may reach sufficient 
exposure in the gastric mucosa and/or the liver (during absorption) to induce (upregulate) 
CYP3A4 and/or CYP3A5 protein expression in these organs. 
Induced expression levels of CYP3A4 and CYP3A5 may not return to baseline levels until after 
discontinuation of IMR-687 dosing, which is likely to require approximately 1 week of washout 
due to the CYP3A protein half-life. Consequently, if a subject in this study is started on a 
medication that is primarily metabolized (and cleared) by CYP3A4/5, the subject should be 
followed appropriately to determine if the exposure to the concomitant medication is maintained 
at levels sufficient for efficacy. For example, if a subject is started on oxycodone for pain 
management or ondansetron for nausea, symptom resolution should be followed to determine if 


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higher doses of either medication are required to reach target outcomes, as co-administration of 
IMR-687 may result in a reduction in the overall exposure to oxycodone or ondansetron. 
In addition, because IMR-687 is expected to be at least partially cleared by CYP3A4-mediated 
metabolism, a drug interaction could also result from co-administration of other concomitant 
medications, like oxycodone or ondansetron, that at least partially (or solely) rely on CYP3A4-
mediated metabolism for their in vivo clearance. The underlying mechanism for this would be in 
vivo competition for CYP3A4 metabolism in the gastric mucosa and/or the liver. In this case, 
exposure increases in IMR-687 and/or the CYP3A-dependent concomitant drug(s) may occur. 
CYP3A competition could also result in exposure changes for active circulating metabolites that 
contribute to the overall efficacy. Finally, co-administration of CYP3A selective inhibitors, such 
as ketoconazole, should be avoided as this may increase the exposure of IMR-687. 
It should be noted that there are examples of drugs that primarily rely on polymorphic CYPs 
(e.g., CYP2C19, CYP2D6) for their in vivo metabolism and/or clearance. In poor metabolizers, 
drug exposure may increase, and often other drug metabolizing enzymes then play an increased 
role in drug clearance. As a consequence, CYP3A4-mediated clearance may become more 
prominent in poor metabolizers. One example of this is cimetidine, which relies on CYP2C19 
and/or CYP3A4/5 for its in vivo clearance. Caution should also be employed in administering 
such drugs with IMR-687. 
CYP3A4/5-mediated drug-drug interactions (DDIs) are the largest group of clinically relevant 
metabolism-mediated interactions. In addition, CYP3A4/5-mediated drug interactions produce 
the largest magnitude changes in exposure for the victim drug. Moderate inhibitors can result in a 
2- to 5-fold increase in exposure, while strong inhibitors may produce a 5-fold increase or 
greater. Sensitive CYP3A substrates can have at least a 5-fold change (or up to an approximately 
240-fold change) in systemic exposure due to a CYP3A-mediated drug interaction. Moderate 
inducers can result in up to a 50% reduction in exposure, while strong inducers may cause 
exposure loss of up to 80% (or more). In the case of strong inducers, a 400% increase in 
clearance may occur. It should be noted that there are some drugs for which a formal clinical 
DDI assessment is not feasible because increased exposure may lead to SAEs such as death (e.g., 
fentanyl, paclitaxel). In instances such as these, it may be difficult to assess the potential for a 
CYP3A4-mediated DDI; however, these drugs generally have significant warnings on the front 
page of the corresponding package inserts. It is recommended that all warnings in the product 
package insert should be considered prior to concomitant use with IMR-687. 
As IMR-687 is also a substrate of P-gp (Km >500 µM) as well as a substrate of BCRP 
(Km = 44.5 µM) and an inhibitor of BCRP (IC50 = 32.5 µM), co-administration of substrates or 
inhibitors of P-gp and BCRP should also proceed with caution. It should be noted that sometimes 
CYP3A4/5 substrates are also P-gp substrates just as IMR-687 is a substrate for both.  
See the Appendix 3 references for a list of in vivo CYP3A-sensitive substrates, inhibitors of 
CYP3A probes, and inducers of CYP3A probes; a list of in vivo inhibitors of P-gp probes; and a 
list of in vivo inducers of CYP3A probes from published drug interactions. Currently there are 
no such listings for BCRP. 
Finally, an earlier nonclinical (rat) study suggested the potential for co-administration of 
IMR-687 to decrease the exposure of HU when IMR-687 was administered at a supratherapeutic 
dose (HED ~40 mg/kg/day) and HU was administered at a therapeutic dose (HED 


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~10 mg/kg/day). In the absence of knowing the exact mechanism for HU clearance in rats or 
humans, it was unclear whether or not this observation would have clinical implications. 
However, an interim IMR-SCD-102 analysis found that 100 mg IMR-687 dosed qd had no 
notable impact on HU exposure for daily HU doses ranging from 500 to 1500 mg. In addition, 
PK was comparable for IMR-687 when administered as monotherapy or in combination with 
HU, implying no notable impact of HU on IMR-687 exposure.  
The anti-platelet and anti-coagulant drugs with a high potential for a clinically relevant DDI 
include direct acting oral anti-coagulants (DOACs) apixaban, dabigatran, rivaroxaban, edoxaban, 
and ticagrelor, as well as the Vitamin K antagonist warfarin, based on published clinical drug 
interaction studies. This is due to their dependence on CYP3A4/5 and/or P-gp for in vivo 
clearance (e.g., the DOACs) or their limited therapeutic window (warfarin). Ticagrelor is a 
sensitive CYP3A substrate, i.e., there are published drug interactions with >7-fold changes in 
ticagrelor exposure when co-administered with strong CYP3A inhibitors or inducers.  
The anti-platelet and anti-coagulant drugs with an intermediate potential (40% to 50% change 
in exposure) for a clinically relevant drug-drug interaction include rivaroxaban, dabigatran 
etexilate, and apixaban. Caution should be applied in the co-administration of IMR-687 and 
these drugs to ensure that anti-platelet and anti-coagulant activities are not compromised. 
Caution may be required with co-administration of IMR-687 and clopidogrel. Co-administration 
of clopidogrel with danshen (herbal supplement; CYP3A induction possible) resulted in a 49% 
loss of clopidogrel exposure, and IMR-687 is a potential CYP3A inducer. 
The anti-platelet and anti-coagulant drugs with a low potential for a clinically relevant DDI 
include heparin, enoxaparin, fondaparinux, prasugrel, dipyridamole, ticlopidine, and eptfibatide. 
New DDIs are continually being discovered and published. Questions that are not fully addressed 
by the references in Appendix 3 should be directed to the medical monitor or may be addressed 
by review of the relevant package insert and prescribing information for the proposed 
concomitant medication. If there is any question as to whether a substance is permitted, please 
consult the medical monitor and/or sponsor. 
See also Section 9.7.2 on prohibited concomitant medications/therapies. 


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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Primary Objective 
The primary objective of this study in both Population 1 (TDT) and Population 2 (NTDT) is to 
assess the safety and tolerability of IMR-687 in adult subjects with β-thalassemia. 
6.2. 
Secondary Objectives 
6.2.1. 
Population 1: Transfusion-dependent β-Thalassemia 
The secondary objectives in TDT subjects are:  
• To evaluate the effect of IMR-687 versus placebo on reduction in RBC transfusion 
burden. 
• To evaluate the effect of IMR-687 versus placebo on the change in iron overload. 
• To characterize the PK profile of IMR-687 and collect data for population PK 
analysis. 
6.2.2. 
Population 2: Non-transfusion-dependent β-Thalassemia 
The secondary objectives in NTDT subjects are:  
• To evaluate the effect of IMR-687 versus placebo on anemia (as defined by total 
hemoglobin).  
• To evaluate the effect of IMR-687 versus placebo on HbF.  
• To evaluate the effect of IMR-687 versus placebo on the change in iron overload. 
• To characterize the PK profile of IMR-687 and collect data for population PK 
analysis. 
6.3. 
Exploratory Objectives 
6.3.1. 
Population 1: Transfusion Dependent β-Thalassemia 
The exploratory objectives in TDT subjects are:  
• To characterize the PD profile of IMR-687 versus placebo with respect to 
erythropoiesis, iron metabolism, and hemolysis. 
• To evaluate the effect of IMR-687 versus placebo on the proportion of subjects who 
are transfusion independent. 
• To evaluate the effect of IMR-687 versus placebo on time to and duration of 
reduction in RBC transfusion burden.  
• To evaluate the effect of IMR-687 versus placebo on functional and health-related 
QoL. 
• To evaluate responses to IMR-687 per genotypes in subjects with TDT. 


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6.3.2. 
Population 2: Non-transfusion Dependent β-Thalassemia 
The exploratory objectives in NTDT subjects are:  
• To characterize the PD profile of IMR-687 versus placebo with respect to 
erythropoiesis, iron metabolism, and hemolysis. 
• To evaluate the effect of IMR-687 versus placebo on functional and health-related 
QoL. 
• To evaluate the effect of IMR-687 versus placebo on β-thalassemia-related symptoms 
and severity. 
• To evaluate responses to IMR-687 per genotypes in subjects with of NTDT. 
6.4. 
Endpoints 
The objectives will be assessed by the endpoints described in Table 1 in the indicated 
populations. 
Table 1: 
Study Endpoints 
Primary Endpoint 
TDT 
NTDT 
IMR-687 safety and tolerability as measured by: 
• 
Incidence and severity of adverse events and serious adverse 
events 
• 
Observed values and changes from baseline in 12-lead ECG 
parameters, clinical laboratory tests (chemistry, hematology, 
coagulation, urinalysis), and vital signs for any timepoint 
• 
Physical examination findings 
• 
Use of concomitant medications and therapies 
X 
X 
Secondary Endpoints 
TDT 
NTDT 
Proportion of subjects with a ≥20% hematological improvement (as 
measured by reduced transfusion burden)a from Week 12 to Week 24 and 
Week 24 to Week 36, compared to the 12 weeks prior to Baseline (Day 1). 
X 
 
Proportion of subjects with a ≥20% hematological improvement (as 
measured by reduced transfusion burden)a from Week 12 to Week 36, 
compared to the 12 weeks prior to Baseline (Day 1). 
X 
 
Proportion of subjects with a ≥33% hematological improvement (as 
measured by reduced transfusion burden)a from Week 12 to Week 24 and 
Week 24 to Week 36, compared to the 12 weeks prior to Baseline (Day 1). 
X 
 
Proportion of subjects with a ≥33% hematological improvement (as 
measured by reduced transfusion burden)a from Week 12 to Week 36, 
compared to the 12 weeks prior to Baseline (Day 1). 
X 
 
Mean number of transfusion events from baseline to Week 36. 
X 
 


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Secondary Endpoints (continued) 
TDT 
NTDT 
The plasma PK profile of IMR-687 (and metabolites) after administration 
to subjects will be evaluated by determination of PK parameters (e.g., Cmax, 
tmax, t½, and AUC0-24) and population PK, based on drug concentration 
levels in plasma obtained over time. 
X 
X 
Mean change from baseline to Week 36 for iron chelation therapy daily 
dose and serum ferritin. 
X 
X 
Proportion of subjects with an increase from baseline of ≥1.0 g/dL in mean 
Hb values at Weeks 12 to 24 and Weeks 24 to 36 in the absence of 
transfusions. 
 
X 
Mean change from baseline in mean Hb values at Weeks 12 to 24 and 
Weeks 24 to 36 in the absence of transfusions. 
 
X 
Mean change from baseline in mean HbF values at Weeks 12 to 24 and 
Weeks 24 to 36 in the absence of transfusions. 
 
X 
Proportion of subjects with an increase from baseline of ≥3% in mean HbF 
values at Weeks 12 to 24 and Weeks 24 to 36 in the absence of 
transfusions. 
 
X 
Exploratory Endpoints 
TDT 
NTDT 
The PD effects of IMR-687 from baseline to Week 36, as measured by the 
mean change from baseline in serum PD markers of erythropoiesis, iron 
metabolism, and hemolysis. 
X 
X 
Mean change in transfusion burden expressed as either units of RBCs or 
mL/kg as a continuous variable during Week 12 to Week 24, Week 24 to 
Week 36, and Week 12 to Week 36, compared to the 12 weeks prior to 
Baseline (Day 1).  
X 
 
The proportion of subjects who are transfusion independent for ≥8 weeks 
during treatment. 
X 
 
Mean change from baseline in TranQOL quality of life tool at Weeks 12, 
24, and 36. 
X 
 
Mean change from baseline in SF-36 quality of life tool at Weeks 12, 24, 
and 36. 
X 
X 
Pharmacogenomic analyses of genes that may affect treatment response 
(including α-globin, gamma-globin XmnI polymorphism, and BLC11A). 
X 
X 
Proportion of subjects who have an Hb increase of ≥1.0 g/dL from baseline 
for ≥14 days in the absence of RBC transfusions. 
 
X 
Proportion of subjects who are RBC transfusion-free over 36 weeks and 
other variables of transfusion burden. 
 
X 
Duration of the mean Hb increase from baseline of ≥1.0 g/dL over 
36 weeks. 
 
X 


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Exploratory Endpoints (continued) 
TDT 
NTDT 
Proportion of subjects who have an increase from baseline ≥1.5 g/dL in 
mean of Hb values at Week 24 and Week 36 compared to baseline in the 
absence of transfusions. 
 
X 
Mean change from baseline in NTDT-PRO score over a continuous 
12-week interval from Week 12 to Week 24 and Week 24 to Week 36. 
 
X 
Mean change from baseline in NTDT-PRO domain total score at Week 24. 
 
X 
Mean change in biomarkers from baseline to Week 36, stratified by 
genotype. 
X 
X 
AUC = area under the concentration-time curve; AUC0-24 = AUC from time 0 to 24; Cmax = maximum plasma 
concentration; ECG = electrocardiogram; Hb = hemoglobin; HbF = fetal hemoglobin; LDH = lactate 
dehydrogenase; NTDT = non-transfusion dependent β-thalassemia; NTDT-PRO = non-transfusion dependent 
β-thalassemia patient reported outcome; PD = pharmacodynamics; PK = pharmacokinetics; pRBC = packed red 
blood cells; PRO = patient-reported outcome; RBC = red blood cell; SF-36 = Short Form (36) Health Survey; 
t½ = half-life; tmax = time to maximum plasma concentration; TDT = transfusion dependent β-thalassemia; 
TranQOL = transfusion-dependent quality of life. 
a Hematological improvement is defined as a reduction in pRBC units (transfusion burden) with reduction of at least 
2 units of RBCs, compared to the 12 weeks prior to Baseline (Day 1).  


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a phase 2 randomized, double-blind, placebo-controlled study to evaluate the safety, 
tolerability, PK, and PD of IMR-687 (PDE9 inhibitor) administered qd for 36 weeks in 
2 populations of adult subjects with β-thalassemia: Population 1 (TDT subjects) and Population 2 
(NTDT subjects). A schematic of the study is provided in Figure 1. 
This study will enroll approximately 120 subjects with β-thalassemia (60 subjects with TDT and 
60 subjects with NTDT), aged 18 through 65 years. This study consists of a retrospective data 
collection period, a screening period, a double-blind treatment period, and safety follow-up 
period. During the screening period of up to 28 days, subjects will provide informed consent and 
be evaluated on eligibility criteria as stated in Section 8.1 and Section 8.2.  
Subjects will receive either IMR-687 (lower dose [≥3.0 to ≤5.0 mg/kg] or higher dose [>4.5 to 
≤6.7 mg/kg]; the precise exposure ranges for different groups of subjects are dependent on the 
weight gate for tablet strength as summarized in Section 5.1) or placebo in a blinded fashion. 
Subjects will be randomly assigned in a 2:1 ratio to receive either IMR-687 lower dose or 
placebo. Prior to the introduction of IMR-687 higher dose, the DMC will review safety data for 
at least 5 subjects who received IMR-687. If the DMC recommends inclusion of the higher dose, 
randomization will then proceed in a 1:2:1 ratio (IMR-687 lower dose, IMR-687 higher dose, or 
placebo). The DMC may request additional data and/or meeting(s) in order to make the 
recommendation on whether to move forward with inclusion of the higher dose. During study 
conduct under Protocol Version 4.0, the DMC approved the opening of enrollment in the higher 
dose IMR-687 group, which went into effect on 01 February 2021. 
Subjects will return to the investigational site at Week 1 for a safety assessment, and qualified 
site personnel will contact the subject by telephone at Week 2 to capture potential AEs and 
concomitant medications. Subjects will be seen at the investigational site approximately every 
3 weeks (TDT subjects) or every 4 weeks (NTDT subjects) throughout the remainder of the 
study. Safety will be monitored throughout the study, and PK, PD, QoL, and clinical outcome 
measures will be performed at the visits shown in the schedule of assessments for the TDT and 
NTDT populations (Table 2 and Table 3, respectively). 
The informed consent will specifically indicate that data will be retrospectively collected on 
transfusion burden, defined as the dates of transfusion events and the number of packed red 
blood cell (pRBC) units per event during the 12 weeks preceding the Baseline (Day 1) visit. If 
available, the following data should also be collected for each transfusion event: volume and 
hematocrit of each pRBC unit, pre-transfusion Hb, and pre-transfusion weight. 


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Figure 1:  Overview of Study Design and Dose Groups 
 
DMC = data monitoring committee 
* Prior to the introduction of IMR-687 higher dose, the DMC will review safety data for at least 5 subjects who received IMR-687 lower dose. If the DMC recommends inclusion 
of the higher dose, randomization across 3 dose groups will then proceed as shown. The DMC may request additional data and/or meeting(s) in order to make its recommendations. 
During study conduct under Protocol Version 4.0, the DMC approved the opening of enrollment in the higher dose IMR-687 group, which went into effect on 01 February 2021. 
Refer to Section 5.1 for additional details on the dose groups. 
 


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Table 2: 
Schedule of Assessments: Population 1 (TDT β-Thalassemia) 
 
Screening 
Baseline 
Double-blind, Placebo-controlled Treatment 
EOTa / ET 
End of Study 
(Safety FU) 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Study Week(s) 
-4 to 0 
NA 
1 
2 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
40 
Study Day(s) 
-28 
to -1 
1b 
7 
±2 
14 
±2 
21 
±7 
42 
±7 
63 
±7 
84 
±7 
105 
±7 
126 
±7 
147 
±7 
168 
±7 
189 
±7 
210 
±7 
231±7 
252±7 
280±7 
On-site visits 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Telephone visitsc 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PGx ICF and blood 
draw (optional)d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic 
information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/disease 
historye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG score 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinically indicated 
virology (Hep A, B, 
and C and HIV) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Historical transfusion 
burdenf 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsg 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Table 2: 
Schedule of Assessments: Population 1 (TDT β-Thalassemia) (Continued) 
 
Screening 
Baseline 
Double-blind, Placebo-controlled Treatment 
EOTa / ET 
End of Study 
(Safety FU) 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Study Week(s) 
-4 to 0 
NA 
1 
2 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
40 
Study Day(s) 
-28 
to -1 
1b 
7 
±2 
14 
±2 
21 
±7 
42 
±7 
63 
±7 
84 
±7 
105 
±7 
126 
±7 
147 
±7 
168 
±7 
189 
±7 
210 
±7 
231±7 
252±7 
280±7 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Transfusion burdenh 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examinationi 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECGj 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Hematology and 
Chemistry  
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Coagulation studies 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Urinalysis 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Pregnancy testingk 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Specialty hematologyl 
X 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
PD markersm 
X 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
IMR-687 plasma PKn 
 
X 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
QOL assessmentso 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Study drug dispensing 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Study drug admin at 
sitep 
 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Study drug admin 
 
Oral administration of IMR-687 or placebo qd 
 
AEs and concomitant 
medications 
Continuousq 
AE = adverse event; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; ET= early termination; EOT = end of treatment; FU = follow-up; 
Hb = hemoglobin; HbF = fetal hemoglobin; HIV = human immunodeficiency virus; hsCRP = highly sensitive C-reactive protein; ICAM-1 = intercellular adhesion molecule 1; 


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ICF = informed consent form; NT-proBNP = N-terminal pro B-type natriuretic peptide; PD = pharmacodynamics; PE = physical examination; PGx = pharmacogenomics; 
PK = pharmacokinetic; pRBC = packed red blood cells; QOL = quality of life; SD = standard deviation; SF-36 = Short Form (36) Health Survey; TEAE = treatment-emergent 
adverse event, TIBC = total iron binding capacity; TranQOL = Transfusion-dependent QoL Questionnaire; VCAM-1 = vascular cell adhesion molecule 1. 
Note: Unless otherwise specified, all assessments should be completed prior to dosing at any given timepoint. 
Note: Unscheduled visits may occur, limited to visits resulting from potential TEAEs, drug dispensation, or other urgent study-related procedures 
a The last day of dosing will be at Week 36 visit; subject should consume their last dose of study drug on site, after pre-dose assessments have been completed. The Week 36 visit 
will also be the ET visit. During the study visit, assessments should be collected from any subject who discontinues study drug or study prematurely. Early termination visits will 
have the same procedures as the Week 36 visit, except that study drug will not be administered and trough PK will not be collected. 
b  The first day study drug is taken is considered Baseline (Day 1). Day 1 assessments should be performed prior to study drug administration. If a subject requires a transfusion on 
this day, the transfusion may occur only after all study assessments are completed.  
c  Qualified site personnel will contact the subject by telephone at Week 2 to capture potential TEAEs and concomitant medications. Subjects will also be reminded of compliance 
with drug and the next visit schedule. If any AEs of significant clinical concern are identified during the telephonic visit, the subject will be requested to come into the site to be 
assessed.  
d Pharmacogenomic evaluation is optional and may be performed at screening if subject provides informed consent.  
e Disease history should contain a confirmed diagnosis of β-thalassemia or hemoglobin E/β-thalassemia. Concomitant alpha gene deletion, duplication, or triplication is allowed. 
f After obtaining signed informed consent, the subject’s transfusion history for the 12 weeks prior to Baseline (Day 1) visit date should be recorded. In order to be eligible for the 
study, the dates of transfusion events and the number of pRBC units per event within the 12 weeks prior to the Baseline (Day 1) visit must be available. If available, the 
following data should also be collected for each transfusion event: volume and hematocrit of each pRBC unit, pre-transfusion Hb, and pre-transfusion weight. 
g Vital signs include heart rate, respiratory rate, blood pressure, and body temperature. At Day 1 and Week 3, vital signs will be taken pre-dose and 2 hours (± 20 minutes) 
post-dose, during the PK assessments. At all other timepoints, vital signs can be taken irrespective of taking study drug. Vital signs should be consistently measured in either the 
sitting or semi-supine position. 
h Transfusion burden will be assessed using the following variables: dates of transfusion events, number of pRBC units per event, volume and hematocrit of each pRBC unit, 
pre-transfusion Hb, and pre-transfusion weight. 
i Complete PEs will be performed at Screening, Week 24, and Week 36 and will include a general examination of the body including the abdomen, heart, lungs, lymph nodes, 
back/neck, neurological system, skin, extremities, head, eyes, nose, and throat. At all other visits, symptom-directed PEs will be obtained after identification of AEs deemed by 
the investigator to be of significant clinical concern. 
j All ECGs to be performed in triplicate. At Baseline and Week 3, ECGs will be obtained at pre-dose and 2 hours (±30 minutes) post-dose. At all other timepoints, ECGs will be 
taken pre-dose. 
k Females of childbearing potential only. A serum pregnancy test will be performed at screening via a central laboratory; all subsequent tests will be urine performed locally (with 
test kits provided by the central laboratory). 
l Includes HbF and percent F cells. Blood samples should be obtained prior to administration of study drug. 
m Includes serum ferritin, soluble transferrin receptor, hepcidin-25, haptoglobin, E-selectin, P-selectin, ICAM-1, VCAM-1, hsCRP, serum NT-proBNP, serum iron and TIBC for 
calculated transferrin saturation, and erythropoietin. Blood samples should be obtained prior to administration of study drug. PD markers will need to be collected prior to RBC 
transfusion (if applicable). 
n At Baseline and Week 3, serial blood samples for IMR-687 and concentrations of metabolite(s) will be drawn pre-dose (within 30 minutes) and at 15 minutes (±5 minutes), 
30 minutes (±5 minutes), and 3 hours (±20 minutes) after administration of study drug. A trough blood sample will be drawn pre-dose at Week 1, Week 24, and Week 36. The 
date/time of the previous dose will be recorded. If a subject requires a transfusion on the day of a PK draw, the transfusion can only be performed after the final PK sampling. 
For ET visits, a trough blood sample will not be collected. 
o  Quality of life assessments will be assessed by the TranQOL and SF-36 QoL tools. The QoL assessments will be administered at Baseline and at Weeks 12, 24, and 36. Baseline 
QoL assessments should be completed before administration of study drug. 
p On days when study drug is taken in the clinic, food details will also be recorded. 
q Adverse events and concomitant medications, including iron chelation therapy and hydroxyurea use, will be recorded at each visit throughout the study from Screening (after 
signing the ICF) through the end of study visit (Week 40). 


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Table 3: 
Schedule of Assessments: Population 2 (NTDT β-Thalassemia) 
 
Screenin
g 
Baseline 
Double-blind, Placebo-controlled Treatment 
EOTa / 
ET 
End of Study 
(Safety FU) 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Study Week(s) 
-4 to 0 
NA 
1 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
Study Day(s) 
-28 to -1 
1b 
7±2 
14±2 
28±5 
56±
7 
84±7 
112±7 
140±7 
168±7 
196±7 
224±7 
252±7 
280±7 
On-site visits 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Telephone visitsc 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PGx ICF and blood 
draw (optional)d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic 
information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/disease 
historye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG score 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinically indicated 
virology (Hep A, B, 
and C and HIV) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Historical transfusion 
burdenf 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsg 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Transfusion burdenh 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Table 3: 
Schedule of Assessments: Population 2 (NTDT β-Thalassemia) (Continued) 
 
Screenin
g 
Baseline 
Double-blind, Placebo-controlled Treatment 
EOTa / 
ET 
End of Study 
(Safety FU) 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Study Week(s) 
-4 to 0 
NA 
1 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
Study Day(s) 
-28 to -1 
1b 
7±2 
14±2 
28±5 
56±
7 
84±7 
112±7 
140±7 
168±7 
196±7 
224±7 
252±7 
280±7 
Physical examinationi 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECGj 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology and 
chemistry  
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation studies 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
Urinalysis 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
Pregnancy testingk 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Specialty hematologyl 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
PD markersm 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
IMR-687 plasma PKn 
 
X 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
QOL assessmentso 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
Study drug admin at 
sitep 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study drug dispensing 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Study drug admin 
 
Oral administration of IMR-687 or placebo qd 
 
AEs and concomitant 
medications 
Continuousq 
AEs = adverse events; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; ET= early termination; EOT = end of treatment; FU = follow-up; 
Hb = hemoglobin; HIV = human immunodeficiency virus; hsCRP = highly sensitive C-reactive protein; ICAM-1 = intercellular adhesion molecule 1; ICF = informed consent 
form; NTDT-PRO = non-transfusion dependent β-thalassemia patient reported outcome; NT-proBNP = N-terminal pro B-type natriuretic peptide; PD = pharmacodynamics; 
PE = physical examination; PGx = pharmacogenomics; PK = pharmacokinetic; pRBC = packed red blood cells; QOL = quality of life; RBC = red blood cell; SD = standard 


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deviation; SF-36 = Short Form (36) Health Survey; TEAE = treatment-emergent adverse event; TIBC = total iron binding capacity; VCAM-1 = vascular cell adhesion molecule 
1. 
Note: Unless otherwise specified, all assessments should be completed prior to dosing at any given timepoint. 
Note: In the case of a subject receiving a transfusion after signing the ICF, but prior to randomization, the investigator would inform the medical monitor. The intent is to avoid 
transfusions within the 2-week period leading to randomization. Approval could be obtained for the screening period to be extended by a maximum of 14 days.  
Note: Unscheduled visits may occur, limited to visits resulting from potential TEAEs, drug dispensation, or other urgent study-related procedures. 
a The last day of dosing will be at Week 36 visit; subject should consume their last dose of study drug on site, after pre-dose assessments have been completed. The Week 36 visit 
will also be the ET visit. During the study visit, assessments should be collected from any subject who discontinues study drug or study prematurely. Early termination visits will 
have the same procedures as the Week 36 visit, except that study drug will not be administered and trough PK will not be collected. 
b The first day study drug is taken is considered Baseline (Day 1). Day 1 assessments should be performed prior to study drug administration. If a subject requires a transfusion on 
this day, the transfusion may occur only after all study assessments are completed.  
c Qualified site personnel will contact the subject by telephone at Week 2 to capture potential TEAEs and concomitant medications. Subjects will also be reminded of compliance 
with drug and the next visit schedule. If any AEs of significant clinical concern are identified during the telephonic visit, the subject will be requested to come into the site to be 
assessed. 
d Pharmacogenomic evaluation is optional and may be performed at screening if subject provides informed consent.  
e Disease history should contain a confirmed diagnosis of β-thalassemia or hemoglobin E/β-thalassemia. Concomitant alpha gene deletion, duplication, or triplication is allowed. 
f After obtaining signed informed consent, the subject’s transfusion history for the 12 weeks prior to Baseline (Day 1) visit date should be recorded. In order to be eligible for the 
study, the dates of transfusion events and the number of pRBC units per event within the 12 weeks prior to the Baseline (Day 1) visit must be available. If available, the 
following data should also be collected for each transfusion event: volume and hematocrit of each pRBC unit, pre-transfusion Hb, and pre-transfusion weight. 
g Vital signs include heart rate, respiratory rate, blood pressure, and body temperature. At Day 1 and Week 4, vital signs will be taken pre-dose and 2 hours (± 20 minutes) 
post-dose, during the PK assessments. At all other timepoints, vital signs can be taken irrespective of taking study drug. Vital signs should be consistently measured in either the 
sitting or semi-supine position. 
h Transfusion burden will be assessed using the following variables: dates of transfusion events, number of pRBC units per event, volume and hematocrit of each pRBC unit, 
pre-transfusion Hb, and pre-transfusion weight. 
i Complete PEs will be performed at Screening, Week 24, and Week 36 and will include a general examination including the abdomen, heart, lungs, lymph nodes, back/neck, 
neurological system, skin, extremities, head, eyes, nose, and throat. At all other visits, symptom-directed PEs will be obtained after identification of AEs deemed by the 
investigator to be of significant clinical concern. 
j All ECGs to be performed in triplicate. At Baseline and Week 4, ECGs will be obtained at pre-dose and 2 hours (±30 minutes) post-dose. At all other timepoints, ECGs will be 
taken pre-dose. 
k Females of childbearing potential only. A serum pregnancy test will be performed at screening via central laboratory; all subsequent tests will be urine performed locally (with 
test kits provided by the central laboratory). 
l Includes HbF and percent F cells. Blood samples should be obtained prior to administration of study drug. 
m Includes serum ferritin, soluble transferrin receptor, hepcidin-25, haptoglobin, E-selectin, P-selectin, ICAM-1, VCAM-1, hsCRP, serum NT-proBNP, serum iron and TIBC for 
calculated transferrin saturation, and erythropoietin. Blood samples should be obtained prior to administration of study drug. PD markers will need to be collected prior to RBC 
transfusion (if applicable). 
n At Baseline and Week 4, serial blood samples for IMR-687 and concentrations of metabolite(s) will be drawn pre-dose (within 30 minutes) and at 15 minutes (±5 minutes), 
30 minutes (±5 minutes), and 3 hours (±20 minutes) after administration of study drug. A trough blood sample will be drawn pre-dose at Week 1, Week 24, and Week 36. The 
date/time of the previous dose will be recorded. If a subject requires a transfusion on the day of a PK draw, the transfusion can only be performed after the final PK sampling. 
For ET visits, a trough blood sample will not be collected. 
o Quality of life assessments will be performed by the NTDT-PRO and SF-36 QoL tools. The QoL assessments will be administered at Baseline and at Weeks 12, 24, and 36. 
Baseline QoL assessments should be completed before administration of study drug. 
p On days when study drug is taken in the clinic, food details will also be recorded. 
q Adverse events and concomitant medications, including iron chelation therapy and hydroxyurea use, will be recorded at each visit throughout the study from Screening (after 
signing the ICF) through the end of study visit (Week 40). 


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7.2. 
Data Monitoring Committee 
The specific activities of the DMC will be governed by a charter which will define the DMC’s 
membership, meeting frequency, procedures/conduct, and requirements for reporting its 
observations to the sponsor. 
To ensure safety oversight throughout the trial, the DMC will review safety and preliminary 
efficacy data and provide recommendations to the sponsor as described below. 
The DMC will convene at the following times and for the following activities during the trial: 
• Review safety data for at least 5 subjects who received IMR-687 at the lower dose 
and make recommendation as to the inclusion of the higher dose. 
• Review safety data to confirm acceptable safety and tolerability of the higher dose of 
IMR-687. Make recommendation as to whether the dose level(s) could be modified; 
the proposed modification would occur only after a substantial protocol amendment 
was submitted to and approved by any applicable regulatory authorities. 
• At any time during the trial – upon request by the sponsor, medical monitor, or 
DMC– should a concern arise from emerging safety data for which DMC review and 
assessment is desired. This includes the emergence of a frequency or pattern of AEs 
or SAEs that suggest an unexpected or otherwise concerning safety signal. 
The DMC may review the following subject data, depending on the scope of the meeting, and 
may recommend to continue the study as planned, modify the study, or terminate the study for 
safety or lack of efficacy concerns: 
• Unblinded safety, preliminary efficacy, and PK data, which may include TEAEs, 
SAEs, PK data, clinical laboratory test results, vital signs, and other relevant data for 
all subjects randomized. 
• Additionally, the DMC chairperson will receive copies of all SAE reports for ongoing 
review during the trial. The DMC chairperson may forward the SAE reports to the 
full DMC if he/she feels that their immediate input on, or awareness of the SAE 
would be helpful. 
All assessments and decisions by the DMC will be documented in writing as noted in the DMC 
charter and prior to any resultant changes to the study unless their immediate implementation is 
considered necessary for subject safety. The composition of the DMC will be detailed in the 
DMC charter. 


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8. 
SELECTION OF STUDY POPULATION 
Up to approximately 60 subjects in Population 1 (TDT) and 60 subjects in Population 2 (NTDT) 
are expected to enroll, for a total of approximately 120 enrolled subjects. 
8.1. 
Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for the study: 
1. Subjects must understand and voluntarily provide informed consent and sign an ICF prior 
to any study-related assessments/procedures being conducted. Although RBC 
transfusions and associated Hb laboratory measurements prior to Screening are not study 
related, the ICF will specifically request subject consent to collect these data. 
2. Subjects must be ≥18 to ≤65 years of age at the time of signing the ICF. 
3. Subjects must have documented diagnosis of β-thalassemia or HbE/β-thalassemia in their 
medical history. Concomitant alpha gene deletion, duplication, or triplication is allowed. 
4. For TDT subjects only: Subjects must be regularly transfused, defined as >3 to 10 pRBC 
units† in the 12 weeks prior to the Baseline (Day 1) visit and no transfusion-free period 
for >35 days during that period. 
For NTDT subjects only: Subjects must be transfusion independent, defined as 0 to 
≤3 units† of pRBCs received during the 12-week period prior to the Baseline (Day 1) 
visit, must not be on a regular transfusion program, must be RBC transfusion-free for at 
least ≥ 4 weeks prior to randomization, and must not be scheduled to start a regular 
hematopoietic stem cell transplantation within 9 months.  
5. Subjects must have documentation of the dates of transfusion events and the number of 
pRBC units per event within the 12 weeks prior to the Baseline (Day 1) visit. 
6. Subjects must be willing and able to complete all study assessments and procedures, and 
to communicate effectively with the investigator and site staff. 
7. Subjects must have Eastern Cooperative Oncology Group (ECOG) performance score of 
0 to 1 (Appendix 1). 
8. Female subjects must not be pregnant or breastfeeding and be highly unlikely to become 
pregnant. Male subjects must be unlikely to impregnate a partner. Male or female 
subjects must meet at least one of the following criteria: 
• A female subject who is not of reproductive potential is eligible without requiring the 
use of contraception. A female subject who is not of reproductive potential is defined 
                                                 
 
† One unit in this protocol refers to one bag of packed RBCs. The dates of transfusion events and the number of 
pRBC units per event during the 12 weeks preceding the Baseline (Day 1) visit will be collected. If available, the 
following data should also be collected for each transfusion event: volume and hematocrit of each pRBC unit, 
pre-transfusion Hb, and pre-transfusion weight. Transfusion burden as expressed in mL/kg transfused RBC may be 
calculated. 
 


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as one who: (1) has reached natural menopause (defined as 12 months of spontaneous 
amenorrhea without an alternative medical cause, and can be confirmed with serum 
follicle-stimulating hormone levels in the postmenopausal range as determined by the 
central laboratory); (2) is 6 weeks post-surgical bilateral oophorectomy with or 
without hysterectomy; or (3) has undergone bilateral tubal ligation. Spontaneous 
amenorrhea does not include cases for which there is an underlying disease that 
causes amenorrhea (e.g., anorexia nervosa). 
• A female of reproductive potential must have 2 negative pregnancy tests as verified 
by the investigator prior to starting study therapy. She must agree to ongoing 
pregnancy testing during the course of the study, at the end of treatment visit, and at 
the end of study visit. This applies even if the subject practices true abstinence from 
heterosexual contact. 
• A male subject who is not of reproductive potential is eligible without requiring the 
use of contraception. A male subject who is not of reproductive potential is defined as 
one who has undergone a successful vasectomy. A successful vasectomy is defined as 
(1) microscopic documentation of azoospermia, or (2) a vasectomy more than 2 years 
ago with no resultant pregnancy despite sexual activity post-vasectomy. 
• A male or female subject who is of reproductive potential agrees to remain truly 
abstinent or use (or have their partner use) acceptable methods of highly effective 
contraception starting from the time of consent through 3 months after the completion 
of study therapy. True abstinence is defined as abstinence that is in line with the 
preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the 
duration of the study, and withdrawal are not acceptable methods of contraception. 
Acceptable methods of highly effective birth control are combined or 
progesterone-only hormonal contraception that is associated with inhibition of 
ovulation, intrauterine device, and intrauterine hormone-releasing system.  
9. Subjects receiving hydroxyurea must have received it continuously for at least 6 months 
prior to signing the ICF, and must have been on a stable dose for at least 3 months prior 
to signing the ICF, with no anticipated need for dose adjustments during the study 
including the screening period, in the opinion of the investigator. 
10. For NTDT subjects only: Subjects must have Hb ≤10.0 g/dL at Screening; the screening 
Hb sample must be collected 7 to 28 days prior to randomization. Hb values within 
21 days post-transfusion will be excluded. 
8.2. 
Exclusion Criteria 
Subjects meeting any of the following criteria must be excluded from the study: 
1. Any significant medical condition, laboratory abnormality, or psychiatric illness that 
would prevent the subject from participating in the study, including the presence of 
laboratory abnormalities that may place the subject at unacceptable risk if he/she were to 
participate in the study. 


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2. Any situation or condition that confounds the ability to interpret data from the study 
(e.g., subjects also receiving RBC transfusions at centers not able to obtain laboratory 
samples for central processing). 
3. Diagnosis of α-thalassemia (e.g., HbH) or HbS/β-thalassemia. 
4. Body mass index (BMI) <17.0 kg/m2 or a total body weight <45 kg; or BMI >35 kg/m2.  
5. Subjects with known active hepatitis A, hepatitis B, or hepatitis C, with active or acute 
event of malaria, or who are known to be positive for human immunodeficiency virus 
(HIV). 
6. Stroke requiring medical intervention ≤24 weeks prior to randomization. 
7. Subjects taking direct acting oral anti-coagulants (DOACs) apixaban, dabigatran, 
rivaroxaban, edoxaban, or ticagrelor, or taking warfarin, are excluded due to the 
possibility of a cytochrome P450 (CYP)3A-mediated drug interaction, unless they 
stopped the treatment at least 28 days prior to randomization (Day 1); other oral 
anti-coagulants and anti-platelet drugs are permitted. Anti-coagulant therapies for 
prophylaxis of venous thromboembolism, including pulmonary emboli including when 
undergoing surgery or high-risk procedures, are allowed if low molecular weight heparins 
are used in the peri-operative period. Aspirin use (<100 mg per day) is allowed before 
and during the study.  
8. Participated in another clinical study of an investigational agent (or medical device) 
within 30 days or 5 half-lives of date of informed consent, whichever is longer, or is 
currently participating in another study of an investigational agent (or medical device).  
9. Platelet count >1000 × 109/L. 
10. For subjects on iron chelation therapy (ICT) at the time of ICF signing, initiation of ICT 
less than 24 weeks before the predicted randomization date. ICT can be initiated at any 
time during treatment and should be used according to the label. 
11. Subjects who have had treatment with erythropoietin-stimulating agents ≤24 weeks prior 
to randomization. 
12. Uncontrolled hypertension as defined by systolic BP ≥160 mm Hg or diastolic BP 
≥100 mm Hg, medical intervention indicated, and more than one drug or more intensive 
therapy than previously used indicated. 
13. Poorly controlled diabetes mellitus, in the opinion of the investigator, for example 
1) Hb A1c >9.0% within 12 weeks prior to randomization (in the medical history); 
2) short-term hyperglycemia leading to hyperosmolar or ketoacidotic crisis; and/or 
3) history of diabetic cardiovascular complications. 
14. Subjects who have major organ damage, including: 
a. Liver disease with ALT or AST >3× ULN; direct bilirubin >3× ULN with proportion 
of direct/total bilirubin >0.3; or history/evidence of cirrhosis, liver transplant, or 
presence of clinically significant mass/tumor. 
b. Heart disease, heart failure as classified by the New York Heart Association 
classification 3 or higher, or significant arrhythmia requiring treatment, or recent 


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myocardial infarction within 6 months of randomization, or significant cardiac iron 
overload. 
c. Severe lung disease, including pulmonary fibrosis or pulmonary hypertension, 
i.e., ≥Grade 3 NCI CTCAE version 5.0. 
d. Significant kidney disease as indicated by, for example, estimated glomerular 
filtration rate <45 mL/min/1.73 m2 (per Modification of Diet in Renal Disease 
formula). 
15. Subjects who have received chronic systemic glucocorticoids ≤12 weeks prior to 
randomization (≥5 mg/day prednisone or equivalent). Physiologic replacement therapy 
for adrenal insufficiency is allowed. 
16. Major surgery ≤8 weeks prior to randomization. 
17. A history of a clinically significant allergic reaction or hypersensitivity, as judged by the 
investigator, to any drug or any component of the study drug formulations used in the 
study (see Investigator’s Brochure). 
18. History or current malignancies (solid tumors and hematological malignancies) unless the 
subject has been free of the disease (including completion of any active or adjuvant 
treatment for prior malignancy) for ≥5 years. However, subjects with the following 
history/concurrent conditions are allowed if, in the opinion of the investigator, the 
condition has been adequately diagnosed and is determined to be clinically in remission, 
and the subject’s participation in the study would not represent a safety concern: 
a. Basal or squamous cell carcinoma of the skin 
b. Carcinoma in situ of the cervix 
c. Carcinoma in situ of the breast 
d. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, 
metastasis clinical staging system) 
19. Screening or Baseline (Day 1) ECG demonstrating a QTcF >450 ms in men and >470 ms 
in women on 2 or more of the triplicate ECGs, or the presence of clinically significant 
ECG abnormalities as determined by the investigator. 
20. Consumption/use of the following drugs or other substances within the specified time 
periods before randomization or plans to consume/use at any time during the study. If 
there is any question as to whether a substance is permitted, please review the product 
labelling (if applicable) and consult the medical monitor and/or sponsor. 
a. PDE type 5 inhibitors (including but not limited to sildenafil, tadalafil, and 
vardenafil) within 7 days prior to randomization (Day 1) or plans to use during the 
study. 
b. Grapefruit, grapefruit juice, grapefruit products, or herbal supplements with 
CYP-altering abilities within 1 week prior to randomization (Day 1) or plans to 
consume during the study. 
c. CYP3A-sensitive substrates, including the synthetic opioid fentanyl and alfentanil, or 
moderate to strong CYP3A inhibitors or inducers within 28 days prior to 
randomization (Day 1) or plans to use during the study. 


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d. Any drugs or substances known to be substrates or inhibitors of P-gp or BCRP within 
28 days prior to randomization (Day 1) or plans to use during the study. 
21. Other prior or ongoing medical condition, physical findings, or laboratory abnormality 
that, in the investigator’s opinion, could adversely affect the safety of the subject, make it 
unlikely that the course of treatment or follow-up would be completed, or impair the 
assessment of study results (e.g., a history of drug or alcohol abuse as judged by the 
investigator within the past 1 year).  
22. Any clinically significant bacterial, fungal, parasitic, or viral infection requiring antibiotic 
therapy should delay screening/randomization (Day◦1) until the course of antibiotic 
therapy has been completed. This includes but is not limited to long-term tuberculosis 
treatment. 
23. Prior exposure to any of following: 
a. IMR-687 or gene therapy 
b. Sotatercept or luspatercept (Reblozyl®) within 6 months prior to randomization 
(Day 1) 
24. In the opinion of the investigator, the subject is unable to meet the requirements of the 
study.  
8.3. 
Screen Failures  
Any subject who consents to participate in the study but is not randomized will be considered a 
screen failure. Demographics, eligibility criteria, primary reason for screen failure, and any SAEs 
(if applicable) will be recorded and reported in the subject’s electronic case report form (eCRF) 
for subjects who are screen failures.  
If a subject is considered a screen failure, then he/she may be rescreened once with sponsor 
approval.  
8.4. 
Guidelines for Withdrawal of Subjects from Study Participation 
Subjects will be informed that they can discontinue their participation in the study at any time 
and for any reason. 
The investigator may also remove a subject from the study at their discretion if, in the 
investigator’s opinion, it is not in the best interest of the subject to continue in the study. 
If a subject must be discontinued from study participation, the medical monitor should be 
informed and consulted regarding possible appropriate assessments to be completed in advance 
of study discontinuation. In case of discontinuation from the study, every effort will be made to 
complete the early termination visit assessments, if possible. If a subject does not complete the 
early termination assessments, then every effort should be made to obtain end of study 
assessments. If a final visit is not feasible, every effort to collect follow-up medical records will 
be attempted.  
In the case of subjects who are lost to follow-up, the study site must attempt to contact the 
subject by phone, making at least 3 documented attempts, each at least one week apart. 


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Additionally, one registered letter must have been sent with a copy on file. The study site should 
only deem the subject as lost to follow-up no less than 30 days following the first documented 
phone call attempt, unless circumstances preclude this (e.g., phone service has been discontinued 
or there is other evidence that contact is not feasible). 
If the subject discontinues the study, the specific circumstances surrounding the discontinuation 
must be recorded in the subject’s eCRF. 
Refer to Section 7 for details about randomization and treatment assignments. All data collected 
prior to discontinuation must be recorded in the subject’s eCRF. 
Justifiable reasons to discontinue a subject from treatment (Section 8.5) and/or from the study 
may include, but are not limited to the following: 
• The subject was erroneously included in the study (i.e., did not meet eligibility 
criteria) 
• The subject experiences an SAE assessed as possibly or probably related to study 
drug 
• The subject is unable to comply with the requirements of the protocol 
• The subject participates in another investigational study 
• The subject withdraws consent to participate in the study 
• A subject for whom the blind is intentionally or accidentally broken 
8.5. 
 Guidelines for Study Drug Dose Withholding or Discontinuation  
8.5.1. 
Safety Criteria for Study Dose Interruption or Discontinuation 
In consultation with the medical monitor, the investigator may decide to withhold the study drug 
or withdraw the subject in cases where tolerability or safety concerns emerge. Table 4 provides 
recommended guidelines for these decisions. 
If a study drug dosing is withheld due to an AE (Section 12), subjects who continue on the study 
will have all assessments (except study drug administration) performed as per protocol. 
If study drug dosing is discontinued for any reason, the specific circumstances surrounding the 
discontinuation must be recorded in the subject’s eCRF. Any subject who discontinues study 
drug dosing must also be withdrawn from the study; however, all appropriate safety assessments 
and follow-up should be completed prior to withdrawal (Section 8.4). 


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Table 4: 
Safety Guidelines for Study Dose Reduction, Interruption, or 
Discontinuation  
Dose Reduction 
Event 
Recommended Action 
A Grade 2 or higher TEAE that, in the opinion of 
the investigator, is both study drug related and 
that makes continued dosing at the current dose 
level inadvisable due to safety concern or lack of 
tolerability. 
Study drug may be reduced by one tablet for up to 
14 continuous days. 
If, in the opinion of the investigator, a longer dose 
reduction is clinically needed, the medical 
monitor should be contacted. 
If, in the opinion of the investigator, the severity 
of the Grade ≥2 TEAE has reduced to Grade ≤1, 
the subject may resume study drug at the original 
dose. If the TEAE recurs after re-introduction of 
the original dose, the subject should be withdrawn 
from the study. 
Dose Interruption (Hold) 
 
Event 
Recommended Action 
A Grade 3 or higher TEAE that, in the opinion of 
the investigator, is both study drug related and 
that makes continued dosing at the current dose 
level inadvisable due to safety concern or lack of 
tolerability. 
Study drug should be held for up to 7 continuous 
days until reduction in severity of the TEAE to 
Grade ≤2, then resumed at the original dose. 
If, in the opinion of the investigator, dosing 
should be resumed at a lower dose, the medical 
monitor should be contacted. 
If, in the opinion of the investigator, a longer dose 
hold is clinically needed, the medical monitor 
should be contacted or the subject should be 
withdrawn from the study. 
Positive test results for COVID-19 and/or similar 
illness (asymptomatic and symptomatic). 
Study drug should be held until 7 days after 
subject tests negative. Please consult with the 
medical monitor if there are any questions. 
COVID-19 = coronavirus disease 2019; TEAE = treatment-emergent adverse event. 
 
8.6. 
Replacement of Subjects 
If a subject discontinues or is discontinued at the discretion of the investigator or DMC up to and 
including the Week 12 visit, the subject may be replaced with another subject meeting the 
eligibility criteria; up to 10 subjects for Population 1 and up to 10 subjects for Population 2 may 
be replaced. Refer to Section 7 for details about randomization and treatment assignments. Refer 
to Section 8.5 for guidelines on study drug dose withholding and discontinuation and to 
Section 8.4 for guidelines on withdrawal of subjects from study participation. All data collected 
prior to withdrawal must be recorded in the replaced subject’s eCRF. 


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8.7. 
Stopping Rules and Study Termination 
It is anticipated that AEs will occur frequently in this population based on the underlying disease, 
and that these can also be SAEs. There is no predefined type or frequency of AEs or SAEs for a 
stopping rule in this study. Review of SAEs and deaths on study will be performed routinely by 
the DMC, as defined in this protocol and in the DMC charter. 
If a safety concern arises that warrants review for possible study termination, the DMC (or party 
identifying such concern) will notify the sponsor immediately. Enrollment in the study may be 
temporarily halted for further review of safety data. This further assessment of safety and/or 
preliminary efficacy data will include review by the DMC, which may include the 
recommendation to terminate the study early or stop a treatment arm for safety or lack of 
efficacy, as outlined in the DMC charter. 
Termination of the clinical study may also occur due to a regulatory authority decision or if the 
sponsor or regulatory authority decides that subject safety may be compromised by continuing 
the study. 
If the study is halted temporarily or prematurely terminated, a written statement fully 
documenting the reasons for study halt or termination will be provided to the Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) and appropriate regulatory 
authorities. 


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9. 
STUDY TREATMENTS 
9.1. 
Storage Conditions 
Upon receipt of the study drug, an inventory must be performed, and a drug receipt log 
completed and signed by the person accepting the shipment. It is important that the designated 
study staff counts and verifies that the shipment contains all the items noted in the shipment 
inventory.  
Only subjects enrolled in the study may receive study drug, and only authorized site staff may 
supply or administer study drug to subjects. All study drug must be stored in a secure, 
environmentally controlled, and monitored (manual or automatic) location in accordance with 
the labelled storage conditions and with access limited to the investigator and authorized site 
staff.  
The study site must maintain accurate records demonstrating dates and quantity of study drug 
received, to whom dispensed (subject-by-subject accounting), any amount returned, and accounts 
of any study drug that was accidentally destroyed.  
9.2. 
Study Drug 
IMR-687 will be supplied as 100, 150, or 200 mg white tablets. Subjects will be advised to take 
two IMR-687 tablets orally with food qd for 36 weeks. To maintain appropriate exposures, 60 kg 
will be used as the weight gate for tablet strength. Subjects in the lower dose group weighing 
<60 kg will be dispensed 100 mg tablets and those weighing ≥60 kg will be dispensed 150 mg 
tablets. Subjects in the higher dose group weighing <60 kg will be dispensed 150 mg tablets and 
those weighing ≥60 kg will be dispensed 200 mg tablets. The different doses of IMR-687 are 
visually identical in tablet form.  
Placebo will consist of tablets containing matrix absent IMR-687 and will be identical in 
appearance to the IMR-687 tablets. Subjects will be advised to take two placebo tablets orally 
with food qd for 36 weeks. 
Subjects will be directed to take study drug (either IMR-687 or placebo) with food, but if a 
subject does not do so, it will not be considered a protocol deviation. 
9.3. 
Packaging and Labeling 
Finished tablets will be packaged in round, 60 cc high-density polyethylene bottles with a 
polypropylene cap. Each bottle contains 84 tablets. The bottles are induction sealed and capped. 
Each bottle will be labelled with a suitable Annex 13 country compliant product label.  
9.4. 
Study Drug Preparation 
9.5. 
Administration 
Subjects will be advised to take two IMR-687 or matched placebo tablets orally with food qd for 
36 weeks. On days when study drug is taken in the clinic, food details will also be recorded. 


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9.6. 
Treatment Compliance 
The investigator or designee must ensure that all subjects are adequately informed of study drug 
administration requirements for compliance/adherence with the study protocol. 
Treatment compliance/adherence with scheduled oral administration of study drug will be 
assessed at the study site starting at Week 3 for TDT subjects or Week 4 for NTDT subjects; all 
study drug administration will be documented on the appropriate pages of the eCRF. Subjects 
falling below an 80% treatment compliance rate between consecutive visits will be reported as a 
protocol deviation. 
9.7. 
Concomitant Medications 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the subject receives from the time of signing the ICF through the 
end of the study must be recorded along with: 
• Reason for use 
• Dates of administration, including start date/time and stop date/time 
• Dose and frequency of administration 
Subjects receiving hydroxyurea must have received it continuously for at least 6 months prior to 
signing the ICF, and have been on a stable dose for at least 3 months prior to signing the ICF, 
with no anticipated need for dose adjustments during the study including the screening period, in 
the opinion of the investigator. 
Over-the-counter medications such as analgesics and nonsteroidal anti-inflammatory drugs that 
are taken on an as needed basis can be continued as long as they are not medications that 
interfere with metabolism, transport, or assessments (refer to Appendix 3 for additional 
information). All concomitant medications and/or therapies must be recorded on the appropriate 
pages of the eCRF. Use of any prohibited medication and/or therapy must also be recorded on 
the eCRF and must be documented as a protocol deviation. 
9.7.1. 
Non-investigational Medicinal Products 
Not applicable. 
9.7.2. 
Prohibited Concomitant Medications/Therapies 
The investigator, in consultation with the medical monitor, will determine if any of the following 
concomitant medications/therapies are necessary for the well-being of the subject. The subject 
will be withdrawn from the study if the following are determined to be necessary: 
• PDE5 inhibitors; any drugs or substances, including grapefruit juice or herbal 
supplements with CYP altering properties, that are known to strongly or moderately 
inhibit or induce CYP/CYP3A enzymes; and any drugs or substances that are substrates 
or significant inhibitors of P-gp or BCRP. Sensitive substrates of CYP3A4/5 are also 
prohibited. If there is any question as to whether a substance is permitted, please review 
the product labeling (if applicable), and consult the medical monitor and/or sponsor. 


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• Concomitant use of erythropoietin. 
• Any concomitant use of sotatercept or luspatercept (Reblozyl®), or previous use within 
6 months prior to randomization (Day 1). 
• Any other investigational drug or device. 
Because IMR-687 is a CYP3A4 substrate as well as a possible CYP3A4 inducer, caution should 
be employed in the co-administration of IMR-687 with other medications that are known 
CYP3A4 substrates. This potentially helps manage the competition for in vivo CYP3A4-
mediated clearance, which could result in a DDI. This approach includes applying caution with 
dosing other oral medications to minimize the chance of a drug interaction at the site of 
absorption (e.g., the GI tract). Additional information on potential drug interactions and how to 
proceed can be found in Section 5.2.3. 
Medications prohibited prior to study entry are described in the exclusion criteria in Section 8.2. 
9.7.3. 
Prohibited Concomitant Procedures 
Procedures prohibited prior to study entry are described in the exclusion criteria in Section 8.2. 
Subjects should not receive a blood transfusion at the Day 1 or Week 4 visit. If a subject does 
require a blood transfusion at the Day 1 or Week 4 visit, the medical monitor should be notified 
for further guidance. 
9.8. 
Handling and Disposal 
At the end of the study, a final reconciliation must be made between the quantity of study drug 
supplied, dispensed, and subsequently returned to the sponsor. A written explanation must be 
provided for any discrepancies. After accountability has been performed by the sponsor or 
sponsor’s designee, any unused study drug remaining at the end of the study will be returned to 
the sponsor for destruction. Onsite destruction of unused study drug will be permitted with prior 
notice and approval from the sponsor. 


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10. 
RANDOMIZATION AND BLINDING 
10.1. 
Randomization 
All subjects who are screened (including screen failures) will be assigned a unique subject 
identification number.  
On Day 1, eligible subjects in Population 1 (TDT) and Population 2 (NTDT) will be assigned 
another unique number (randomization number) in sequential order. The randomization number 
codes the subject’s initial treatment assignment according to the randomization schedule 
generated prior to the study. Initially, subjects will be randomly assigned in a 2:1 ratio to receive 
either IMR-687 lower dose or placebo. If the DMC recommends inclusion of the higher dose, 
randomization will then proceed in a 1:2:1 ratio (IMR-687 lower dose, IMR-687 higher dose, or 
placebo).  
Subject randomization will be stratified by TDT/NTDT status. 
Randomization numbers will not be re-used once assigned. If a subject discontinues or is 
discontinued at the discretion of the investigator or DMC up to and including the Week 12 visit, 
the subject may be replaced with another subject meeting the eligibility criteria. In the event that 
a subject is replaced, the replacement subject will receive the same treatment as the replaced 
subject, and a different leading number will be used for the replacement randomization number. 
10.2. 
Blinding 
To ensure that the subject and site are blinded with respect to each subject’s treatment 
assignment, placebo tablets and tablets for each dose level of IMR-687 are identical in 
appearance and are supplied in identical packaging. Each bottle will contain a code that identifies 
the contents as either 100 mg IMR-687, 150 mg IMR-687, 200 mg IMR-687, or placebo. 
Every attempt should be made to preserve the integrity of study drug blinding. Except for cases 
of emergency unblinding, as described in Section 10.4, the randomization code will remain 
unbroken for subjects and study personnel at the site until the database has been locked for each 
study population. The blinded sponsor and CRO study team members will only be unblinded to 
the analysis results at the conclusion of the study (e.g., database lock).  
10.3. 
Unblinding for Interim Analysis 
To facilitate the analyses, certain sponsor representatives and designees will be unblinded to 
treatment assignments prior to and during the interim analysis (including the unblinded contract 
research organization [CRO] biostatistician and external groups for bioanalytical, PK, and 
PK/PD analyses and QoL analyses). Details will be provided in the study unblinding plan. 
10.4. 
Emergency Unblinding 
Unblinding is not always necessary to provide effective medical intervention and subject 
management in the event a subject experience an SAE, or an event that results in cessation of 
treatment (see Section 8.7). However, in the exceptional circumstance where the investigator 
believes that knowledge of the study drug assignment is essential to provide appropriate medical 
management, the treatment assignment for that subject will be provided to the investigator 


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according to standard operating procedures at the CRO. The medical monitor and sponsor are 
available to the investigator as needed for any considerations of unblinding a specific subject; 
however, the decision to unblind a specific subject relies solely on the clinical judgement of the 
investigator. That is, there is no requirement to discuss with the medical monitor and/or sponsor 
prior to unblinding a specific subject by the investigator; however, consultation is preferred. In 
the event that the investigator must unblind a subject and has not consulted with the medical 
monitor and/or sponsor, the investigator should notify the medical monitor and sponsor of the 
unblinding within 24 hours of breaking the blind. 
After breaking the blind, the site staff should record the reason(s) for breaking the blind and any 
AEs leading to the breaking of the blind in the source documents and the appropriate eCRF 
pages. After breaking the blind, the subject will be discontinued from the study and should 
proceed with early termination and end of study visits as described in Section 8.4 and per the 
schedule of assessments (Table 2 and Table 3). 


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11. 
ASSESSMENTS 
Table 2 and Table 3 list all of the study assessments and procedures for Population 1 (TDT) and 
Population 2 (NTDT), respectively. All data obtained from these assessments must be 
documented in the subject’s source documentation.  
Subjects should be seen for all visits on the designated day or within the defined allowable visit 
window (Table 2 and Table 3). The visits are as follows: 
• Screening (up to 28 days prior to Baseline) 
• Baseline (Day 1) 
• Treatment Period (Week 1 to Week 36) 
− Telephone visit will be performed at Week 2 
• End of Treatment/Early Termination (Week 36) 
• End of Study (Week 40) 
Unless otherwise specified, all assessments should be completed prior to dosing at any given 
timepoint. 
11.1. 
Screening and Baseline Activities  
The descriptions below are for screening-specific activities. For descriptions of activities that 
occur during both the screening and treatment periods, refer to Section 11.2 for preliminary 
efficacy and PD assessments, Section 11.3 for safety assessments, and Section 11.4 for PK 
assessments. 
11.1.1. 
Informed Consent 
The subject must read, understand, and sign the IRB/IEC-approved ICF confirming his or her 
willingness to participate in this study before initiating any screening activity that is not standard 
of care. The investigator will ensure that the subject has received adequate language translation if 
needed and understands the ICF before signing as per the local IRB/IEC’s requirement. Subjects 
must also grant permission or be informed of national laws for the processing and dissemination 
of their personal data, including data concerning health (sensitive/protected health information) 
and the use and retention of their specimens for study-related purposes. 
Informed consent for an optional pharmacogenomics evaluation will be offered at screening.  
11.1.2. 
Demographic Information and Medical/Disease History 
Subject demographics (age, sex, race, and ethnicity) and medical disease history (by thorough 
review of medical records and by interview) will be recorded at screening, in accordance with 
country requirements and institutional policies, and captured in the eCRF. Concurrent medical 
signs and symptoms must be documented to establish baseline severities.  
Disease history should contain a confirmed diagnosis of β-thalassemia or HbE/β-thalassemia. 
Concomitant alpha gene deletion, duplication, or triplication is allowed.  


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11.1.3. 
Inclusion/Exclusion Criteria Evaluation 
Eligibility will be assessed at screening and baseline based on the inclusion and exclusion criteria 
provided in Section 8. All inclusion and exclusion criteria will be assessed at the Screening visit; 
continued eligibility based on these criteria will be confirmed on Day 1. 
11.1.4. 
Eastern Cooperative Oncology Group Performance Score 
Subjects’ performance status will be measured by ECOG at Screening (Appendix 1). 
11.1.5. 
Historical Transfusion Burden 
After obtaining signed informed consent, the subject’s transfusion history for the 12 weeks prior 
to Baseline (Day 1) visit date should be recorded, relying on the documentation examples 
detailed below. Note that any transfusion on Day 1 (i.e., after randomization) should not be 
included in the transfusion history. 
In order to be eligible for the study, the dates of transfusion events and the number of pRBC 
units per event within the 12 weeks preceding the Baseline (Day 1) visit must be available. If 
available, the following data should also be collected for each transfusion event: volume and 
hematocrit of each pRBC unit, pre-transfusion Hb, and pre-transfusion weight. 
For TDT subjects: In the case of a subject receiving a transfusion after signing the ICF, a 
transfusion on the day of the Baseline (Day 1) visit may occur only after all study assessments 
are completed, including all PK sampling.  
For NTDT subjects: In the case of a subject receiving a transfusion after signing the ICF, but 
prior to randomization, the investigator would inform the medical monitor. The intent is to avoid 
transfusions within the 2-week period leading to randomization. Approval could be obtained for 
the screening period to be extended by a maximum of 14 days.  
11.1.6. 
Height 
Height in centimeters (cm) will be measured at screening. 
11.1.7. 
Serum Virology 
Blood samples will be collected for serum virology (screening assessment) only if clinically 
indicated. Testing will be performed through a central laboratory and may include hepatitis B 
surface antigen (HBsAg), hepatitis A immunoglobulin M (IgM), and hepatitis C virus (HCV) 
antibody, as well as HIV testing. 
11.1.8. 
Pharmacogenomic Evaluation (Optional) 
Blood samples may be collected at screening if the subject provides informed consent. The 
pharmacogenomic evaluation will include alpha-globin, gamma-globin XmnI polymorphism, and 
BAF chromatin remodeling complex subunit 11A (BCL11A), among other potential markers. 
The results of pharmacogenomic analyses may be reported separately from the clinical study 
report. Pharmacogenomic samples will be stored for up to 5 years post-study completion. 


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11.2. 
Preliminary Efficacy and Pharmacodynamic Assessments 
11.2.1. 
Transfusion Burden 
Transfusion burden will be assessed according the schedule of assessments (Table 2 and Table 3) 
using the following variables: dates of transfusion events, number of pRBC units per event, 
volume and hematocrit of each pRBC unit, pre-transfusion Hb, and pre-transfusion weight. 
These variables may also follow the same documentation requirements outlined in 
Section 11.1.5. 
If a subject requires a transfusion on days when PK samples will be drawn (i.e., the Baseline 
[Day 1] or the Week 1, Week 3 [TDT]/Week 4 [NTDT], Week 24, or Week 36 visits), the 
transfusion can only be performed after the final PK sampling. 
11.2.2. 
Quality of Life 
Quality of life will be assessed using the TranQOL and SF-36 QoL tools in the TDT population 
(Table 2) and the NTDT-PRO and SF-36 QoL tools in the NTDT population (Table 3). 
The TranQoL (Klaassen 2013; Klaassen 2014) is a disease-specific QoL measure for children 
and adults with thalassemia major. It has four versions: (i) a child self-report, (ii) an adult self-
report, (iii) a parent self- report (measuring the impact of the disease on the parent), and (iv) a 
parent proxy report (measuring the child’s QoL). The questionnaire length ranges from 29 items 
(child) to 39 items (parent). The questions are grouped into 4 domains: physical health, 
emotional health, family functioning, and school and career functioning. The adult and parent 
self-report questionnaires include a fifth category on sexual activity which is only one item. For 
this study only, the adult self-report will be used. 
The SF-36 (Hays 2004) is a 36-item, patient-reported survey of patient health. The SF-36 
consists of 8 scaled scores, which are the weighted sums of the questions in their section. Each 
scale is directly transformed into a 0 to 100 scale based on each scale having equal weight. The 
lower the score the more disability and the higher the score the less disability (i.e., a score of 0 is 
equivalent to maximum disability and a score of 100 is equivalent to no disability). The 
8 sections are: vitality, physical functioning, bodily pain, general health perceptions, physical 
role functioning, emotional role functioning, social role functioning, and mental health.  
The NTDT-PRO (Taher 2019) is a new disease-specific health-related QoL tool for patients with 
NTDT. The NTDT-PRO was designed as a daily diary with recall of thalassemia-related 
symptoms over the previous 24 hours. The relatively short recall period is used due to the high 
level of day-to-day variation in symptoms experienced by patients with NTDT.  
The 6 NTDT-PRO items assess the presence or severity of specific symptoms using a numerical 
rating scale ranging from 0 (“absent/minimal”) to 10 (“extreme/high”): tiredness with or without 
physical activity, weakness with or without physical activity, and shortness of breath with or 
without physical activity. NTDT-PRO items are grouped into 2 domains: tiredness/weakness 
(tiredness with physical activity, tiredness without physical activity, weakness with physical 
activity, and weakness without physical activity) and shortness of breath (shortness of breath 
with physical activity, shortness of breath without physical activity). For this study, the 


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NTDT-PRO will not be used as a daily diary; data will be collected as per the schedule of 
assessments (Table 3). 
11.2.3. 
Specialty Hematology 
Blood samples will be collected prior to study drug administration for HbF and percent F-cells at 
selected study visits as shown in the schedule of assessments (Table 2 and Table 3). Refer to the 
specialty laboratory manual for details on the collection, handling, and processing of blood 
samples. 
11.2.4. 
Pharmacodynamic Markers 
Blood samples will be collected prior to study drug administration for the following PD 
laboratory assessments at selected study visits as shown in the schedule of assessments (Table 2 
and Table 3). 
Pharmacodynamic assessments will include the following: 
• Haptoglobin 
• Hepcidin-25 
• Serum ferritin 
• Soluble transferrin receptor 
• Soluble E-selectin 
• Soluble P-selectin 
• Soluble intercellular adhesion molecule 1 (ICAM-1) 
• Vascular cell adhesion molecule 1 (VCAM-1) 
• High-sensitivity C-reactive protein (hsCRP)  
• Serum N-terminal pro-B-type natriuretic peptide (serum NT-proBNP) 
• Serum iron and total iron binding capacity (TIBC) for calculated transferrin saturation 
• Erythropoietin 
Refer to the central laboratory manual for details on the collection, handling, and processing of 
blood samples. 
11.3. 
Safety Assessments 
11.3.1. 
Telephone Visits 
Qualified site personnel will contact the subject by telephone at Week 2 to capture potential 
TEAEs and concomitant medications. Subjects will also be reminded of compliance with study 
drug and the next visit schedule. If any AEs of significant clinical concern are identified during 
the telephonic visit, the subject will be requested to come into the site to be assessed. 


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11.3.2. 
Vital Signs 
Vital signs include heart rate, respiratory rate, blood pressure, and body temperature. Vital signs 
should be consistently measured in either the sitting or semi-supine position. Vital signs will be 
collected at every visit except for the telephone visits. Vital signs will be taken pre-dose and 
2 hours (±20 minutes) post-dose on Day 1 and Week 3 for TDT subjects and on Day 1 and 
Week 4 for NTDT subjects (during PK assessments). At all other timepoints, vital signs can be 
taken irrespective of taking study drug. Vital signs that are clinically significant and not 
explained by the underlying disease or concomitant medications should be recorded as AEs in 
the eCRF. 
11.3.3. 
Weight 
Weight in kilograms (kg) will be measured at every visit except for the telephone visits. 
11.3.4. 
Physical Examinations 
A complete PE will be conducted at selected study visits (including screening) as shown in the 
schedule of assessments (Table 2 and Table 3); at other visits, a symptom-driven PE may be 
conducted. The complete physical examination will include a general examination of the body, 
including the abdomen, heart, lungs, lymph nodes, back/neck, neurological system, skin, 
extremities, head, eyes, nose, and throat.  
A symptom-directed physical examination will be conducted throughout the course of the study 
(except on visits where a complete physical examination will be conducted) following 
identification of AEs of significant clinical relevance as determined by the investigator.  
Clinically significant findings that were present prior to the signing of informed consent must be 
included in the medical history eCRF. Clinically significant new findings that begin (or 
pretreatment findings that worsen) after signing the ICF and that meet the definition of adverse 
events must be recorded on the AE eCRF. 
11.3.5. 
Electrocardiogram 
Triplicate 12-lead ECGs will be performed to evaluate the change from baseline in ECG 
parameters (heart rate, PR interval, RR interval, QRS duration, QT interval, and QTcF interval). 
For TDT subjects, ECGs will be obtained at pre-dose and 2 hours (±30 minutes) post-dose at 
Baseline and at Week 3. For NTDT subjects, ECGs will be obtained at pre-dose and 2 hours 
(±30 minutes) post-dose at Baseline and at Week 4. At all other timepoints, ECGs will be taken 
pre-dose. 
Interpretation of ECG tracings must be made by a qualified physician and documented on the 
ECG eCRF(s). The instrument used in the study to assess the ECG should be calibrated per the 
institution’s standard policy. 
Clinically significant abnormalities present prior to the subject’s signed informed consent should 
be reported on the medical history eCRF. New or worsened clinically significant findings 
occurring after informed consent must be recorded on the AE eCRF as described in 
Section 12.1.2.3. 


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11.3.6. 
Central Laboratory Assessments 
Blood and urine samples will be collected for routine clinical safety laboratory assessments 
according to the schedule of assessments (Table 2 and Table 3). Clinical safety tests will be 
assessed to evaluate IMR-687 safety and tolerability.  
All abnormal clinical laboratory pages should be initialed and dated by an investigator, along 
with a comment regarding clinical significance. Each clinically significant laboratory result is to 
be recorded as medical history at screening and as an AE subsequently. If known, the diagnosis 
associated with an abnormality in clinical laboratory results considered clinically significant by 
the investigator should be recorded on the AE eCRF. 
11.3.6.1. Hematology 
Hematology assessments will be performed through a central laboratory and will include the 
following: RBC count (mean corpuscular volume [MCV], mean corpuscular Hb, and mean 
corpuscular Hb concentration), hematocrit (Hct), Hb, platelets, WBC count (with differential: 
basophils, eosinophils, neutrophils, monocytes, and lymphocytes), erythrocyte count, 
reticulocyte count, and reticulocyte percentage. Some of these assessments are also considered 
PD endpoints (refer to Section 11.2). 
11.3.6.2. Coagulation 
Coagulation assessments will include PT, aPTT, and INR. Some of these assessments are also 
considered PD endpoints (refer to Section 11.2). 
11.3.6.3. Serum Chemistry 
Serum chemistries will be performed through a central laboratory and will include but not be 
limited to the following: ALT, albumin, alkaline phosphatase (ALP), AST, bicarbonate, blood 
urea nitrogen (BUN), chloride, calcium, creatinine, glucose, LDH, sodium, potassium, 
magnesium, phosphate, bilirubin (total, direct, and indirect), creatine kinase, total protein, 
glomerular filtration rate (GFR), and gamma-glutamyl transferase. FSH is added for 
post-menopausal women at screening. Some of these assessments are also considered PD 
endpoints (refer to Section 11.2). 
11.3.6.4. Urinalysis 
Urine will be assessed for appearance, color, pH, specific gravity, ketone, protein, glucose, 
bilirubin, and urobilinogen, including occult blood and microscopic examination of sediment 
(only if occult blood is detected). 
11.3.6.5. Pregnancy Test 
Serum pregnancy tests will be performed during screening via a central laboratory for all female 
subjects of childbearing potential who are not post-menopausal or surgically sterile. All 
subsequent pregnancy tests will be urine pregnancy tests performed locally (with test kits 
provided by the central laboratory). If a urine pregnancy test is positive, the result must be 
confirmed with a serum pregnancy test. 


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11.3.7. 
Adverse Event Collection  
Details of AE data collection are described in Section 12. Adverse events will be collected at 
every visit. 
11.3.8. 
Concomitant Medications 
Concomitant medications will be recorded at every visit in the medical record and on the 
appropriate eCRF. Any additions, discontinuations, or changes of these medications will be 
documented. 
11.4. 
Pharmacokinetic Assessments 
11.4.1. 
Plasma Pharmacokinetics 
Serial blood samples will be collected at the timepoints indicated in the schedule of assessments 
(Table 2 and Table 3) for determination of IMR-687 concentration (including metabolites). At 
Baseline (all subjects) and Week 3 (TDT subjects) or Week 4 (NTDT subjects), serial blood 
samples will be drawn pre-dose (within 30 minutes) and at 15 minutes (±5 minutes), 30 minutes 
(±5 minutes), and 3 hours (±20 minutes) after administration of study drug. A trough blood 
sample will be drawn pre-dose at Week 1, Week 24, and Week 36. The date/time of the previous 
dose will be recorded. 
Refer to the laboratory manual for details on the collection, handling, and processing of blood 
samples. 


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12. 
SAFETY MONITORING AND REPORTING 
12.1.1. 
Adverse Event and Serious Adverse Event Collection 
12.1.1.1. Time Period Adverse Event Collection 
All AEs and SAEs, related and unrelated, will be recorded from the signing of informed consent 
through the end of study safety follow-up visit (Week 40). Events that occur following 
administration of study drug will be considered TEAEs.  
All SAEs will be recorded and reported to the sponsor or sponsor’s designee within 24 hours, as 
indicated in Section 12.1.2.3. The investigator will also submit any updated SAE data to the 
sponsor within 24 hours of the data being available. 
12.1.1.2. Follow-up 
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits and phone contacts. All SAEs will be followed until resolution, stabilization, 
the event is otherwise explained, or the subject is lost to follow-up. 
12.1.2. 
Adverse Event Recording and Reporting 
12.1.2.1. Definitions 
12.1.2.1.1. Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a clinical study subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with 
this treatment. An AE can therefore be any unfavorable or unintended sign (for example, an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product.  
Examples of AEs include but are not limited to: 
• Abnormal test findings 
• Clinically significant symptoms and signs 
• Changes in physical examination findings 
• Hypersensitivity 
• Drug abuse 
• Drug dependency 
Additionally, they may include the signs or symptoms resulting from: 
• Drug overdose 
• Drug withdrawal 
• Drug misuse 


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• Drug interactions 
• Extravasation 
• Exposure during pregnancy 
• Exposure via breastfeeding 
• Medication error 
12.1.2.1.2. Definition of a Serious Adverse Events 
An SAE is any AE that results in one or more of the following outcomes: 
• Death 
• Requires or prolongs hospitalization (In general, hospitalization signifies that the 
subject has been detained, usually involving at least an overnight stay, at the hospital 
or emergency ward for observation and/or treatment that would not have been 
appropriate in the physician’s office or outpatient setting. Complications that occur 
during hospitalization are AEs. If a complication prolongs hospitalization or fulfils 
any other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious.) 
• Is life-threatening (In general, an AE is considered to be life-threatening if the 
subject is at immediate risk of death. It does not include an AE that, had it occurred in 
a more severe form, might have caused death.) 
• Persistent or significant disability/incapacity (In general, this means a substantial 
disruption of a person’s ability to conduct normal life functions. This definition is not 
intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, or accidental trauma 
[e.g., sprained ankle] that may interfere with or prevent everyday life functions, but 
do not constitute a substantial disruption.) 
• Congenital anomaly or birth defect (that occurs in the offspring of a subject 
exposed to the investigational product) 
• Other medically important event (In general, this means an AE that based upon 
appropriate medical judgment is considered to jeopardize the subject’s safety and may 
require medical or surgical intervention to prevent one of the outcomes listed above.) 
Reporting requirements for SAEs are described in Section 12.1.2.3. 
12.1.2.1.3. Definition of a Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is an SAE that, in the opinion of the 
investigator, is believed with reasonable probability (i.e., suspected) to be due to the 
investigational product, but the nature or severity of which is not consistent with the reference 
safety information (i.e., is unexpected). 
Reporting requirements for SUSARs are described in Section 12.1.2.4. 


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12.1.2.2. Evaluation of Adverse Events/Serious Adverse Events 
12.1.2.2.1. Assessment of Severity 
Adverse event severity (intensity) will be graded using NCI CTCAE, version 5.0 (Appendix 2). 
The CTCAE is a descriptive terminology utilized for AE reporting. A grading scale is provided 
for each AE term.  
Grade refers to the severity (intensity) of the AE. The CTCAE provides unique clinical 
descriptions of severity for each AE based on the following general guideline: 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL. * 
Grade 3 
Severe or medically significant, but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL**. 
Grade 4 
Life-threatening consequences: urgent intervention indicated. 
Grade 5 
Death related to AE. 
ADL = activities of daily living; AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
Note: The CTCAE terminology provides grading for specific laboratory test abnormalities (Appendix 2). Grade 4 
laboratory abnormalities do not automatically signify life-threatening AEs. Abnormal laboratory test results will 
be considered AEs only if the investigator, based on his or her medical judgement, deems the abnormality to be 
clinically significant. 
 
Change in severity of an AE should be documented based on specific guidelines in the eCRF 
Completion Guidelines. 
Severity and seriousness must be differentiated: Severity describes the intensity of an AE, while 
the term seriousness refers to an AE that has met the criteria for an SAE (defined in 
Section 12.1.2.1.2). 


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12.1.2.2.2. Assessment of Causality 
The investigator will assess the potential relatedness of each AE to the investigational product. 
An investigator causality assessment (unlikely/not related, possible, probable/likely, or 
certain/related) must be provided for all AEs (both serious and non-serious). This assessment 
must be recorded on the eCRF and any additional forms as appropriate. 
Unlikely/Not Related: 
• 
Event or laboratory test abnormality, with a time to drug intake 
that makes a relationship improbable (but not impossible) 
• 
Disease or other drugs provide plausible explanations 
 
 
 
Possible: 
• 
Event or laboratory test abnormality, with reasonable time 
relationship to drug intake 
• 
Could also be explained by disease or other drugs 
• 
Information on drug withdrawal may be lacking or unclear 
 
 
Probable/Likely: 
• 
Event or laboratory test abnormality, with reasonable time 
relationship to drug intake 
• 
Unlikely to be attributed to disease or other drugs 
• 
Response to withdrawal clinically reasonable 
• 
Rechallenge not required 
 
 
Certain/Related: 
• 
Event or laboratory test abnormality, with plausible time 
relationship to drug intake 
• 
Cannot be explained by disease or other drugs 
• 
Response to withdrawal plausible (pharmacologically, 
pathologically) 
• 
Event definitive pharmacologically or phenomenologically (i.e., 
an objective and specific medical disorder or a recognized 
pharmacological phenomenon) 
• 
Rechallenge satisfactory, if necessary 
12.1.2.2.3. Outcome of Adverse Events 
Outcome describes the status of the AE. Once the outcome is clear or at the end of the study, the 
investigator assigns one of the following outcomes for each AE: fatal, not recovered/not resolved, 
recovering/resolving, recovered/resolved, recovered/resolved with sequelae, or unknown. 
12.1.2.3. Recording and Reporting Adverse Events and Serious Adverse Events 
All AEs, both serious and non-serious, must be recorded in the eCRF.  
Study site personnel must notify the sponsor or its designee of any SAE within 24 hours of 
becoming aware of the event. The notification must occur via a sponsor-approved (official) 
method. If the sponsor or its designee is initially notified by telephone, the phone call is to be 
immediately followed by notification via sponsor-approved method. The investigator must 


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complete, sign, and date the SAE pages, verify the accuracy of the information recorded on the 
SAE pages with the corresponding source documents, and send a copy via email. Facsimile 
transmission may be used in the event of electronic submission or email failure. 
Safety Reporting: North America  
Telephone: +1 800 772 2215 or +1 434 951 3489 
Fax: +1 888 772 6919 or +1 434 951 3482 
Safety Reporting: Europe, Middle East, Asia-Pacific, and Africa 
Telephone: +49 621 878 2154 
Fax: +44 1792 525 720 
Initial SAE reports must be followed by detailed descriptions. These should include copies of 
de-identified hospital case records and other documents when requested. If further information 
becomes available, the SAE Form should be updated with the new information and reported. The 
24-hour notification requirement refers to reporting both initial SAE information and all 
follow-up SAE information once the site is made aware. 
Serious adverse events occurring up to and including the subject’s last study visit will be 
collected, regardless of the investigator’s opinion of causation. A death occurring during the 
study and within 30 days after the last study visit must be reported to the sponsor or its designee 
with 24 hours of knowledge of the death regardless of causality. In addition, if the investigator 
learns of any SAE, including a death, at any time after a subject has been discharged from the 
study, and he/she considers the event to be reasonably related to the study drug or study 
participation, the investigator must promptly notify the sponsor. 
For all SAEs the investigator must provide the following: 
• Appropriate and requested follow-up information in the timeframe detailed above 
• Causality of the SAE(s) 
• Outcome of the SAE(s) 
• Medical records and laboratory/diagnostic information 
12.1.2.4. Regulatory Reporting Requirements 
Sponsor’s Reporting Requirements 
The sponsor or its legal representative is responsible for notifying the relevant regulatory 
authorities of SAEs and SUSARs meeting the reporting criteria. This protocol will use the 
current Investigator’s Brochure as the Reference Safety Document. The expectedness and 
reporting criteria of an SAE will be determined by the sponsor from the Reference Safety 
Document. 
Investigator’s Reporting Requirements 
The investigator must fulfil all local regulatory obligations required of investigators for the 
study. It is the investigator’s responsibility to notify the IRB/IEC of all SAEs that occur at his or 
her site. Investigators will also be notified of all SUSARs that occur during the clinical study. 


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Investigators will receive blinded information unless unblinded information is judged necessary 
for safety reasons. 
12.1.2.5. Exposure During Pregnancy 
Pregnancy data will be collected for all subjects. Exposure during pregnancy (also referred to as 
exposure in utero) can be the result of either maternal exposure or transmission of the 
investigational product via semen following paternal exposure. 
Exposure during pregnancy must be recorded and the subject must be followed until the outcome 
of the pregnancy is known (spontaneous miscarriage, elective termination, normal birth, or 
congenital abnormality) even though the subject will be withdrawn from the study per 
Section 8.7. 
If a subject or a subject’s partner becomes pregnant while treated or exposed to investigational 
product, the investigator must submit a pregnancy form to the sponsor via the same method as 
SAE reporting. When the outcome of the pregnancy becomes known, the form should be 
completed and returned to the sponsor or the sponsor’s designee. If additional follow-up is 
required, the investigator will be requested to provide the information. 
12.1.3. 
Medication Error and Reporting 
In the event of a medication error, including overdose (accidental or intentional), it will be 
captured as an AE. A medication error associated with an SAE (including overdose, inadvertent 
exposure, and/or accidental exposure) will also be reported (see Section 12.1.2.3). 
Medication errors that result, for example, from the administration or consumption of the wrong 
drug, by the wrong subject, at the wrong time, or at the wrong dosage strength will also be 
captured as a protocol deviation. In the event of medication dosing error or an overdose, the 
medical monitor and sponsor should be notified immediately. 
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including: 
• Medication errors involving subject exposure to the product.  
• Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject. 
The sponsor does not recommend specific treatment for an overdose with IMR-687. Decisions 
regarding dose withholding will be made by the investigator in consultation with the medical 
monitor based on the clinical evaluation of the subject. 
Whether or not the medication error is accompanied by an AE, the medication error and, if 
applicable, any associated adverse event(s) is captured as an AE.  


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13. 
STATISTICAL METHODS 
13.1. 
General Considerations 
Descriptive summary statistics will be provided for demographics, disposition, and IMR-687 
exposure. The number and percentage of subjects who discontinue from the study, along with 
reasons for discontinuations will be tabulated. 
Continuous data will be summarized using descriptive statistics (number of subjects, mean, SD, 
median, Q1, Q3, minimum, and maximum) and, where appropriate, coefficient of variation 
(%CV) and graphic representation. Categorical data will be summarized by sample size and 
proportions. Data will be summarized by population (TDT, NTDT) and dose cohort at each 
timepoint as appropriate. Graphs of actual values and changes over time may also be created as 
appropriate. 
Interim analyses will be conducted at each of the following milestones: 
• 30 subjects in the TDT population have completed 24 weeks of treatment 
• 30 subjects in the NTDT population have completed 24 weeks of treatment 
• 60 subjects in the TDT population have completed 24 weeks of treatment 
• 60 subjects in the NTDT population have completed 24 weeks of treatment 
13.2. 
Analysis Sets 
Note that each of the following populations are defined for TDT and NTDT populations 
separately. Combined TDT and NTDT populations may also be used as appropriate. 
The safety analysis set will include all subjects who have received any amount of study drug and 
from whom informed consent has been obtained and will be used to summarize all safety and 
tolerability data. In safety summaries, subjects will be analyzed according to the actual treatment 
they received. 
The per protocol set will include all subjects in the safety population who have provided 
sufficient data without major protocol deviations or events that would be expected to affect the 
analysis. The per protocol set will be identified based on blinded data prior to unblinding the 
final analysis dataset. The per protocol set will be used to generate PD and clinical outcomes 
data. 
The PK analysis set will be defined as a subset of the safety analysis set that includes all subjects 
who are enrolled in the study, have received at least 1 dose of IMR-687, and have sufficient 
IMR-687 concentration data; this set will be used in the PK analyses. 
13.3. 
Safety Analyses 
Descriptive statistics will be used to summarize all safety endpoints, by population and treatment 
group as appropriate. Data summaries will be displayed for incidence of AEs, clinical laboratory 
variables, vital signs, and ECG parameters. 
Safety data summaries will use the safety analysis set. 


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All AEs will be coded using MedDRA. Data will be summarized using preferred term and 
primary system organ class. AE summaries will include AEs leading to study discontinuation 
and severity and frequency of AEs and SAEs. 
All safety data will be summarized in by-subject listings. 
13.4. 
Preliminary Efficacy Analyses 
13.4.1. 
Population 1: Transfusion Dependent β-Thalassemia 
Hematological improvement will be evaluated using a Cochran-Mantel-Haenzel (CMH) test to 
compare the proportion of subjects who achieved improvement between the placebo group and 
each of the 2 active treatment arms (IMR-687 lower dose and IMR-687 higher dose). 
Hematological improvement is defined as a ≥20% reduction in pRBC units transfused measured 
over 12 weeks (from Week 12 to Week 24 and from Week 24 to Week 36) as compared to the 
12-week period prior to the Baseline (Day 1) visit. The safety and per protocol populations will 
be used, and no multiple comparisons adjustment will be made.  
The mean number of transfusion events from baseline to Week 36 will be summarized by 
treatment group. Comparisons between placebo and each of the 2 active treatment arms 
(IMR-687 lower dose and IMR-687 higher dose) will be made using a t-test.  
The mean change from baseline to Week 36 for ICT mean daily dose and serum ferritin will be 
analyzed using an analysis of covariance (ANCOVA) model with baseline value as a covariate 
and treatment as a factor.  
13.4.2. 
Population 2: Non-Transfusion Dependent β-Thalassemia 
The baseline value of Hb will be defined as the mean of non-missing Hb values from Screening 
(7 to 28 days prior to randomization) and randomization (Day 1) measurements. The baseline 
value of HbF will be defined in an analogous manner.  
The proportion of subjects with increase from baseline of ≥1.0 g/dL in mean Hb values (at 
Weeks 12 to 24 and Weeks 24 to 36) will be evaluated using a Cochran-Mantel-Haenzel (CMH) 
test to compare the proportion of subjects who achieved improvement between the placebo group 
and each of the 2 active treatment arms (IMR-687 lower dose and IMR-687 higher dose). 
The average Hb concentrations in the absence of transfusions over a continuous 12-week interval 
(from Week 12 to Week 24 and from Week 24 to Week 36) as well as the change from baseline 
will be summarized by treatment group and timepoint. The change from baseline in average Hb 
at Weeks 12 to 24 and Weeks 24 to 36 will be compared between the placebo group and each of 
the 2 active treatment arms (IMR-687 lower dose and IMR-687 higher dose) using a mixed 
model for repeated measures (MMRM) with fixed effects for treatment group and timepoint and 
a random subject effect. The safety and per protocol populations will be used, and no multiple 
comparisons adjustment will be made. Mean change in HbF concentrations from baseline to 
Week 24 and to Week 36 will be analyzed in the same manner.  
The number and proportion of subjects with HbF response of ≥3% using the mean values at 
Weeks 12 to 24 and Weeks 24 to 36 will be summarized by timeframe and treatment group. 


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Comparisons of each of the 2 active treatment arms (IMR-687 lower dose and IMR-687 higher 
dose) to placebo will be made using a CMH test. 
The mean change from baseline to Week 36 for ICT mean daily dose and serum ferritin will be 
analyzed using an ANCOVA model with baseline value as a covariate and treatment as a factor.  
13.5. 
Pharmacokinetic Analyses 
Summary statistics for trough plasma concentration (Ctrough) data will be provided. Accumulation 
may be assessed. 
PK data from this study will also be used to explore any relationship between IMR-687 exposure 
and clinical response, PD endpoints, or AEs, as data permit. These data will be analyzed together 
with PK data from other clinical studies for a population PK analysis, as appropriate. 
13.6. 
Analyses of Exploratory Endpoints 
Exploratory PD and clinical outcomes data for each timepoint will be listed by subject and 
summarized by treatment group separately for Population 1 (TDT) and Population 2 (NTDT) as 
appropriate. Correlations between PK and the exploratory endpoints may be assessed. 
Descriptive statistics will be computed as appropriate. 
Summary statistics for QoL scores from the prespecified domains will be calculated at each 
administration timepoint. Summary statistics will also be calculated for change from baseline in 
each score at each administration timepoint. 
Exploratory PD outcomes will be based on the PD analysis set, and QoL outcomes will be based 
on the safety and per protocol sets. 
13.7. 
Sample Size Calculations 
Both populations will have primary objectives of safety, and the sample sizes are not based on 
statistical assumptions.  
13.7.1. 
Population 1: Transfusion Dependent β-Thalassemia 
For the secondary efficacy endpoint of percentage of subjects with hematologic improvement 
(reduction in transfusion burden), 16 subjects in each treatment arm provide 82% power to detect 
a difference of 10% of subjects improving in the placebo arm versus 50% of subjects improving 
in either of the active treatment arms, using an alpha level of 0.1. No multiple comparisons 
adjustments will be made as these are secondary analyses. 
13.7.2. 
Population 2: Non-transfusion Dependent β-Thalassemia 
For the secondary efficacy endpoints of proportion of subjects with increase from baseline of 
≥1.0 g/dL in mean Hb values at Weeks 12 to 24 or Weeks 24 to 36, 17 subjects in each treatment 
arm provide 84% power to detect a difference of 10% of subjects improving in the placebo arm 
versus 50% of subjects improving in either of the active treatment arms, using an alpha level of 
0.1. No multiple comparisons adjustments will be made as these are secondary analyses. 
 


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14. 
DATA COLLECTION AND QUALITY CONTROL  
Data collection is the responsibility of the staff at the study site under the supervision of the 
investigator. The designated study site staff will enter the data required by the protocol into the 
eCRFs. The eCRF is the primary data collection instrument for the study. The eCRFs have been 
built using fully validated secure web-enabled software that conforms to US Code of Federal 
Regulations (CFR) Title 21 Part 11 requirements. The investigator should ensure the accuracy, 
completeness, legibility, and timeliness of the data reported in the eCRFs and all other required 
reports. Data reported on the eCRF that are derived from source documents should be consistent 
with the source documents, or the discrepancies should be explained. All data requested on the 
eCRF must be recorded. Any missing data must be explained. For eCRFs, an audit trail will be 
maintained by the system to capture data changes. Study site staff will not be given access to the 
electronic data capture system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs and allow modification or verification of the entered 
data by the study site staff. 
The investigator is responsible for assuring that the data recorded on eCRFs are complete and 
accurate, and that entry and updates are performed in a timely manner. 
14.1. 
Database Management and Data Quality Control 
The sponsor or designee will review the data entered by investigational staff for completeness 
and accuracy. Electronic data queries stating the nature of the problem and requesting 
clarification will be created for discrepancies and missing values by generating appropriate error 
messages. In addition, the outsourced vendor Data Management staff will review the data using 
validation programs and database listings and enter electronic queries for discrepancies allowing 
modification or verification of the entered data by the designated study staff. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization Drug Reference List, which employs the Anatomical Therapeutic 
Chemical classification system. Medical history and AEs will be coded using the Medical 
Dictionary for Regulatory Activities (version 21.0) terminology. 
14.2. 
Study Site Monitoring 
Before study initiation at a study site, sponsor personnel or designee will review the protocol and 
eCRFs with the investigators and their study staff during an initiation visit or at an investigator’s 
meeting. During the study, the blinded clinical monitors will visit the study site regularly to 
check the completeness of subject records, the accuracy of entries on the eCRFs, the adherence 
to the protocol and Good Clinical Practice (GCP), the progress of enrollment, and to ensure that 
IMR-687/placebo is being stored, dispensed, and accounted for according to sponsor 
specifications. Key study personnel must be available to assist the clinical monitors during these 
visits. 
The investigator must maintain source documents for each subject in the study, consisting of 
hospital or clinic medical records including but not limited to demographic and medical 
information, laboratory data, ECGs, and the results of any other tests or assessments. All 
information recorded on eCRFs must be traceable to source documents in the subject’s file.  


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The investigator must also keep the original signed ICF (a signed and dated copy is given to the 
subject/legally authorized representative). 
The investigator must give the clinical monitors access to all relevant source documents to 
confirm their consistency with the eCRF entries. Monitoring standards require verification for 
the presence of signed/dated informed consent, adherence to the inclusion/exclusion criteria, and 
documentation of SAEs. Additional checks of the consistency of the source data with the eCRFs 
are performed according to the study-specific monitoring plan. 
14.3. 
Subject Data Protection and Confidentiality  
Information about study subjects will be obtained, processed, kept confidential, and protected 
according to the applicable laws and regulations, such as the US Health Insurance Portability and 
Accountability Act of 1996 (HIPAA) or General Data Protection Regulation (GDPR) on the 
protection of natural persons with regard to the processing of personal data and on the free 
movement of such data. 
Those regulations require a signed and dated subject consent informing the subject of the 
following: 
• The sponsor’s (e.g., Data Controller’s) identity. 
• The EU Data Protection Representative’s identity. 
• Contact information for the Data Protection Officer of the site and the Data 
Controller. 
• The right to complain with a Data Protection Authority and the address of it. 
• What personal data, including sensitive/personal health information will be collected 
from subjects in the study and for what purpose. 
• Who will have access to that information and why. 
• Who will process or disseminate that information. 
• The right of a research subject to discontinue study participation and revoke consent 
at any time for any reason. 
• In the event that a subject revokes consent, the investigator retains the ability to use 
all information collected prior to the revocation. For subjects who have revoked 
consent, attempts should be made to obtain permission to collect follow-up safety 
information (e.g., has the subject experienced any new or worsened AEs) at the end 
of their scheduled study period. 
• Possible risks to the subject associated with the transfer of his/her data to third 
countries or international organizations. 
• The suitable safeguards implemented to protect subject confidentiality and ensure 
subject data protection. 
• An explanation that study subjects who do not consent to the forwarding of such data 
will not be included in the clinical study. 


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The data collection system for this study uses built-in security features to encrypt all transmitted 
data, preventing unauthorized access to confidential subject information. Access to the system 
will be controlled by a sequence of individually assigned user identification codes and 
passwords, made available only to authorized personnel. 
In order to maintain subject confidentiality and to ensure subject data protection, the system will 
not solicit subject’s initials or exact date of birth. Instead, each subject will be identified by a 
subject identification number and age will be solicited to establish that the subject satisfies 
protocol age requirements. 
Any subject-related study documents sent to the sponsor (or designee) must be pseudonymized, 
i.e., must not contain direct identifiers such as subject’s name, initials, date of birth, etc. 


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15. 
ADMINISTRATIVE, ETHICAL, AND REGULATORY 
CONSIDERATIONS 
15.1. 
Protocol 
15.1.1. 
Protocol Amendments 
Any change to the protocol will be in the form of a written protocol amendment or administrative 
change document that will be issued by the sponsor or designee. 
Amendments specifically affecting the safety of subjects, the scope of the investigation, or the 
scientific quality of the study require additional approval by the applicable IRB(s)/IEC(s) of all 
study sites. Sites will not implement the protocol changes as described in an amendment until 
both regulatory authority and IRB/IEC approvals have been received. 
The protocol requirements should in no way prevent any immediate action from being taken by 
the investigator/medically qualified designee (must be MD), or by the sponsor (or designee), in 
the interest of preserving the safety of subjects included in the study. Changes affecting only 
administrative aspects of the study do not require formal protocol amendments or IRB/IEC 
approval, but the IRB/IEC must be kept informed of such changes. Therefore, the study site will 
send the administrative change document to the IRB/IEC according to the IRB’s/IEC’s 
documented process. 
15.1.2. 
Protocol Adherence 
It is the responsibility of the investigators to apply due diligence to avoid protocol deviations. If 
protocol deviations are identified, the sponsor or designee may be consulted to determine the 
best course of action to protect subject safety and maintain the integrity of the study data. The 
sponsor does not anticipate approving protocol deviations (i.e., waiving of inclusion/exclusion 
criteria or planned protocol deviations). If the investigator feels a protocol deviation would 
improve the conduct of the study, this must be considered a protocol amendment, and unless 
such an amendment is agreed upon by the sponsor and approved by the regulatory authority and 
IRB/IEC, it cannot be implemented. All significant protocol deviations will be recorded and 
reported in the clinical study report. 
15.1.3. 
Discontinuation of Site Participation 
If, in the opinion of the investigator or sponsor, the clinical observations in the study suggest that 
it may be unwise to continue, the investigator may discontinue their participation in the study or 
part of the study. A written statement fully documenting the reasons for discontinuation will be 
provided to the sponsor (or designee) and IRB/IEC. 
15.1.4. 
Protocol Disclosure and Confidentiality 
This protocol will be registered and maintained on ClinicalTrials.gov and other regulatory 
registries in accordance with applicable regulations. 
The contents of this protocol and any amendments and results obtained during the course of this 
study will be kept confidential by the investigator, the study site staff, and IRB/IEC and will not 


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be disclosed in whole or in part to others or used for any purpose other than reviewing or 
performing the study without the written consent of the sponsor. Accordingly, the investigator is 
prohibited from publishing any data collected or results obtained during the course of this study 
without the prior written approval of the sponsor. These obligations of confidentiality and 
non-use shall in no way diminish such obligations as set forth in the confidentiality agreement 
between the sponsor and the investigator. 
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in the confidentiality agreement between the investigator 
and sponsor or designee. 
15.2. 
Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) 
The protocol, any protocol amendments, and the ICF will be reviewed and approved by each 
site’s IRB/IEC before subjects are screened for entry into the study. Verification of the 
IRB’s/IEC’s unconditional approval of the protocol will be transmitted to the sponsor (or 
designee) prior to the study site(s) being initiated. The investigator(s) will submit, depending on 
local regulations, periodic reports and inform the IRB/IEC of any reportable AEs per ICH 
guidelines and local IRB/IEC standards of practice. 
A list of IRBs/IECs that approved this study will be included in the clinical study report. 
15.3. 
Ethical Conduct of the Study 
The study will be conducted in accordance with this protocol and applicable country-specific 
laws and regulations, including but not limited to:  
• US Code of Federal Regulations 
• ICH E6(R2) Good Clinical Practice: Consolidated Guidance (GCP) 
• Declaration of Helsinki (“Recommendations Guiding Physicians in Biomedical 
Research Involving Human Patients”) and all its accepted amendments to date 
concerning medical research in humans 
15.4. 
Subject Informed Consent 
In accordance with ICH E6 (Section 4.8) and US CFR Title 21 Part 50, informed consent will be 
documented by the use of a written ICF approved by the IRB/IEC prior to protocol-specific 
procedures being performed. 
The investigator (or designee) will explain the nature of the study and the action(s) of IMR-687. 
The subjects will be informed that participation is voluntary and that they can withdraw from the 
study at any time. They will be provided ample time and opportunity to inquire about details of 
the study and to decide whether or not to participate in the study.  
The subjects must read, understand, sign, and date the IRB/IEC-approved ICF confirming their 
willingness to participate in this study before any screening activity that is not standard of care is 
initiated. Subjects must also agree and grant permission for the collection, use and retention of 
their biological samples, as applicable, until the end of the study when select samples will be 


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analyzed, and to the processing and dissemination of their personal data, including data 
concerning health (sensitive/protected health information). Specifically, in relation to biological 
samples, once study-related testing has been completed, any remaining samples will be destroyed 
in compliance with the subject informed consent and applicable law. Samples will not be 
processed for future use. The subjects or their guardians/legally authorized representatives will 
be given a signed and dated copy of the ICF and any other written subject information, and the 
original ICF will be maintained at the study site with the subjects’ records. 
The investigator must ensure that the subject has received adequate language translation if 
needed and understands the ICF before signing as per the local IRB’s/IEC’s requirement. 
Subjects who refuse to have their biological specimens collected and retained until the end of the 
study when select samples will be analyzed, and/or do not agree and grant permission for the 
processing and dissemination of their personal data, including data concerning health 
(sensitive/protected health information), may not participate in the study. 
15.5. 
Publication of Study Protocol and Results 
The sponsor assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as ClinicalTrials.gov. The clinical study report will be submitted to the 
IRBs/IECs and regulatory authorities within one year of the end of the study (worldwide). 
The detailed obligations regarding the publication of any data, material results, or other 
information generated or created in relation to the study shall be set out in the agreement 
between each investigator and the sponsor. 
15.6. 
Correlative Studies 
Correlative studies may be proposed in the context of this clinical study and must include 
appropriate documentation including ethics approval and subject informed consent prior to 
proceeding. In addition, investigators interested in conducting correlative studies must obtain the 
sponsor’s prior approval. Correlative studies will consider the impact on study data, if any, and 
priority will be given to samples defined in this protocol. Requests for correlative studies must be 
made in writing to the sponsor. 
15.7. 
Investigators and Study Personnel 
This study will be conducted by qualified investigators under the sponsorship of IMARA, Inc. at 
multiple study sites internationally. In relevant countries, all study staff members will receive 
and acknowledge a data processing notice. 
A CRO will be retained by the sponsor to implement and manage the study and is referred to in 
this protocol as the sponsor’s designee. 
The names of the CRO and the medical monitor, along with contact information (email 
addresses, telephone and fax numbers, etc.) of other contact persons at the CRO, will be listed in 
study-related documents retained at each study site. 
The names of study site staff trained for this study and their responsibilities must appear on the 
site delegation of authority log. 


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A DMC will be established early in the study to monitor subject safety. The DMC will meet 
periodically as the study is ongoing to review the accumulating safety data and make 
recommendations as necessary to the sponsor regarding early termination of the study, 
continuation of the study, or modification of the study protocol as needed based on safety 
assessments. Additional details are provided in the DMC charter. 
15.8. 
Study Documentation, Record Keeping, and Retention of Documents 
The investigator has the responsibility to retain all study documents, including but not limited to 
the protocol, study site source documents, copies of eCRFs, Investigator’s Brochure, and 
regulatory documents (e.g., Form FDA 1572/Statement of Investigator, ICFs, and IRB/IEC 
correspondence) in accordance with Section 4.9 of the ICH E6(R2) GCP, US CFR 21 
Part 312.62(c), and other regulatory and institutional requirements.  
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical study necessary for the reconstruction and evaluation of the study. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
study. 
The investigator/institution should maintain the study documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6[R2] Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents. 
Sponsor-specific essential documents (hard copy and electronic) should be retained by the 
investigator until at least 2 years after the last approval of a marketing application in an ICH 
region and until there are no pending or contemplated marketing applications in an ICH region or 
at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational medicinal product. However, these documents should be retained for a longer 
period if required by the applicable regulatory requirements or by an agreement with the sponsor. 
The study site should plan on retaining study documents per the study site contract. 
15.9. 
Audits and Inspections 
Upon request by representatives of national regulatory authorities, IRBs/IECs, or the sponsor or 
the sponsor’s designee, investigators and institutions involved in the clinical study will permit 
study-related monitoring, audits, and regulatory inspections, including direct access to source 
data and documents generated by this study. Audits and inspections may be conducted during the 
study or after its completion. If an audit or inspection is requested by parties other than sponsor, 
the investigator or designee must immediately inform the sponsor that a request has been made. 


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16. 
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Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, et al. Mortality in sickle 
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9;330(23):1639-44. 
Schwam EM, Nicholas T, Chew R, Billing CB, Davidson W, Ambrose D, et al. A multicenter, 
double-blind, placebo-controlled trial of the PDE9A inhibitor, PF-04447943, in Alzheimer’s 
disease. Curr Alzheimer Res. 2014;11(5):413-21. 
Sheehan VA, Luo Z, Flanagan JM, Howard TA, Thompson BW, Wang WC, et al. Genetic 
modifiers of sickle cell anaemia in the BABY HUG cohort: influence on laboratory and clinical 
phenotypes. Am J Hematol. 2013 Jul;88(7):571-6.  
Taher A, Viprakasit V, Cappellini MD, Sutcharitchan P, Ward R, Mahmoud D, et al. 
Development of a patient-reported outcomes symptom measure for patients with 
nontransfusion-dependent thalassemia (NTDT-PRO©). Am J Hematol. 2019 Feb;94(2):171-6. 
van der Staay FJ, Rutten K, Bärfacker L, Devry J, Erb C, Heckroth H, et al. The novel selective 
PDE9 inhibitor BAY 73-6691 improves learning and memory in rodents. Neuropharmacology. 
2008 Oct;55(5):908-18.  
van Staveren WC, Glick J, Markerink-van Ittersum M, Shimizu M, Beavo JA, et al. Cloning and 
localization of the cGMP-specific phosphodiesterase type 9 in the rat brain. J Neurocytol. 2002 
Sep-Nov;31(8-9):729-41. 


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17. 
APPENDICES


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Appendix 1: Eastern Cooperative Oncology Group (ECOG) Performance 
Status 
The ECOG performance status scoring criteria were developed by the Eastern Cooperative 
Oncology Group (Oken, Creech, and Torney et al. 1982).  
 
GRADE 
ECOG PERFORMANCE STATUS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light housework, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; up and 
about more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
5 
Dead 


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Appendix 2: National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE, v5.0) 
Adverse events will be graded according to CTCAE v5.0. 
The NCI CTCAE criteria are available at the following web location: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 
 
 


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Appendix 3: Lists of Potential In Vivo CYP3A Drug-Drug Interactions 
The list of in vivo CYP3A-sensitive substrates, inhibitors of CYP3A probes, inducers of CYP3A 
probes; list of in vivo inhibitors of P-gp probes; and list of in vivo inducers of CYP3A probes 
can be found online at, for instance, the following websites: 
• https://www.druginteractionsolutions.org 
• https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers 
If there is any question as to whether a substance is permitted, the medical monitor and/or 
sponsor should be consulted. 
 

SAP_001.pdf: 
Statistical Analysis Plan 
Version Date: 14-Oct-2021  
 
Sponsor: Imara, Inc. 
 
Protocol no: IMR-BTL-201 
 
Page 1 of 82 
Statistical Analysis Plan (SAP) 
Protocol Title: 
A Phase 2 Study to Evaluate the Safety and Tolerability of IMR-687 in 
Subjects with Beta Thalassemia 
Protocol Version No./Date: 
5.0/15-Mar-2021 
CRF Version No./Date: 
3.0/08-Jun-2021 
SAP Version No./Date: 
1.0/14-Oct-2021 
 
 Approvals 
Sponsor 
Sponsor Name: 
Imara, Inc. 
Representative / Title: 
Constance Barysauskas, MS/ Principal Biostatistician 
Signature / Date: 
 
 
 
 
 
 
Representative / Title: 
Kenneth M. Attie, MD/ Senior Vice President & Chief Medical Officer 
Signature / Date: 
 
 
 
 
 
 
Everest Clinical Research 
Biostatistician / Title: 
Meleana Dunn, M.S. / Principal Biostatistician 
Signature / Date: 
 
 
 
 
 
Review Biostatistician 
/ Title: 
Christine Kollar, M.Sc. / Principal Biostatistician 
Signature / Date: 
 
 
 
 
 
 
 


Statistical Analysis Plan 
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Protocol no: IMR-BTL-201 
 
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 Change History 
Version/Date 
Change Log 
0.1/18-Feb-2020 
Created as new 
1.0/14-Oct-2021 
Final 
 
 
 


Statistical Analysis Plan 
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Protocol no: IMR-BTL-201 
 
Page 3 of 82 
 Table of Contents 
 Approvals ................................................................................................................................................ 1 
 Change History ....................................................................................................................................... 2 
 Table of Contents .................................................................................................................................... 3 
 Purpose ................................................................................................................................................... 5 
 Scope ...................................................................................................................................................... 5 
 Introduction ............................................................................................................................................. 5 
6.1 Changes from Protocol ....................................................................................................................... 5 
 Study Objectives ..................................................................................................................................... 7 
7.1 Primary Objective ................................................................................................................................ 7 
7.2 Secondary Objectives ......................................................................................................................... 7 
7.2.1 Population 1: Transfusion-dependent β-Thalassemia ................................................................. 7 
7.2.2 Population 2: Non-transfusion-dependent β-Thalassemia .......................................................... 7 
7.3 Exploratory Objectives ........................................................................................................................ 7 
7.3.1 Population 1: Transfusion-dependent β-Thalassemia ................................................................. 7 
7.3.2 Population 2: Non-transfusion-dependent β-Thalassemia .......................................................... 7 
 Study Design ........................................................................................................................................... 8 
8.1 Sample Size Considerations ............................................................................................................. 11 
8.1.1 Population 1: Transfusion-dependent β-thalassemia ................................................................ 11 
8.1.2 Population 2: Non-transfusion-dependent β-thalassemia .......................................................... 11 
8.2 Randomization .................................................................................................................................. 11 
 Study Endpoints, Variables and Covariates.......................................................................................... 11 
 Conventions and Derivations .............................................................................................................. 15 
10.1.1 Method for Handling Missing Data ........................................................................................... 15 
10.1.2 Definition of Baseline and Change from Baseline Values ....................................................... 15 
10.1.3 Definition of Study Days ........................................................................................................... 15 
10.1.4 Definition of Treatment-Emergence ......................................................................................... 15 
10.1.5 Red Blood Cell Transfusion Reduction: 12-Week Fixed Interval ............................................. 15 
10.1.6 Red Blood Cell Transfusion Reduction: 24-Week Fixed Interval ............................................. 15 
10.1.7 Red Blood Cell Transfusion Reduction: 12-Week Rolling Interval .......................................... 15 
10.1.8 Red Blood Cell Transfusion Reduction: 14-Week Rolling Interval .......................................... 16 
10.1.9 Quality of Life Assessments ..................................................................................................... 16 
10.1.10 Windowing Conventions ........................................................................................................ 16 
 Analysis Sets ....................................................................................................................................... 20 
11.1 Safety Analysis Set ......................................................................................................................... 21 
11.2 Intent-to-Treat Analysis Set ............................................................................................................ 21 
11.3 Modified Intent-to-Treat Analysis Set .............................................................................................. 21 
11.4 Per Protocol Analysis Set................................................................................................................ 21 
11.5 PK Analysis Set ............................................................................................................................... 22 
11.6 PK Evaluable Set ............................................................................................................................ 22 
 Interim Analyses .................................................................................................................................. 22 
12.1 Data Monitoring Committee ............................................................................................................ 29 
 Statistical Methods .............................................................................................................................. 30 
13.1 Subject Disposition .......................................................................................................................... 30 
13.2 Important Protocol Deviations ......................................................................................................... 31 
13.3 Treatment ........................................................................................................................................ 31 
13.3.1 Extent of Study Drug Exposure and Drug Accountability ........................................................ 31 
13.4 Demographic and Baseline Characteristics .................................................................................... 32 
13.4.1 Medical and Surgical History ................................................................................................... 33 
13.5 Prior and Concomitant Treatments and Procedures ...................................................................... 33 
13.5.1 Prior and Concomitant Beta-Thalassemia Treatment .............................................................. 33 
13.5.2 Prior and Concomitant Medications ......................................................................................... 34 
13.5.3 Concomitant Procedures ......................................................................................................... 34 
13.5.4 Prior and Concomitant Iron Chelation Therapy ....................................................................... 34 


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13.6 Endpoint Analyses .......................................................................................................................... 35 
13.6.1 Hypothesis Testing Strategy and Multiplicity ........................................................................... 35 
13.6.2 Safety Analyses ....................................................................................................................... 35 
13.6.3 Imputation Methods for Endpoints ........................................................................................... 41 
13.6.4 Efficacy Analyses (Secondary Endpoints) ............................................................................... 41 
13.6.5 Pharmacokinetic Analyses ....................................................................................................... 49 
13.6.6 Exploratory Efficacy Analyses .................................................................................................. 51 
13.6.7 Specialty Hematology Endpoints ............................................................................................. 60 
13.6.8 Pharmacodynamic Endpoints .................................................................................................. 60 
13.7 Other Data ....................................................................................................................................... 61 
 References .......................................................................................................................................... 62 
 Glossary of Abbreviations ................................................................................................................... 63 
 Appendices ......................................................................................................................................... 65 
Appendix 1 Schedule of Assessments – TDT Population .......................................................................... 65 
Appendix 2 Schedule of Assessments – NTDT Population ........................................................................ 70 
Appendix 3 Data Handling Rules ................................................................................................................ 74 
Appendix 4 Clinical Laboratory CTCAE Grading ........................................................................................ 77 
Appendix 5 Regions .................................................................................................................................... 81 
Appendix 6 Shell Column Headers ............................................................................................................. 82 
 


Statistical Analysis Plan 
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Protocol no: IMR-BTL-201 
 
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 Purpose 
The Statistical Analysis Plan (SAP) describes the statistical methods to be used during the reporting and 
analyses of data collected under Imara Protocol IMR-BTL-201. 
 Scope 
The Statistical Analysis Plan outlines the following: 
• 
Study Objectives 
• 
Study Design 
• 
Endpoints to be Analyzed and the Analysis sets 
• 
Applicable Study Definitions 
• 
Statistical Methods 
 Introduction 
This SAP should be read in conjunction with the study protocol and case report form (CRF). Any further 
changes to the protocol or CRF may necessitate updates to the SAP prior to database lock. 
6.1 Changes from Protocol 
In this SAP three analysis sets were added - the Intent-to-Treat (ITT) Analysis Set, which is defined in 
Section 11.2, the Modified Intent-to-Treat (mITT) Analysis Set, which is defined in Section 11.3, and the 
PK Evaluable Set, which is defined in Section 11.6. The ITT and mITT Analysis Sets were added to 
summarize the efficacy analysis. The ITT Analysis set will allow for an assessment of all randomized 
subjects. The mITT Analysis set allows for an assessment of all randomized subjects who received at 
least one dose of study drug, regardless of their compliance with or any deviations from the protocol. The 
Per Protocol (PP) Analysis Set definition in Section 11.4 has been clarified to include subjects with any 
post-baseline assessment and who did not discontinue prior to week 12 for reasons other than AEs.  
The definition of the Safety Analysis Set was clarified to remove the requirement for the subject to give 
informed consent. This does not change the definition in practice as all subjects in the Safety Analysis Set 
are required to receive at least one dose of study drug which would only happen after the subject gave 
informed consent. 
The definition of the PK analysis set was modified. As per protocol, the PK Analysis Set was defined as a 
subset of the Safety Analysis Set that included all subjects who were enrolled in the study, received at 
least 1 dose of IMR-687, and had sufficient IMR-687 concentration data to be used in the PK analyses. 
This has been further delineated with the addition of a PK Evaluable Set and for each of these PK 
population subsets, the definitions were updated as follows: 
• 
The PK Analysis Set, will be defined as a subset of the Safety Analysis Set that includes all 
subjects who are enrolled in the study, have received at least 1 dose of IMR-687, and have any 
measurable post-dose IMR-687 concentration-time data. This set will be used to generate the 
corresponding PK concentration summaries and plots. 
• 
The PK Evaluable Set will be defined as all subjects in the Safety Analysis Set who are 
randomized, have received at least 1 dose of IMR-687, and have at least 4 consecutive non-zero 
post-dose IMR-687 concentration-time data points. The PK Evaluable Set will be used to 
generate the corresponding PK parameter assessments. 
An interim analysis was added (IA 0.5) for the NTDT population to be performed when approximately 15 
NTDT subjects have completed 12 weeks of treatment. 
Several secondary efficacy endpoints were added: 
• 
Proportion of subjects with a ≥20% reduction in RBC transfusion burden with a reduction of at 
least 2 units of RBCs (hematological improvement) over any 12-week rolling time period – Day 2 


Statistical Analysis Plan 
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Protocol no: IMR-BTL-201 
 
Page 6 of 82 
to 85, Day 3 to 86, etc. through Day 170 to Day 253 (Week 36) – compared to the 12 weeks prior 
to Baseline (Day 1). 
• 
Proportion of subjects with a ≥20% reduction in RBC transfusion burden with a reduction of at 
least 2 units of RBCs (hematological improvement) over any 14-week rolling time period – Day 2 
to 99, Day 3 to 100, etc. through Day 156 to Day 253 (Week 36) – compared to the 12 weeks 
prior to Baseline (Day 1). 
• 
Proportion of subjects with a ≥33% reduction in RBC transfusion burden with a reduction of at 
least 2 units of RBCs (hematological improvement) over any 12-week rolling time period – Day 2 
to 85, Day 3 to 86, etc. through Day 170 to Day 253 (Week 36) – compared to the 12 weeks prior 
to Baseline (Day 1). 
• 
Proportion of subjects with a ≥33% reduction in RBC transfusion burden with a reduction of at 
least 2 units of RBCs (hematological improvement) over any 14-week rolling time period – Day 2 
to 99, Day 3 to 100, etc. through Day 156 to Day 253 (Week 36) – compared to the 12 weeks 
prior to Baseline (Day 1). 
• 
Proportion of subjects with a ≥50% reduction in RBC transfusion burden with a reduction of at 
least 2 units of RBCs (hematological improvement) from Week 12 to Week 24 and Week 24 to 
Week 36, compared to the 12 weeks prior to Baseline (Day 1). 
• 
Proportion of subjects with a ≥50% reduction in RBC transfusion burden with a reduction of at 
least 2 units of RBCs (hematological improvement) from Week 12 to Week 36, compared to the 
12 weeks prior to Baseline (Day 1). 
• 
Proportion of subjects with a ≥50% reduction in RBC transfusion burden with a reduction of at 
least 2 units of RBCs (hematological improvement) over any 12-week rolling time period – Day 2 
to 85, Day 3 to 86, etc. through Day 170 to Day 253 (Week 36) – compared to the 12 weeks prior 
to Baseline (Day 1). 
• 
Proportion of subjects with a ≥50% reduction in RBC transfusion burden with a reduction of at 
least 2 units of RBCs (hematological improvement) over any 14-week rolling time period – Day 2 
to 99, Day 3 to 100, etc. through Day 156 to Day 253 (Week 36) – compared to the 12 weeks 
prior to Baseline (Day 1). 
Several exploratory efficacy endpoints were added: 
• 
Change from Baseline in mean pre-transfusion Hb values at Weeks 12 to 24, Weeks 24 to 36, 
and Weeks 12 to 36 [using pre-transfusion Hb from the Historical Transfusion Burden and the 
Transfusion Burden CRFs] 
• 
Proportion of subjects with an increase from Baseline of ≥1.0 g/dL in mean pre-transfusion Hb 
values or a Reduction in RBC Transfusion Burden (≥33% reduction) Endpoint at Weeks 12 to 24, 
Weeks 24 to 36, and Weeks 12 to 36 [using pre-transfusion Hb from the Historical Transfusion 
Burden and the Transfusion Burden CRFs] 
• 
Time to first Hb increase (≥1.0 g/dL) 
Two exploratory efficacy endpoints were modified: 
• 
The mean change from Baseline in NTDT-PRO score over a continuous 12-week interval from 
Week 12 to Week 24 and Week 24 to Week 36 was modified to the mean change from Baseline 
NTDT-PRO total score and domain scores including tiredness/weakness and shortness of breath 
domains over a continuous 12-week interval from Week 12 to Week 24 and Week 24 to Week 36 
• 
The mean change from Baseline in NTDT-PRO domain total score at Week 24 was changed to 
the mean change from Baseline in NTDT-PRO total score and domain scores including 
tiredness/weakness and shortness of breath domain scores at Week 24 and Week 36.  


Statistical Analysis Plan 
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Protocol no: IMR-BTL-201 
 
Page 7 of 82 
Per protocol, plasma concentrations of IMR-687 and metabolites could have been analyzed and used 
for PK analyses. The PK analyses for this study will only include IMR-687 plasma concentration-time 
data. No PK analysis of IMR-687 metabolites will be performed. 
 Study Objectives 
7.1 Primary Objective 
The primary objective of this study in both Population 1 (transfusion-dependent thalassemia; TDT) and 
Population 2 (non-transfusion-dependent thalassemia; NTDT) is to assess the safety and tolerability of 
IMR-687 in adult subjects with β-thalassemia. 
7.2 Secondary Objectives 
7.2.1 Population 1: Transfusion-dependent β-Thalassemia 
The secondary objectives in TDT subjects are: 
• 
To evaluate the effect of IMR-687 versus placebo on reduction in red blood cell (RBC) transfusion 
burden. 
• 
To evaluate the effect of IMR-687 versus placebo on the change in iron overload.  
• 
To characterize the pharmacokinetic (PK) profile of IMR-687 and collect data for population PK 
analysis. 
7.2.2 Population 2: Non-transfusion-dependent β-Thalassemia 
The secondary objectives in NTDT subjects are: 
• 
To evaluate the effect of IMR-687 versus placebo on anemia (as defined by total hemoglobin). 
• 
To evaluate the effect of IMR-687 versus placebo on fetal hemoglobin (HbF). 
• 
To evaluate the effect of IMR-687 versus placebo on the change in iron overload. 
• 
To characterize the PK profile of IMR-687 and collect data for population PK analysis. 
7.3 Exploratory Objectives 
7.3.1 Population 1: Transfusion-dependent β-Thalassemia 
The exploratory objectives in TDT subjects are: 
• 
To characterize the pharmacodynamic (PD) profile of IMR-687 versus placebo with respect to 
erythropoiesis, iron metabolism, and hemolysis.  
• 
To evaluate the effect of IMR-687 versus placebo on the proportion of subjects who are 
transfusion independent. 
• 
To evaluate the effect of IMR-687 versus placebo on time to and duration of reduction in RBC 
transfusion burden. 
• 
To evaluate the effect of IMR-687 versus placebo on functional and health-related quality of life 
(QoL). 
• 
To evaluate responses to IMR-687 per genotypes in subjects with TDT. 
7.3.2 Population 2: Non-transfusion-dependent β-Thalassemia 
The exploratory objectives in NTDT subjects are: 


Statistical Analysis Plan 
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Protocol no: IMR-BTL-201 
 
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• 
To characterize the PD profile of IMR-687 versus placebo with respect to erythropoiesis, iron 
metabolism, and hemolysis. 
• 
To evaluate the effect of IMR-687 versus placebo on functional and health-related QoL. 
• 
To evaluate the effect of IMR-687 versus placebo on β-thalassemia-related symptoms and 
severity. 
• 
To evaluate responses to IMR-687 per genotypes in subjects with NTDT. 
 Study Design 
This is a phase 2 randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, 
PK, and PD of IMR-687 (PDE9 inhibitor) administered QD for 36 weeks in 2 populations of adult subjects 
with β-thalassemia: Population 1 (TDT subjects) and Population 2 (NTDT subjects). A schematic of the 
study is provided in Figure 1. 
 
This study will enroll approximately 120 subjects with β-thalassemia (60 subjects with TDT and 60 subject 
with NTDT), aged 18 through 65 years across approximately 50 sites in North America, the United 
Kingdom, European Union, Middle East, Asia-Pacific, and Africa. This study consists of a retrospective 
data collection period, a screening period, a double-blind treatment period, and safety follow-up period. 
The planned maximum duration of study participation is approximately 44 weeks. During the screening 
period of up to 28 days, subjects will provide informed consent and be evaluated on eligibility criteria as 
stated in Sections 8.1 and 8.2 of the study protocol. 
 
Randomization will be stratified by TDT/NTDT status. Subjects will be randomly assigned in a 2:1 ratio to 
receive either IMR-687 lower dose or placebo. Prior to the introduction of IMR-687 higher dose, the Data 
Monitoring Committee (DMC) was to review safety data for at least 5 subjects who received IMR-687. If 
the DMC recommended inclusion of the higher dose, randomization was then to proceed in a 1:2:1 ratio 
(IMR-687 lower dose, IMR-687 higher dose, or placebo). The DMC could request additional data and/or 
meeting(s) in order to make the recommendation on whether to move forward with inclusion of the higher 
dose. During study conduct under Protocol Version 4.0, the DMC approved the opening of enrollment in 
the higher dose IMR-687 group, which went into effect on 01 February 2021. With approval of enrollment 
in the higher dose arm, subjects receive IMR-687 lower dose ([≥3.4 to ≤5.0 mg/kg], higher dose [>4.5 to 
≤6.7 mg/kg] or placebo in a blinded fashion; the precise exposure ranges for different groups of subjects 
are dependent on the weight gate for tablet strength as summarized below). 
 
IMR-687 will be supplied as 100, 150, or 200 mg white tablets. Subjects will be advised to take two IMR-
687 tablets with food QD for 36 weeks. To maintain appropriate exposures, 60 kg will be used as the 
weight gate for tablet strength. Subjects in the lower dose group weighing <60 kg will be dispensed 100 
mg tablets and those weighing ≥60 kg will be dispensed 150 mg tablets (daily dose 200 mg and 300 mg, 
respectively). Subjects in the higher dose group weighing <60 kg will be dispensed 150 mg tablets and 
those weighing ≥60 kg will be dispensed 200 mg tablets (daily dose 300 mg and 400 mg, respectively). 
The different doses of IMR-687 are visually identical in tablet form. 
 
Placebo will consist of tablets containing matrix absent IMR-687 and will be identical in appearance to the 
IMR-687 tablets. Subjects will be advised to take two placebo tablets orally with food QD for 36 weeks. 
 
Subjects will be directed to take study drug (either IMR-687 or placebo) with food, but if a subject does 
not do so, it will not be considered a protocol deviation. 
 
Interim analyses will be conducted at each of the following milestones: 
• 
Approximately 15 subjects in the NTDT population have completed 12 weeks of treatment 
• 
Approximately 30 subjects in the TDT population have completed 24 weeks of treatment 
• 
Approximately 30 subjects in the NTDT population have completed 24 weeks of treatment 
• 
Approximately 60 subjects in the TDT population have completed 24 weeks of treatment 


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Protocol no: IMR-BTL-201 
 
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• 
Approximately 60 subjects in the NTDT population have completed 24 weeks of treatment 


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Protocol no: IMR-BTL-201 
 
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Figure 1: Overview of Study Design and Dose Groups 
 
 
 
* Prior to the introduction of IMR-687 higher dose, the DMC will review safety data for at least 5 subjects who received IMR-687 lower dose. If the DMC recommends 
inclusion of the higher dose, randomization across 3 dose groups will then proceed as shown. The DMC may request additional data and/or meeting(s) in order to 
make its recommendations. During study conduct under Protocol Version 4.0, the DMC approved the opening of enrollment in the higher dose IMR-687 group, which 
went into effect on 01 February 2021. 
Refer to Protocol Section 5.1 for additional details on the dose groups. 
Note: There will be an additional interim analysis (IA 0.5) for approximately 15 subjects in the NTDT population that have completed 12 weeks of treatment.


Statistical Analysis Plan 
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Protocol no: IMR-BTL-201 
 
Page 11 of 82 
 
8.1 Sample Size Considerations 
Both populations, TDT and NTDT have a primary objective of safety, therefore the population sample 
sizes are not based on statistical assumptions. 
8.1.1 Population 1: Transfusion-dependent β-thalassemia 
For the secondary efficacy endpoint of percentage of subjects with hematologic improvement (reduction 
in transfusion burden), 30 subjects in an active treatment arm and 20 subjects in the placebo arm will 
provide approximately 79% power to detect a difference of 10% of subjects improving in the placebo arm 
versus 50% of subjects improving in an active treatment arm, using a two-sided alpha level of 0.05. No 
multiple comparisons adjustments will be made as these are secondary analyses. 
8.1.2 Population 2: Non-transfusion-dependent β-thalassemia 
For the secondary efficacy endpoints of proportion of subjects with increase from Baseline of ≥1.0 g/dL in 
mean Hb values at Weeks 12 to 24 or Weeks 24 to 36, 30 subjects in an active arm and 15 subjects in 
the placebo arm will provide approximately 67% power to detect a difference of 10% of subjects 
improving in the placebo arm versus 50% of subjects improving in an active treatment arm, using a two-
sided alpha level of 0.05. No multiple comparisons adjustments will be made as these are secondary 
analyses. 
8.2 Randomization 
All subjects who are screened (including screen failures) will be assigned a unique subject identification 
number. 
On Day 1, eligible subjects in Population 1 (TDT Population) and Population 2 (NTDT Population) will be 
assigned another unique number (randomization number) in sequential order. The randomization number 
codes the subject’s initial treatment assignment according to the randomization schedule generated prior 
to the study. Initially, subjects will be randomly assigned in a 2:1 ratio to receive either IMR-687 lower 
dose or placebo. If the DMC recommends inclusion of the higher dose, randomization will then proceed in 
a 1:2:1 ratio (IMR-687 lower dose, IMR-687 higher dose, or placebo). 
Randomization schedules will be generated by Cytel, a subcontractor of the IXRS vendor Suvoda. 
Subject randomization will be stratified by TDT/NTDT status. 
Randomization number will not be reused once assigned. If a subject discontinues or is discontinued at 
the discretion of the investigator or DMC up to and including the Week 12 visit, the subject may be 
replaced with another subject, from the same TDT/NTDT stratum, meeting the eligibility criteria. In the 
event that a subject is replaced, the replacement subject will receive the same treatment as the replaced 
subject, and a different leading number will be used for the replacement randomization. Subjects who are 
replaced, or who are replacement subjects, will be included in the analyses sets according to the same 
criteria used for all other subjects, as described in Section 11.0. 
 Study Endpoints, Variables and Covariates 
 
Primary Endpoints 
TDT 
NTDT 
IMR-687 safety and tolerability assessed using: 
• 
Incidence and severity of adverse events and serious 
adverse events 
• 
Incidence of subjects with a post-Baseline clinically significant 
worsening in the CTCAE laboratory grade for a lab parameter  
X 
X 


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Protocol no: IMR-BTL-201 
 
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• 
Incidence of subjects with a post-Baseline clinically significant 
change in a vital signs parameter 
• 
Incidence of subjects meeting the clinically significant criteria for an 
electrocardiogram (ECG) parameter 
• 
Changes from Baseline in 12-lead ECG clinical laboratory test 
(chemistry, hematology, coagulation, and urinalysis), and vital signs 
parameters (continuous parameters only) 
• 
Changes in physical examination findings relative to the Baseline 
physical examination 
Secondary Endpoints 
TDT 
NTDT 
Proportion of subjects with a ≥20% reduction in RBC transfusion burden 
with a reduction of at least 2 units of RBCs (hematological improvement)  
for Week 12 to Week 24 and Week 24 to Week 36, compared to the 12 
weeks prior to Baseline (Day 1). 
X 
 
Proportion of subjects with a ≥20% reduction in RBC transfusion 
burden with a reduction of at least 2 units of RBCs (hematological 
improvement) for Week 12 to Week 36, compared to the 12 weeks 
prior to Baseline (Day 1). 
X 
 
Proportion of subjects with a ≥20% reduction in RBC transfusion 
burden with a reduction of at least 2 units of RBCs (hematological 
improvement) for any 12-week rolling time period – Day 2 to 85, Day 
3 to 86, etc. through Day 170 to Day 253 (Week 36) – compared to 
the 12 weeks prior to Baseline (Day 1). 
X 
 
Proportion of subjects with a ≥20% reduction in RBC transfusion 
burden with a reduction of at least 2 units of RBCs (hematological 
improvement) for any 14-week rolling time period – Day 2 to 99, Day 
3 to 100, etc. through Day 156 to Day 253 (Week 36) – compared to 
the 12 weeks prior to Baseline (Day 1). 
X 
 
Proportion of subjects with a ≥33% reduction in RBC transfusion burden 
with a reduction of at least 2 units of RBCs (hematological improvement) 
for Week 12 to Week 24 and Week 24 to Week 36, compared to the 12 
weeks prior to Baseline (Day 1). 
X 
 
Proportion of subjects with a ≥33% reduction in RBC transfusion 
burden with a reduction of at least 2 units of RBCs (hematological 
improvement) for Week 12 to Week 36, compared to the 12 weeks 
prior to Baseline (Day 1). 
X 
 
Proportion of subjects with a ≥33% reduction in RBC transfusion 
burden with a reduction of at least 2 units of RBCs (hematological 
improvement) for any 12-week rolling time period – Day 2 to 85, Day 
3 to 86, etc. through Day 170 to Day 253 (Week 36) – compared to 
the 12 weeks prior to Baseline (Day 1). 
X 
 
Proportion of subjects with a ≥33% reduction in RBC transfusion 
burden with a reduction of at least 2 units of RBCs (hematological 
improvement) for any 14-week rolling time period – Day 2 to 99, Day 
3 to 100, etc. through Day 156 to Day 253 (Week 36) – compared to 
the 12 weeks prior to Baseline (Day 1). 
X 
 


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Proportion of subjects with a ≥50% reduction in RBC transfusion 
burden with a reduction of at least 2 units of RBCs (hematological 
improvement) for Week 12 to Week 24 and Week 24 to Week 36, 
compared to the 12 weeks prior to Baseline (Day 1). 
X 
 
Proportion of subjects with a ≥50% reduction in RBC transfusion 
burden with a reduction of at least 2 units of RBCs (hematological 
improvement) for Week 12 to Week 36, compared to the 12 weeks 
prior to Baseline (Day 1). 
X 
 
Proportion of subjects with a ≥50% reduction in RBC transfusion 
burden with a reduction of at least 2 units of RBCs (hematological 
improvement) for any 12-week rolling time period – Day 2 to 85, Day 
3 to 86, etc. through Day 170 to Day 253 (Week 36) – compared to 
the 12 weeks prior to Baseline (Day 1). 
X 
 
Proportion of subjects with a ≥50% reduction in RBC transfusion 
burden with a reduction of at least 2 units of RBCs (hematological 
improvement) for any 14-week rolling time period – Day 2 to 99, Day 
3 to 100, etc. through Day 156 to Day 253 (Week 36) – compared to 
the 12 weeks prior to Baseline (Day 1). 
X 
 
Mean number of transfusion events from Baseline to Week 36. 
X 
 
The plasma PK profile of IMR-687 after administration to subjects will be 
evaluated by determination of PK parameters, as appropriate, for Study 
Day 1 and Week 3/Week 4 and population PK, based on drug 
concentration levels in plasma obtained over time. 
X 
X 
Mean change from Baseline to Week 36 for iron chelation therapy daily 
dose and serum ferritin. 
X 
X 
Proportion of subjects with an increase from Baseline of ≥1.0 g/dL in mean 
Hb values at Weeks 12 to 24 and Weeks 24 to 36 in the absence of 
transfusions. 
 
X 
Mean change from Baseline in mean Hb values at Weeks 12 to 24 
and Weeks 24 to 36 in the absence of transfusions. 
 
X 
Mean change from Baseline in mean HbF values at Weeks 12 to 24 
and Weeks 24 to 36 in the absence of transfusions. 
 
X 
Proportion of subjects with an increase from Baseline of ≥3% in mean HbF 
values at Weeks 12 to 24 and Weeks 24 to 36 in the absence of 
transfusions. 
 
X 
Exploratory Endpoints 
TDT 
NTDT 
The PD effects of IMR-687 from Baseline to Week 36, as measured by 
the mean change from Baseline in serum PD markers of erythropoiesis, 
iron metabolism, and hemolysis. 
X 
X 
Mean change in transfusion burden expressed as units of RBCs as a 
continuous variable during Week 12 to Week 24, Week 24 to Week 36, 
and Week 12 to Week 36, compared to the 12 weeks prior to Baseline 
(Day 1). 
X 
 


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The proportion of subjects who are transfusion independent for ≥8 weeks 
during treatment. 
X 
 
Mean change from Baseline in TranQOL quality of life tool at Weeks 12, 
24, and 36. 
X 
 
Mean change from Baseline in SF-36 quality of life tool at Weeks 12, 24, 
and 36. 
X 
X 
Pharmacogenomic analyses of genes that may affect treatment response 
(including α-globin, gamma-globin XmnI polymorphism, and BCL11A). 
X 
X 
Proportion of subjects who have an Hb increase of ≥1.0 g/dL from Baseline 
for ≥14 days in the absence of RBC transfusions. 
 
X 
Proportion of subjects who are RBC transfusion-free over 36 weeks and 
other variables of transfusion burden. 
 
X 
Duration of the mean Hb increase from Baseline of ≥1.0 g/dL over 
36 weeks. 
 
X 
Proportion of subjects who have an increase from Baseline ≥1.5 g/dL in 
mean of Hb values at Week 24 and Week 36 compared to Baseline in 
the absence of transfusions. 
 
X 
Mean number of transfusion events from Baseline to Week 24. 
X 
 
Mean change from Baseline in NTDT-PRO tiredness/weakness (T/W) 
domain score over a continuous 12-week interval from Week 12 to Week 24 
and Week 24 to Week 36. 
 
X 
Mean change from Baseline in NTDT-PRO total score and T/W domain 
score at Week 24 and Week 36. 
 
X 
Mean change in biomarkers from Baseline to Week 36, stratified by 
genotype.a 
X 
X 
Time to first Hb increase (≥1.0 g/dL) 
 
X 
ECG = electrocardiogram; Hb = hemoglobin; HbF = fetal hemoglobin; LDH = lactate dehydrogenase; NTDT = 
non-transfusion dependent β-thalassemia; NTDT-PRO = non-transfusion dependent β-thalassemia patient 
reported outcome; PD = pharmacodynamics; PK = pharmacokinetics; pRBC = packed red blood cells; PRO = 
patient-reported outcome; RBC = red blood cell; SF-36 = Short Form (36) Health Survey; tmax = time to maximum 
plasma concentration; TDT = transfusion dependent β-thalassemia; TranQOL = transfusion-dependent quality of 
life. 
a See Section 13.6.8 for list of biomarkers. 
 
 
 


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 Conventions and Derivations 
10.1.1 Method for Handling Missing Data 
There will be no imputation of incomplete or missing data unless otherwise specified in this SAP.  
Please refer to Appendix 3 for specific data handling rules, including missing last dose date for the interim 
analysis, missing severity/relationship of adverse events, incomplete/missing dates for adverse events 
and prior/concomitant medications, interpretation of non-numeric results (e.g. “< BLQ”, “>x.xx”) from PK 
and laboratory measures, etc.  
10.1.2 Definition of Baseline and Change from Baseline Values 
Unless otherwise specified, Baseline is defined as the last non-missing measurements prior to the first 
dose of study drug.   
The ECG Baseline and post-Baseline values are averages of the triplicate assessments. The change 
from Baseline is the difference between the post-Baseline and Baseline averages. 
In analyses of pharmacodynamics (PD), including specialty hematology parameters, Baseline is defined 
as the average of non-missing values from the screening and Baseline visits. PD assessments include 
laboratory measurements based on blood samples as listed in sections 13.6.7 and 13.6.8.  
10.1.3 Definition of Study Days 
Study Day 1 is defined as the date on which subjects are administered their first dose of study drug. For 
visits (or events) that occur on or after the date of the first dose of study drug, study day is defined as 
(date of visit [event] – date of first dose of study drug + 1). For visits (or events) that occur prior to Study 
Day 1, study day is defined as (date of visit [event] – date of first dose of study drug). There is no Study 
Day 0. 
10.1.4 Definition of Treatment-Emergence 
A treatment-emergent adverse event (TEAE) is defined as an AE that starts after initiation of study drug, 
or an AE that existed pre-treatment and worsened in severity after initiation of study drug, through 30 
days after the last dose of study drug.  
10.1.5 Red Blood Cell Transfusion Reduction: 12-Week Fixed Interval 
Transfusion burden will be measured using a “fixed” 12-week time interval. The 12-week intervals used 
for analysis are defined as: 
Pre-treatment 12-week interval: from Day -83 to Day 1; 
Week 13–24 interval: from Day 86 to Day 169; 
Week 25–36 interval: from Day 170 to Day 253. 
10.1.6 Red Blood Cell Transfusion Reduction: 24-Week Fixed Interval 
Transfusion burden will also be measured using a “fixed” 24-week time interval. The 24-week intervals 
used for analysis are defined as below.  
Pre-treatment 12-week interval: from Day -83 to Day 1; 
Week 13–36 interval: from Day 86 to Day 253. 
10.1.7 Red Blood Cell Transfusion Reduction: 12-Week Rolling Interval 
Transfusion reduction will also be measured using any consecutive “rolling” 12-week time intervals during 
the study, e.g., Days 2 to 85, Day 3 to 86 and so on, compared to the pre-treatment 12-week interval 
(from Day-83 to Day 1). A transfusion occurring on Day 1 belongs to the pre-treatment period. 


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10.1.8 Red Blood Cell Transfusion Reduction: 14-Week Rolling Interval 
Transfusion reduction will also be measured using any consecutive “rolling” 14-week time intervals during 
the study, e.g., Days 2 to 99, Day 3 to 100 and so on. Day 1 transfusion belongs to baseline. 
10.1.9 Quality of Life Assessments 
Quality of life will be assessed using the TranQOL and SF-36 QoL tools in the TDT population and the 
NTDT-PRO and SF-36 QoL tools in the NTDT population. 
The TranQOL (Klaassen 2013; Klaassen 2014. See protocol section 16.) is a disease-specific QoL 
measure for children and adults with thalassemia major. It has four versions: (i) a child self-report; (ii) an 
adult self-report; (iii) a parent self-report (measuring the impact of the disease on the parent), and (iv) a 
parent proxy report (measuring the child’s QoL). The questionnaire length ranges from 29 items (child) to 
39 items (parent). The questions are grouped into 4 domains: physical health, emotional health, family 
functioning, and school and career functioning. The adult and parent self-report questionnaires include a 
fifth category on sexual activity which is only one item. For this study, only the adult self-report will be 
used which includes 36 items and an open-ended question: “Was there anything else that bothered 
you?”. The mean TranQOL score for each domain ranges from 0 to 100 with higher scores indicating 
higher QoL. Derivations for domain scores are specified in Section 13.6.6.1. A within-patient clinically 
meaningful change from baseline was defined as a ≥ 4-point change for the TranQol total score 
(Cappellini 2020). The criteria may be modified based on further research. 
The SF-36 (Hays 2004. See protocol section 16.) is a 36-item, patient reported survey of patient health. 
The SF-36 consists of 8 scaled scores, which are the weighted sums of the questions in their section. 
Each scale is directly transformed into a 0 to 100 scale based on each scale having equal weight. The 
lower the score the more disability and the higher the score the less disability (i.e., a score of 0 is 
equivalent to a maximum disability and a score of 100 is equivalent to no disability). The 8 sections are: 
vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional 
role functioning, social role functioning, and mental health. Derivations for the scales and component 
scores are specified in Section 13.6.6.1. A within-patient clinically meaningful change from baseline was 
defined as 3.8–7.0-point improvement, based on the prespecified domain-specific cutoff values for the 
domains of the SF-36 questionnaire (Cappellini 2020). 
The NTDT-PRO (Taher 2019. See protocol section 16.) is a new disease-specific health-related QoL tool 
for patients with NTDT. The NTDT-PRO was designed as a daily diary with recall of thalassemia-related 
symptoms over the previous 24 hours. The relatively short recall period is used due to the high level of 
day-to-day variation in symptoms experienced by patients with NTDT. The 6 NTDT-PRO items assess the 
presence or severity of specific symptoms using a numerical ration scale ranging from 0 
(“absent/minimal”) to 10 (“extreme/high”): tiredness with or without physical activity, weakness with or 
without physical activity, and shortness of breath (SOB) with or without physical activity. NTDT-PRO items 
are grouped into 2 domains: tiredness/weakness (T/W) (tiredness with physical activity, tiredness without 
physical activity, weakness with physical activity, and weakness without physical activity) and shortness 
of breath (shortness of breath with physical activity, shortness of breath without physical activity). The 
total score is an average of the responses to questions 1-6. For this study, the NTDT-PRO will not be 
used as a daily diary; data will be collected at Baseline and at Weeks 12, 24, and 36. Derivations for 
domain scores and the total score are specified in Section 13.6.6.3. 
10.1.10 Windowing Conventions 
All scheduled study visits are defined relative to Study Day 1, the date of first dose. Scheduled visit 
windows are defined in Appendix 3. A windowing convention will be used to determine the analysis visit 
value for a given measurement and will be applicable for all by-visit summaries and analyses for efficacy 
and safety data. Refer to Table 1 (TDT) and Table 2 (NTDT) for specific visit windows. 


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Table 1: 
Visit Windows for Efficacy and Safety Analyses – TDT Population 
Safety Analyses – Vital Signs and Weight 
Scheduled Study Visit (Protocol Scheduled Day) 
Analysis Visit Window (Study Day) 
Baseline 
≤ 1 
Week 1 (Day 7 ± 2)  
2 to 15 
Week 3 (Day 21 ± 7) 
16 to 32 
Week 6 (Day 42 ± 7) 
33 to 53 
Week 9 (Day 63 ± 7) 
54 to 74 
Week 12 (Day 84 ± 7) 
75 to 95 
Week 15 (Day 105 ± 7) 
96 to 116 
Week 18 (Day 126 ± 7) 
117 to 137 
Week 21 (Day 147 ± 7) 
138 to 158 
Week 24 (Day 168 ± 7) 
159 to 179 
Week 27 (Day 189 ± 7) 
180 to 200 
Week 30 (Day 210 ± 7) 
201 to 221 
Week 33 (Day 231 ± 7) 
222 to 242 
Week 36 (Day 252 ± 7) 
243 to 267 
Week 40 (Day 280 ± 7) 
≥ 268 
Safety Analyses – 12-Lead ECG, Hematology (Except Specialty Hematology) and Chemistry 
Scheduled Study Visit (Protocol Scheduled Day) 
Analysis Visit Window (Study Day) 
Baseline 
≤ 1 
Week 1 (Day 7 ± 2)  
2 to 15 
Week 3 (Day 21 ± 7) 
16 to 32 
Week 6 (Day 42 ± 7) 
33 to 64 
Week 12 (Day 84 ± 7) 
65 to 106 
Week 18 (Day 126 ± 7) 
107 to 148 
Week 24 (Day 168 ± 7) 
149 to 190 
Week 30 (Day 210 ± 7) 
191 to 232 
Week 36 (Day 252 ± 7) 
233 to 267 
Week 40 (Day 280 ± 7) 
≥ 268 
Safety Analyses – Urinalysis 
Scheduled Study Visit (Protocol Scheduled Day) 
Analysis Visit Window (Study Day) 
Baseline 
≤ 1 


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Week 3 (Day 21 ± 7) 
2 to 53 
Week 12 (Day 84 ± 7) 
54 to 127 
Week 24 (Day 168 ± 7) 
128 to 211 
Week 36 (Day 252 ± 7) 
≥212 
Safety Analyses – Coagulation 
Scheduled Study Visit (Protocol Scheduled Day) 
Analysis Visit Window (Study Day) 
Baseline 
≤ 1 
Week 12 (Day 84 ± 7) 
2 to 127 
Week 24 (Day 168 ± 7) 
128 to 211 
Week 36 (Day 252 ± 7) 
≥212 
Efficacy Analyses – Specialty Hematology 
Scheduled Study Visit (Protocol Scheduled Day) 
Analysis Visit Window (Study Day) 
Baseline 
≤ 1 
Week 3 (Day 21 ± 7) 
2 to 53 
Week 12 (Day 84 ± 7) 
54 to 106 
Week 18 (Day 126 ± 7) 
107 to 148 
Week 24 (Day 168 ± 7) 
149 to 190 
Week 30 (Day 210 ± 7) 
191 to 232 
Week 36 (Day 252 ± 7) 
≥233 
Efficacy Analyses- PD Biomarkers 
Scheduled Study Visit (Protocol Scheduled Day) 
Analysis Visit Window (Study Day) 
Baseline 
≤ 1 
Week 3 (Day 21 ± 7) 
2 to 53 
Week 12 (Day 84 ± 7) 
54 to 106 
Week 18 (Day 126 ± 7) 
107 to 148 
Week 24 (Day 168 ± 7) 
149 to 211 
Week 36 (Day 252 ± 7) 
≥212 
QoL  
Scheduled Study Visit (Protocol Scheduled Day) 
Analysis Visit Window (Study Day) 
Baseline 
≤ 1 
Week 12 (Day 84 ± 5) 
2 to 127 
Week 24 (Day 168 ± 7) 
128 to 211 
Week 36 (Day 252 ± 7) 
≥212 


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Table 2: 
Visit Windows for Efficacy and Safety Analyses – NTDT Population 
Safety Analyses – Vital Signs, Weight, 12-Lead ECG, Hematology (Except Specialty 
Hematology) and Chemistry 
Scheduled Study Visit (Protocol Scheduled Day) 
Analysis Visit Window (Study Day) 
Baseline 
≤ 1 
Week 1 (Day 7 ± 2)  
2 to 18 
Week 4 (Day 28 ± 5) 
19 to 43 
Week 8 (Day 56 ± 7) 
44 to 71 
Week 12 (Day 84 ± 7) 
72 to 99 
Week 16 (Day 112 ± 7) 
100 to 127 
Week 20 (Day 140 ± 7) 
128 to 155 
Week 24 (Day 168 ± 7) 
156 to 183 
Week 28 (Day 196 ± 7) 
184 to 211 
Week 32 (Day 224 ± 7) 
212 to 239 
Week 36 (Day 252 ± 7) 
240 to 267 
Week 40 (Day 280 ± 7) 
≥ 268 
Safety Analyses – Urinalysis 
Scheduled Study Visit (Protocol Scheduled Day) 
Analysis Visit Window (Study Day) 
Baseline 
≤ 1 
Week 4 (Day 28 ± 5) 
2 to 57 
Week 12 (Day 84 ± 7) 
58 to 127 
Week 24 (Day 168 ± 7) 
128 to 211 
Week 36 (Day 252 ± 7) 
≥212 
Safety Analyses – Coagulation 
Scheduled Study Visit (Protocol Scheduled Day) 
Analysis Visit Window (Study Day) 
Baseline 
≤ 1 
Week 12 (Day 84 ± 7) 
2 to 127 
Week 24 (Day 168 ± 7) 
128 to 211 
Week 36 (Day 252 ± 7) 
≥212 
Efficacy Analyses – Specialty Hematology 
Scheduled Study Visit (Protocol Scheduled Day) 
Analysis Visit Window (Study Day) 
Baseline 
≤ 1 
Week 4 (Day 28 ± 5) 
2 to 57 


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Week 12 (Day 84 ± 7) 
58 to 127 
Week 24 (Day 168 ± 7) 
128 to 211 
Week 36 (Day 252 ± 7) 
≥212 
Efficacy Analyses- PD Biomarkers 
Scheduled Study Visit (Protocol Scheduled Day) 
Analysis Visit Window (Study Day) 
Baseline 
≤ 1 
Week 4 (Day 28 ± 5) 
2 to 57 
Week 12 (Day 84 ± 7) 
58 to 127 
Week 24 (Day 168 ± 7) 
128 to 211 
Week 36 (Day 252 ± 7) 
≥212 
QoL  
Scheduled Study Visit (Protocol Scheduled Day) 
Analysis Visit Window (Study Day) 
Baseline 
≤ 1 
Week 12 (Day 84 ± 5) 
2 to 127 
Week 24 (Day 168 ± 7) 
128 to 211 
Week 36 (Day 252 ± 7) 
≥212 
 
Windowing will be applied prior to any missing data calculations. The last non-missing measurement 
taken prior to the date of first dose (including unscheduled assessments) will be labeled as “Baseline”. 
Screening visits that occurred before the Baseline visit will not be assigned an analysis visit. The early 
discontinuation visit will be eligible for allocation to an analysis visit.  
If one or more results for a variable are assigned to the same analysis visit, the result with the date 
closest to the protocol scheduled day will be used in the analysis. If 2 measurements in the same analysis 
visit window are equidistant from the protocol scheduled study day, the earliest measurement will be used 
in the analysis. If multiple assessments are available on the same day (for the same time point), then the 
average of the assessment will be used in the analysis. If both central and local assessments of the same 
lab test are available for the same visit, the central result will take precedence over the local result if 
baseline is collected centrally. If a scheduled assessment is missing, due to clotting for example, and an 
unscheduled retest assessment is available in the visit window for the scheduled visit, the unscheduled 
retest assessment may be used in place of the missing scheduled assessment.  
 Analysis Sets 
Analysis Set 
Definition 
Use 
How Analyzed 
Safety 
All subjects who received at least one dose of 
study drug. 
Safety and 
tolerability 
According to actual 
treatment received 
ITT 
All subjects who are randomized. 
PD and 
Efficacy 
According to 
randomized 
treatment assigned 


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Analysis Set 
Definition 
Use 
How Analyzed 
mITT 
All subjects who are randomized and received 
at least one dose of study drug. 
If all randomized subjects are dosed, the mITT 
Analysis Set will not be created and the ITT 
Analysis Set will be used. 
PD and 
Efficacy 
According to 
randomized 
treatment assigned 
PP 
All subjects in the Safety Analysis Set who 
have provided sufficient data without major 
protocol deviations or events that would be 
expected to affect the analysis.  
Sufficient data is defined as any post-baseline 
assessment and subject did not discontinue 
prior to Week 12 for reasons other than AEs. 
PD and 
Efficacy 
According to actual 
treatment received 
PK (Analysis) 
All subjects in the Safety Analysis Set who 
have received at least 1 dose of IMR-687 and 
have any measurable postdose IMR-687 
concentration-time data. 
PK 
concentrations  
According to actual 
treatment received 
PK (Evaluable) 
All subjects in the Safety Analysis Set who 
have received at least 1 dose of IMR-687 and 
have at least 4 consecutive non-zero postdose 
IMR-687 concentration-time data points. 
PK 
parameters 
According to actual 
treatment received 
 
11.1 Safety Analysis Set 
The Safety Analysis Set will include all subjects who have received at least one dose of study drug and 
will be used to summarize all safety and tolerability data. In safety summaries, subjects will be analyzed 
according to the actual treatment they received.  
11.2 Intent-to-Treat Analysis Set 
The ITT Analysis Set will include all subjects who are randomized. Subjects will be analyzed according to 
their randomized treatment. The ITT Analysis Set will be used for PD and efficacy analyses. 
11.3 Modified Intent-to-Treat Analysis Set 
In the event that any subjects are randomized but not dosed, a mITT Analysis Set will be created that will 
include all subjects who are randomized and receive at least one dose of study drug. Subjects will be 
analyzed according to their randomized treatment. The mITT Analysis Set will be used for PD and 
efficacy analyses.  
11.4 Per Protocol Analysis Set 
The Per Protocol Analysis Set will include all subjects in the Safety Analysis Set who have provided 
sufficient data without major protocol deviations or events that would be expected to affect the analysis. 
Sufficient data is defined as any post-baseline assessment and subject did not discontinue prior to week 
12 for reasons other than AEs. The PP Analysis Set will be identified based on blinded data prior to 
unblinding the final analysis dataset, and the TDT and NTDT populations may have their PP Analysis Set 
components defined at different times. The PP Analysis Set will be the primary analysis set used for PD 
and efficacy analyses. Subjects will be analyzed according to their randomized treatment.  


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11.5 PK Analysis Set 
The PK Analysis Set will be defined as all subjects in the Safety Analysis Set who are randomized, have 
received at least 1 dose of IMR-687, and have any measurable postdose IMR-687 concentration data. 
The PK Analysis Set will be used to generate the corresponding PK concentration summaries and plots. 
11.6 PK Evaluable Set 
The PK Evaluable Set will be defined as all subjects in the Safety Analysis Set who are randomized, have 
received at least 1 dose of IMR-687, and have at least 4 consecutive non-zero postdose IMR-687 
concentration-time data points. The PK Evaluable Set will be used to generate the corresponding PK 
parameter assessments. 
 Interim Analyses 
There will be five unblinded interim analyses (IA) conducted at each of the following milestones: 
• 
IA 0.5: Approximately 15 subjects in the NTDT population have completed 12 weeks of treatment 
• 
IA 1.0: 
o 
Approximately 30 subjects in the TDT population have completed 24 weeks of treatment 
o 
Approximately 30 subjects in the NTDT population have completed 24 weeks of 
treatment 
• 
IA 2.0:  
o 
Approximately 60 subjects in the TDT population have completed 24 weeks of treatment  
o 
Approximately 60 subjects in the NTDT population have completed 24 weeks of 
treatment  
 
To facilitate the IAs, certain Sponsor representatives and designees may be unblinded to individual 
treatment assignments prior to and during the IA (including the unblinded clinical research organization 
(CRO) biostatistician and external groups for bioanalytical, PK, PK/PD analyses, and QoL analyses). 
Details are provided in the study unblinding plan. The blinded Sponsor and CRO study team members 
may be unblinded to the group analysis results (but not individual subject results) at the conclusion of the 
IA(s).   
 
The IA(s) will include the primary endpoint analyses, selected secondary/ exploratory endpoint analyses 
and baseline summaries. The IA analyses will be performed by an unblinded statistical and programming 
team. No alpha spending will be used. 
 
The following is a summary of the key IA tables and figures that will be provided at each IA. Additional IA 
analyses may be added/provided per Imara request/decision. More detailed analyses information will be 
provided in section 13.0 of the SAP. 
 
No minimum and maximum values will be populated on tables and no scattered values will be populated 
on the boxplots, in order to ensure that group blinding is maintained. Further, to avoid unblinding, at IA’s 
0.5 and 1.0, adverse event tables will only present Placebo and pooled IMR-687 dose columns. In the 
Overall Summary of Treatment-Emergent Adverse Events tables, only AE categories with 10% or higher 
in the pooled IMR-687 dose column will be presented. In the remaining Adverse Events tables, only 
preferred terms with 10% or higher in the pooled IMR-687 dose column will be presented. Imara Blinded 
team members will only be group unblinded and cannot be exposed to that information as it could be 
potentially unblinding.  
 
 
 
 
 
 


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Table 3: 
Interim Analysis Tables – TDT Population 
Outputs 
Analysis 
Number 
Timepoints 
Analysis Set(s) 
Tables 
 
Subject Disposition 
IA 1.0, 2.0 
FA 
N/A 
All Screened Subjects 
Demographics and Baseline Characteristics 
IA 1.0, 2.0 
FA 
N/A 
Safety Analysis Set 
Disease History 
IA 1.0, 2.0 
FA 
N/A 
Safety Analysis Set 
Proportion of subjects with ≥20%, 33%, and 50% 
reduction in RBC transfusion burden with a 
reduction of at least 2 units of RBCs 
(hematological improvement) – fixed time periods 
  
IA 1.0  
Week 12 to 24 
Per Protocol Analysis Set 
 
IA 2.0 
Week 12 to 24 
Per protocol analysis set/ 
ITT analysis set 
 
FA 
Week 12 to 24, 
Week 24 to 36, 
Week 12 to 36 
Per protocol analysis set/ 
ITT (mITT) Analysis Set 
 
Proportion of subjects with ≥20%, 33%, and 50% 
reduction in RBC transfusion burden with a 
reduction of at least 2 units of RBCs 
(hematological improvement) – rolling time 
periods 
IA 1.0  
Rolling time periods 
– Days 2 to 85, Day 
3 to 86 and so on 
through Day 86 to 
169, compared to 
the 12-week 
interval prior to 
Baseline (Day 1) 
Per Protocol Analysis Set 
IA 2.0 
Rolling time periods 
– Days 2 to 85, Day 
3 to 86 and so on 
through Day 86 to 
169, compared to 
the 12-week 
interval prior to 
Baseline (Day 1) 
Per Protocol Analysis Set/ 
ITT Analysis Set 
FA 
Rolling time periods 
– Days 2 to 85, Day 
3 to 86 and so on 
through Day 170 to 
253 (Week 36), 
compared to the 
12-week interval 
prior to Baseline 
(Day 1) 
Per Protocol Analysis Set/ 
ITT (mITT) Analysis Set 
Change and Percent Change from Baseline in 
mean Hb, Specialty Hematology, and PD 
parameters (listed in Sections 13.6.7 and 13.6.8) 
IA 1.0  
1.Week 12 to 24 
Mean 
2.Descriptive 
statistics by visit  
 
Per Protocol Analysis Set 


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Outputs 
Analysis 
Number 
Timepoints 
Analysis Set(s) 
IA 2.0 
1.Week 12 to 24 
Mean 
2.Descriptive 
statistics by visit 
3.MMRM of all 
visits up to Week 
24 (Change only) 
Per Protocol Analysis Set/ 
ITT Analysis Set 
FA 
1.Week 12 to 24 
Mean, Week 24 to 
36 Mean 
2.Descriptive 
statistics by visit 
3.MMRM of all 
visits up to Week 
36 (Change only) 
Per Protocol Analysis Set/ 
ITT (mITT) Analysis Set 
Mean number of transfusion events 
IA 2.0 
Through Week 24 
Per Protocol Analysis Set/ 
ITT Analysis Set 
FA 
Through Week 36 
Per Protocol Analysis Set/ 
ITT (mITT) Analysis Set 
Mean change in transfusion burden 
IA 2.0 
Week 12 to Week 
24, compared to 
the 12-week prior 
to Baseline (Day 1) 
Per Protocol Analysis Set/ 
ITT Analysis Set 
FA 
Week 12 to Week 
24, Week 24 to 
Week 36, and 
Week 12 to Week 
36, compared to 
the 12-week prior 
to Baseline (Day 1) 
Per Protocol Analysis Set/ 
ITT (mITT) Analysis Set 
Proportion of subjects who are transfusion-free 
(independent) for ≥8 weeks during treatment 
IA 2.0 
Through Week 24 
Per Protocol Analysis Set/ 
ITT Analysis Set 
FA 
Through Week 36 
Per Protocol Analysis Set/ 
ITT (mITT) Analysis Set 
Proportion of subjects who are RBC transfusion-
free (independent) 
IA 2.0 
Over 24 Weeks 
Per Protocol Analysis Set/ 
ITT Analysis Set 
FA 
Over 36 Weeks 
Per Protocol Analysis Set/ 
ITT (mITT) Analysis Set 
Average number of days between transfusions 
IA 2.0 
Through Week 24 
Per Protocol Analysis Set/ 
ITT Analysis Set 
FA 
Over 36 weeks 
Per Protocol Analysis Set/ 
ITT (mITT) Analysis Set 
Change from Baseline in mean pre-transfusion Hb 
values at Weeks 12 to 24  
[using pre-transfusion Hb from the Historical 
Transfusion Burden and the Transfusion Burden 
CRFs] 
IA 2.0 
Baseline to Week 
12 to Week 24 
Per Protocol Analysis Set/ 
ITT Analysis Set 
FA 
Baseline to Week 
12 to Week 24, 
Week 24 to Week 
36, and Week 12 to 
Week 36 
Per Protocol Analysis Set/ 
ITT (mITT) Analysis Set 
Proportion of subjects with an increase from 
Baseline of ≥1.0 g/dL in mean pre-transfusion Hb 
IA 2.0 
Week 12 to Week 
24 
Per Protocol Analysis Set/ 
ITT Analysis Set 


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Protocol no: IMR-BTL-201 
 
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Outputs 
Analysis 
Number 
Timepoints 
Analysis Set(s) 
values or a Reduction in RBC Transfusion Burden 
(≥33% reduction) Endpoint  
[using pre-transfusion Hb from the Historical 
Transfusion Burden and the Transfusion Burden 
CRFs] 
FA 
Week 24 to Week 
36, Week 12 to 
Week 36 
Per Protocol Analysis Set/ 
ITT (mITT) Analysis Set 
Mean change from Baseline for Serum ferritin 
 
IA 1.0  
Week 24 
Per Protocol Analysis Set 
IA 2.0 
Week 24 
Per Protocol Analysis Set/ 
ITT Analysis Set 
FA 
Week 24, 36 
Per Protocol Analysis Set/ 
ITT (mITT) Analysis Set 
Mean change from Baseline for Iron chelation 
therapy daily dose 
IA 2.0 
Week 24 
Per Protocol Analysis Set/ 
ITT Analysis Set 
FA 
Week 24, 36 
Per Protocol Analysis Set/ 
ITT (mITT) Analysis Set 
Mean change from Baseline in TranQOL quality of 
life tool 
IA 2.0 
Weeks 12, 24 
ITT Analysis Set 
FA 
Weeks 12, 24, and 
36 
ITT (mITT) Analysis Set 
Mean change from Baseline in SF-36 quality of 
life 
IA 2.0 
Weeks 12, 24 
ITT analysis set 
FA 
Weeks 12, 24, and 
36 
ITT (mITT) Analysis Set 
Summary of exposure 
IA 1.0, 2.0 
All available data 
up to Week 24 at 
the time of IA 
Safety Analysis Set 
FA 
All available data 
Safety Analysis Set 
Overall summary of TEAEs 
IA 1.0, 2.0 
All available data 
up to Week 24 at 
the time of IA 
Safety Analysis Set 
FA 
All available data 
Safety Analysis Set 
TEAEs by SOC & PT 
IA 1.0, 2.0 
All available data 
up to Week 24 at 
the time of IA 
Safety Analysis Set 
FA 
All available data 
Safety Analysis Set 
TEAEs by PT 
IA 1.0, 2.0 
All available data 
up to Week 24 at 
the time of IA 
Safety Analysis Set 
FA 
All available data 
Safety Analysis Set 
Drug-related TEAEs by SOC & PT 
 
IA 1.0, 2.0 
All available data 
up to Week 24 at 
the time of IA 
Safety Analysis Set 
FA 
All available data 
Safety Analysis Set 
Drug-related TEAEs by PT 
IA 1.0, 2.0 
All available data 
up to Week 24 at 
the time of IA 
Safety Analysis Set 
FA 
All available data 
Safety Analysis Set 
TEAEs by SOC, PT & severity 
IA 1.0, 2.0 
All available data 
up to Week 24 at 
the time of IA 
Safety Analysis Set 
FA 
All available data 
Safety Analysis Set 


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Outputs 
Analysis 
Number 
Timepoints 
Analysis Set(s) 
Mean pharmacokinetic parameters for IMR-687 
by dose and by study visit 
IA 1.0 
All available data 
up to Week 24 
PK Evaluable Set 
FA 
All available data 
PK Evaluable Set 
Figures 
 
Bar plot of proportion of subjects with reduction in 
RBC transfusion burden (hematological 
improvement) by treatment arm 
IA 1.0  
Week 12 to 24 
Per Protocol Analysis Set 
IA 2.0 
Week 12 to 24 
Per Protocol Analysis Set/ 
ITT Analysis Set 
FA 
Week 12 to 24, 
Week 24 to 36, 
Week 12 to 36 
Per Protocol Analysis Set/ 
ITT (mITT) Analysis Set 
Arithmetic mean (± SD) plasma concentration of 
IMR-687 by dose and by study visit (linear and 
semi-logarithmic scale) 
1.0 
All available data 
up to Week 3 
PK Analysis Set 
FA 
All available data 
PK Analysis Set 
 
 
Table 4: 
Interim Analysis Tables – NTDT Population 
Outputs 
Analysis 
Number 
Timepoints 
Analysis Set(s) 
Tables 
 
Subject Disposition 
IA 0.5, 1.0, 2.0 
FA 
N/A 
All Screened Subjects 
Demographics and Baseline Characteristics 
IA 0.5, 1.0, 2.0 
FA 
N/A 
Safety Analysis Set 
Disease History 
IA 0.5, 1.0, 2.0 
FA 
N/A 
Safety Analysis Set 
Responder analysis - Analysis of proportion of 
subjects with ≥3% increase from baseline in 
mean HbF in the absence of transfusions 
 
IA 0.5, 1.0  
Week 12 to Week 
24 
Per Protocol Analysis Set 
IA 2.0 
Week 12 to Week 
24 
Per Protocol Analysis Set/ 
ITT Analysis Set 
FA 
Week 12 to Week 
24, and Week 24 
to Week 36 
Per Protocol Analysis Set/ 
ITT (mITT) Analysis Set 
Responder analysis - Analysis of proportion of 
subjects with ≥3% increase from baseline in 
HbF in the absence of transfusions [sensitivity 
analysis] 
IA 1.0, 2.0  
Week 24 
Per Protocol Analysis Set/ 
ITT Analysis Set 
FA 
Week 24, Week 
36 
Per Protocol Analysis Set/ 
ITT (mITT) Analysis Set 
Responder analysis - Analysis of proportion of 
subjects with ≥1.0 g/dL increase from baseline 
in mean Hb in the absence of transfusions 
IA 0.5, 1.0  
Week 12 to Week 
24 
Per Protocol Analysis Set 
IA 2.0 
Week 12 to Week 
24 
Per Protocol Analysis Set/ 
ITT Analysis Set 
FA 
Week 12 to Week 
24, and Week 24 
to Week 36 
Per Protocol Analysis Set/ 
ITT (mITT) Analysis Set 
Responder analysis - Analysis of proportion of 
subjects with ≥1.0 g/dL increase from baseline 
IA 1.0, 2.0  
Week 24 
Per Protocol Analysis Set/ 
ITT Analysis Set 


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Protocol no: IMR-BTL-201 
 
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Outputs 
Analysis 
Number 
Timepoints 
Analysis Set(s) 
in Hb in the absence of transfusions [sensitivity 
analysis] 
FA 
Week 24, Week 
36 
Per Protocol Analysis Set/ 
ITT (mITT) Analysis Set 
Responder analysis - Analysis of proportion of 
subjects with ≥1.5 g/dL increase from baseline 
in mean Hb in the absence of transfusions 
IA 0.5, 1.0  
Week 12 to Week 
24 
Per Protocol Analysis Set 
IA 2.0 
Week 12 to Week 
24 
Per Protocol Analysis Set/ 
ITT Analysis Set 
FA 
Week 12 to Week 
24, and Week 24 
to Week 36 
Per Protocol Analysis Set/ 
ITT (mITT) Analysis Set 
Responder analysis - Analysis of proportion of 
subjects with ≥1.5 g/dL increase from baseline 
in Hb in the absence of transfusions [sensitivity 
analysis] 
 
IA 1.0, 2.0  
Week 24 
Per Protocol Analysis Set/ 
ITT Analysis Set 
FA 
Week 24, Week 
36 
Per Protocol Analysis Set/ 
ITT (mITT) Analysis Set 
Proportion of subjects who have an Hb increase 
of ≥1.0 g/dL from Baseline for ≥14 days in the 
absence of RBC transfusions 
IA 2.0 
14-day periods 
through Week 24 
Per Protocol Analysis Set/ 
ITT Analysis Set 
FA 
14-day periods 
through Week 36 
Per Protocol Analysis Set/ 
ITT (mITT) Analysis Set 
Change and Percent Change from Baseline in 
mean Hb, Specialty Hematology, and PD 
parameters (listed in Sections 13.6.7 and 
13.6.8)  
  
IA 0.5, 1.0  
1.Week 12 to 24 
Mean 
2.Descriptive 
statistics by visit 
Per Protocol Analysis Set 
IA 2.0 
1.Week 12 to 24 
Mean 
2.Descriptive 
statistics by visit 
3.MMRM of all 
visits up to Week 
24 (Change only) 
Per Protocol Analysis Set/ 
ITT Analysis Set 
FA 
1.Week 12 to 24 
Mean, Week 24 to 
36 Mean 
2.Descriptive 
statistics by visit 
3.MMRM of all 
visits up to Week 
36 (Change only) 
Per Protocol Analysis Set/ 
ITT (mITT) Analysis Set 
Duration of the mean Hb increase from 
Baseline of ≥1.0 g/dL 
IA 2.0 
Over 24 weeks 
from Baseline 
Per Protocol Analysis Set/ 
ITT Analysis Set 
FA 
Over 36 weeks 
from Baseline 
Per Protocol Analysis Set/ 
ITT (mITT) Analysis Set 
Proportion of subjects who are transfusion-free 
(independent) for ≥8 weeks during treatment 
IA 2.0 
Through Week 24 
Per Protocol Analysis Set/ 
ITT Analysis Set 
FA 
Through Week 36 
Per Protocol Analysis Set/ 
ITT (mITT) Analysis Set 
Proportion of subjects who are RBC 
transfusion-free (independent)  
IA 2.0 
Over 24 weeks 
Per Protocol Analysis Set/ 
ITT Analysis Set 
FA 
Over 36 weeks 
Per Protocol Analysis Set/ 
ITT (mITT) Analysis Set 
Mean change from Baseline for Serum ferritin 
IA 0.5 
Week 24 
Per Protocol Analysis Set 


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Outputs 
Analysis 
Number 
Timepoints 
Analysis Set(s) 
 
IA 1.0  
Week 24 
Per Protocol Analysis Set 
IA 2.0 
Week 24 
Per Protocol Analysis Set/ 
ITT Analysis Set 
FA 
Week 24, 36 
Per Protocol Analysis Set/ 
ITT (mITT) Analysis Set 
Mean change from Baseline for Iron chelation 
therapy daily dose 
IA 2.0 
Week 24 
Per Protocol Analysis Set/ 
ITT Analysis Set 
FA 
Week 24, 36 
Per Protocol Analysis Set/ 
ITT (mITT) Analysis Set 
Change from Baseline in SF-36 quality of life 
IA 2.0 
Weeks 12, 24 
ITT Analysis Set 
FA 
Weeks 12, 24, 36 
ITT (mITT) Analysis set 
Change from Baseline in mean NTDT-PRO 
total score and domain scores including 
tiredness/weakness domain over a continuous 
12-week interval 
 
 
IA 2.0 
Week 12 to Week 
24 
ITT Analysis Set 
FA 
Week 12 to Week 
24, Week 24 to 
Week 36 
ITT (mITT) Analysis Set 
Change from Baseline in NTDT-PRO total 
score and domain score including 
tiredness/weakness domain  
IA 2.0 
Week 24 
ITT Analysis Set 
FA 
Weeks 24, 36 
ITT (mITT) Analysis Set 
Summary of exposure 
IA 0.5, 1.0, 2.0 
All available data 
up to Week 24 at 
the time of IA 
Safety Analysis Set 
FA 
All available data 
Safety Analysis Set 
Overall summary of TEAEs 
IA 0.5, 1.0, 2.0 
All available data 
up to Week 24 at 
the time of IA 
Safety Analysis Set 
FA 
All available data 
Safety Analysis Set 
TEAEs by SOC & PT 
IA 0.5, 1.0, 2.0 
All available data 
up to Week 24 at 
the time of IA 
Safety Analysis Set 
FA 
All available data 
Safety Analysis Set 
TEAEs by PT 
IA 0.5, 1.0, 2.0 
All available data 
up to Week 24 at 
the time of IA 
Safety Analysis Set 
FA 
All available data 
Safety Analysis Set 
Drug-related TEAEs by SOC & PT 
 
IA 0.5, 1.0, 2.0 
All available data 
up to Week 24 at 
the time of IA 
Safety Analysis Set 
FA 
All available data 
Safety Analysis Set 
Drug-related TEAEs by PT 
IA 0.5, 1.0, 2.0 
All available data 
up to Week 24 at 
the time of IA 
Safety Analysis Set 
FA 
All available data 
Safety Analysis Set 
TEAEs by SOC, PT & severity 
IA 0.5, 1.0, 2.0 
All available data 
up to Week 24 at 
the time of IA 
Safety Analysis Set 
FA 
All available data 
Safety Analysis Set 


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Protocol no: IMR-BTL-201 
 
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Outputs 
Analysis 
Number 
Timepoints 
Analysis Set(s) 
Mean pharmacokinetic parameters for IMR-687 
by dose and by study visit 
1.0 
All available data 
up to Week 12 
PK Evaluable Set 
FA 
All available data 
PK Evaluable Set 
Figures 
 
Line plot of mean change from Baseline in Hb & 
HbF by treatment arm  
IA 1.0 
[arithmetic] 
Week 12 to 24 
Per Protocol Analysis Set 
2.0 [lsmeans] 
Week 12 to 24 
Per Protocol Analysis Set/ 
ITT Analysis Set 
FA 
[lsmeans] 
Week 12 to 24, 
Week 24 to 36 
Per Protocol Analysis Set/ 
ITT (mITT) Analysis Set 
Bar plot of proportion of subjects with ≥1.0 g/dL 
increase from baseline in mean Hb in the 
absence of transfusions 
IA 1.0 
Week 12 to 24 
Per Protocol Analysis Set 
IA 2.0 
Week 12 to 24 
Per Protocol Analysis Set/ 
ITT Analysis Set 
FA 
Week 12 to 24, 
Week 24 to 36 
Per Protocol Analysis Set/ 
ITT (mITT) Analysis Set 
Bar plot of proportion of subjects with ≥3% 
increase from baseline in mean HbF in the 
absence of transfusions 
IA 1.0 
Week 12 to 24 
Per Protocol Analysis Set 
IA 2.0 
Week 12 to 24 
Per Protocol Analysis Set/ 
ITT Analysis Set 
FA 
Week 12 to 24, 
Week 24 to 36 
Per Protocol Analysis Set/ 
ITT (mITT) Analysis Set 
Arithmetic mean (± SD) plasma concentration 
of IMR-687 by dose and by study visit (linear 
and semi-logarithmic scale) 
1.0 
All available data 
up to Week 4 
PK Analysis Set 
FA 
All available data 
PK Analysis Set 
 
12.1 Data Monitoring Committee 
The specific activities of the DMC will be governed by a charter which will define the DMC’s membership, 
meeting frequency, procedures/conduct, and requirements for reporting its observations to the sponsor. 
 
To ensure safety oversight throughout the trial, the DMC will review safety and preliminary efficacy data 
and provide recommendations to the Sponsor as described below. 
 
The DMC will convene at the following times and for the following activities during the trial: 
• 
Review safety data for at least 5 subjects who received IMR-687 at the lower dose and make 
recommendation as to the inclusion of the higher dose. 
• 
Review safety data to confirm acceptable safety and tolerability of the higher dose of IMR-687.  
Make recommendation as to whether the dose level(s) could be modified; the proposed 
modification would occur only after a substantial protocol amendment was submitted to and 
approved by any applicable regulatory authorities. 
• 
At any time during the trial—upon request by the Sponsor, medical monitor, or DMC—should a 
concern arise from emerging safety data for which DMC review and assessment is desired. This 
includes the emergence of a frequency or pattern of AEs or serious adverse events (SAEs) that 
suggest an unexpected or otherwise concerning safety signal. 
 


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The DMC may review the following subject data, depending on the scope of the meeting, and may 
recommend to continue the study as planned, modify the study, or terminate the study for safety or lack of 
efficacy concerns: 
• 
Unblinded safety, preliminary efficacy, and PK data, which may include TEAEs, SAEs, clinical 
laboratory test results, vital signs, and other relevant data for all subjects randomized. 
• 
Additionally, the DMC chairperson will receive copies of all SAE reports for ongoing review during 
the trial. The DMC chairperson may forward the SAE reports to the full DMC if he/she feels that 
their immediate input on, or awareness of the SAE would be helpful. 
 
All assessments and decisions by the DMC will be documented in writing as noted in the DMC charter 
and prior to any resultant changes to the study unless their immediate implementation is considered 
necessary for subject safety. The composition of the DMC will be detailed in the DMC charter. 
 Statistical Methods 
All statistical analyses will be conducted using SAS Version 9.4. 
Descriptive summary statistics will be provided for demographics, disposition, and IMR-687 exposure. 
The number and percentage of subjects who discontinue from the study, along with reasons for 
discontinuation will be tabulated. 
Continuous data will be summarized using descriptive statistics (number of subjects, mean, SD, median, 
first quartile (Q1), third quartile (Q3), minimum, and maximum, %CV). Frequencies and percentages will 
be used for summarizing categorical (discrete) data. For summaries of categorical variables, counts and 
percentages are based on the number of subjects in the analysis set unless otherwise specified. 
All statistical tests and resulting p-values will be reported as 2-sided. Confidence intervals, when 
presented, will be constructed at the two-sided 95% level, unless noted otherwise. 
P-values will be presented to 4 decimal places with values less than 0.0001 presented as “<0.0001” and 
p-values greater than 0.9999 presented as “>0.9999”.   
Means, medians, Q1s, and Q3s will be presented to 1 or more decimal places than the recorded data. 
The SDs will be presented to 2 more decimal places than the recorded data. Confidence intervals about a 
parameter estimate, minimums, and maximums will be presented using the same number of decimal 
places as the parameter estimate. Percentages will be presented to 1 decimal place. 
A month is operationally defined to be 30.4375 days. A year is defined to be 365.25 days. A week is 
defined to be 7 days.  
Where specified, there will be pair-wise comparisons between IMR-687 lower dose vs. placebo, IMR-687 
higher dose vs. placebo and IMR-687 pooled dose vs. placebo. 
Separate table and figure outputs will be produced for each TDT/NTDT population. The TDT population 
may be unblinded and reported at a separate time from the NTDT population depending on enrollment.  If 
this occurs the blind of the unfinished population will be preserved. Listings will include both the TDT and 
NTDT populations with the TDT population presented first in the listing 
13.1 Subject Disposition 
The number of subjects screened, screen failed, randomized, and treated in the study will be presented, 
together with the number and percentage of subjects who completed 24 weeks of treatment, completed 
36 weeks of treatment, discontinued study drug, and discontinued from the study will be tabulated. The 
primary reason for screen failure, study drug discontinuation, and study discontinuation will also be 
tabulated.  
Subjects who completed 24 weeks of treatment are defined as either 1) answered “Yes” to the “Did the 
subject take study drug dose during clinic visit?” question at the Week 24 visit, or later, on the Study Drug 
Administration eCRF, or 2) have a non-missing “Start Date of Dose From This Bottle“ or “Date of Last 


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Dose for this Bottle” on the Study Drug Accountability eCRF that is on or after the Week 24 visit. Subjects 
who completed 36 weeks of treatment are defined similarly relative to the week 36 visit.  
Percentages for screen failed, primary reason for screen failure, and randomized will be based on all 
subjects screened. Percentages for number of subjects treated in the study will be based on all 
randomized subjects. Percentages for number of subjects who completed 24 weeks of treatment, number 
of subjects who completed 36 weeks of treatment, number of subjects who discontinued study drug, 
primary reason for study drug discontinuation, number of subjects discontinued from the study, and the 
primary reason for study discontinuation will be based on all treated subjects.  
Summaries will be based on all subjects screened and tabulated for each treatment arm and the total and 
will be reported separately for TDT and NTDT subjects. 
Tabulation of the number and percentage of subjects included in each analysis set will be provided. All 
percentages will be based on all randomized subjects, for each treatment arm and the total, and will be 
reported separately for TDT and NTDT subjects. 
Details regarding randomization assignments, replacement of randomized subjects, subjects who 
discontinued study drug and/or study, and subject analysis sets will be reported in by-subject listings. 
13.2 Important Protocol Deviations 
Prior to the database lock for the primary analysis, the Sponsor or designee medical and statistics 
personnel will identify and review any deviations from the study protocol. Any protocol deviations that 
might significantly affect the completeness, accuracy, and/or reliability of the study data or that might 
significantly affect a subject's rights, safety, or well-being will be classified as important protocol 
deviations (FDA, ICH, 2013, January).  
Tabulation of the number and percentage of subjects with important protocol deviations by center and 
category within each treatment arm will be presented on the Safety Analysis Set separately for each 
population. Categories will be sorted alphabetically, and deviations within each category will be sorted 
alphabetically. Categories will include: 
• 
Deviations related to study inclusion or exclusion criteria 
• 
Receipt of any prohibited therapies as defined in the protocol 
• 
Significant deviations in study drug administration 
• 
Subjects were not withdrawn after developing withdrawal criteria during the study 
Details for protocol deviations for subjects in the Safety Analysis Set will be provided in protocol deviation 
and important protocol deviation data listings. 
13.3 Treatment 
13.3.1 Extent of Study Drug Exposure and Drug Accountability 
A summary of exposure and compliance, to be reported on the Safety Analysis Set, will include the total 
number of tablets taken, compliance (%), total exposure (mg), average daily dose (mg/day), duration of 
exposure (in weeks), and incidence and duration of dose interruption. These parameters will be 
calculated as follows: 
• 
Duration of exposure (in weeks) will be calculated as [(date of last dose of study medication – 
date of first dose of study medication + 1)/7]. The date of first dose of study medication will be 
collected from the Study Drug Administration CRF page and the date of last dose of study 
medication will be collected from the End of Treatment CRF page. If there is no date for end of 
treatment on the End of Treatment CRF page, the last available dose date will be used.  See 
Appendix 3 for a complete set of data handling rules.   
• 
Total number of tablets taken = total number of tablets dispensed – total number of tablets 
returned. The total number of tablets dispensed and returned will be collected from Study Drug 


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Accountability CRF Page. They are to be collected at study visits and will be summed over the 
whole study treatment period. 
• 
Total exposure (mg) of IMR-687 = Total number of tablets taken * tablet dose level (100/150/200 
mg). IMR-687 will be supplied as 100, 150, or 200 mg white tablets in the study. In the lower dose 
group (≥3.0 to ≤5.0 mg/kg), subjects weighing <60 kg will be dispensed 100 mg tablets and those 
weighing ≥60 kg will be dispensed 150 mg tablets. In the higher dose group (>4.5 to ≤6.7 mg/kg), 
subjects weighing <60 kg will be dispensed 150 mg tablets and those weighing ≥60 kg will be 
dispensed 200 mg tablets. The dose regimen for all subjects is 2 tablets once daily.  The weight 
at the baseline will be used to establish the dose level and the same dose level will be used 
throughout the trial. 
• 
Incidence and duration of dose interruption: as collected from the IP Interruptions CRF page.    
• 
Overall compliance (%) = [(total number of tablets dispensed – total number of tablets returned) / 
duration of exposure (days)] x 100.  
• 
Average daily dose (mg/day) = total exposure (mg) / duration of therapy (days).  
Additional considerations and data handling in exposure and drug accountabilities may be needed for the 
DMC, IA, and final analysis when some of drug dosing and accountability information is deemed 
incomplete. See Appendix 3 for a complete set of data handling rules for drug exposure and 
accountability. 
The same tabulation will be generated for the PP Analysis set if it is not the same as the Safety Analysis 
Set. 
Details of the administration of study drug, including randomized and actual treatment, start date and time 
of each dose, dose per administration, and date, time, and composition of last meal will be listed on the 
Safety Analysis Set. 
Details of study drug accountability including date dispensed, date returned, amount returned, and 
compliance per dosing period (in %, as collected directly from CRF), overall compliance (in %, for the 
whole duration of study drug exposure, as calculated as above) will be listed based on the Safety 
Analysis Set. 
13.4 Demographic and Baseline Characteristics 
By-population tabulation summaries and by-subject listings of demographics, baseline characteristics, 
disease history, and historical transfusion burden will be presented in the Safety Analysis Set. 
The demographic and baseline characteristics consist of: 
• 
Age (years) –as numeric value 
• 
Sex (Female, Male) 
• 
Ethnicity (Categories as collected from CRF) 
• 
Race (Categories as collected from CRF) 
• 
Height (cm) 
• 
Weight (kg) 
• 
BMI (kg/m2) 
• 
Baseline Eastern Cooperative Oncology Group (ECOG) Score (0, 1) 
• 
Region (Europe/North America, Asia/Africa) (see Appendix 5 for countries included in each 
region) 
• 
Beta Thalassemia Diagnosis (Major, Intermediate, E) 
• 
Concomitant Alpha Gene Status (Deletion, Duplication/Triplication, No Alpha) 


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• 
Previous/Ongoing Cardiac and/or Hepatic Co-morbidities due to Iron Overload (TDT) (Yes, No) 
• 
Baseline Transfusion Burden in Packed RBC Units (day -83 to 1) continuously and categorically 
categorized level: Low Transfusion Burden (≤ 5), Medium Transfusion Burden (> 5-< 7) and High 
Transfusion Burden (> 7)) [TDT] 
• 
Pre-transfusion Hemoglobin Threshold, defined as mean of all documented pre-transfusion 
hemoglobin values during the 12 weeks prior to Dose 1 Day 1 (continuous and categorized level: 
< 9 g/dL and ≥ 9 g/dL) [TDT] 
• 
Baseline Serum Ferritin –as numeric value 
• 
Daily Iron Chelation Use (Yes, No) 
• 
Splenectomy (Yes, No) 
• 
Baseline Hemoglobin (≤8.5, >8.5) [NTDT]  
13.4.1 Medical and Surgical History 
Medical and surgical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
Version 23.0 or higher and will be summarized for each population by treatment arm and total in the 
Safety Analysis Set, using System Organ Class (SOC) and MedDRA preferred term (PT). The table will 
include the number and percentage of subjects and will be sorted alphabetically by SOC and in 
decreasing frequency by PT and then alphabetically for ties (based on the total count in the analysis set). 
A subject will only be counted once within a class.  
A by-subject listing for medical and surgical history generated on the Safety Analysis Set.  
13.5 Prior and Concomitant Treatments and Procedures 
13.5.1 Prior and Concomitant Beta-Thalassemia Treatment 
A prior Beta-Thalassemia treatment is any medication taken prior to first dose of study drug that is 
reported on the Prior/Concomitant Medications eCRF and categorized as “Disease Under Study” under 
the “Primary Reason Medication was Taken/Therapy was Given”. A concomitant Beta-Thalassemia 
treatment is any medication ongoing at the time of the first dose of study drug, or that started after first 
dose and within 30 days of the last dose of study drug, that is reported on the Prior/Concomitant 
Medications eCRF and categorized as “Disease Under Study” under the “Primary Reason Medication was 
Taken/Therapy was Given”. 
The number and percentage of subjects taking prior Beta-Thalassemia treatment will be tabulated for 
each population by treatment arm, the combined active arms, and the total using the World Health 
Organization Drug Dictionary (WHO-DD) (01MAR2020 or later) standardized medication name for the 
Safety Analysis Set. Medications will be classified by Anatomical Therapeutic Chemical (ATC) level 2 
groups, then by preferred name within each ATC group. If the ATC level 2 group is missing, the next non-
missing level will be used. Subjects will only be counted once within each ATC group and each preferred 
name. ATC groups will be sorted alphabetically and preferred name will be sorted in descending 
frequency, using the numbers in the combined active arms column, and then alphabetically in the event of 
any ties. 
The number and percentage of subjects taking concomitant Beta-Thalassemia treatment will be tabulated 
for each population by treatment arm and the combined active arms using the World Health Organization 
Drug Dictionary (WHO-DD) (01MAR2020 or later) standardized medication name for the Safety Analysis 
Set. Medications will be classified by Anatomical Therapeutic Chemical (ATC) level 2 groups, then by 
preferred name within each ATC group. If the ATC level 2 group is missing, the next non-missing level will 
be used. Subjects will only be counted once within each ATC group and each preferred name. ATC 
groups will be sorted alphabetically and preferred name will be sorted in descending frequency, using the 
numbers in the combined active arms column, and then alphabetically in the event of any ties. 


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All prior and concomitant Beta-Thalassemia treatment data will be presented in a listing based on the 
Safety Analysis Set for TDT and NTDT subjects. 
13.5.2 Prior and Concomitant Medications 
Prior medications are medications that started before the first dose of study drug. Concomitant 
medications are medications ongoing at the time of the first dose of study drug, or that started after first 
dose and within 30 days of the last dose of study drug. 
The number and percentage of subjects who took prior medications will be tabulated for each population 
by treatment arm, the combined active arms, and the total using the WHO-DD (01MAR2020 or later) 
standardized medication name for the Safety Analysis Set. Medications will be classified by ATC level 2 
groups, then by preferred name within each ATC group. If the ATC level 2 group is missing, the next non-
missing level will be used. Subjects will only be counted once within each ATC group and each preferred 
name.  ATC groups will be sorted alphabetically and preferred name will be sorted in descending 
frequency, using the numbers in the combined active arms column, and then alphabetically in the event of 
any ties. 
The number and percentage of subjects taking concomitant medications will be tabulated for each 
population by treatment arm and the combined active arms using the WHO-DD (01MAR2020 or later) 
standardized medication name for the Safety Analysis Set. Medications will be classified by ATC level 2 
groups, then by preferred name within each ATC group. If the ATC level 2 group is missing, the next non-
missing level will be used. Subjects will only be counted once within each ATC group and each preferred 
name.  ATC groups will be sorted alphabetically and preferred name will be sorted in descending 
frequency, using the numbers in the combined active arms column, and then alphabetically in the event of 
any ties. 
All prior and concomitant medications data will be presented in a listing based on the Safety Analysis Set 
for TDT and NTDT subjects. 
13.5.3 Concomitant Procedures 
Concomitant procedures are procedures ongoing at the time of the first dose of study drug, or that started 
after first dose and within 30 days of the last dose of study drug. The number and percentage of subjects 
having concomitant procedures will be tabulated for each population by treatment arm and the combined 
active arms using MedDRA (version 23.0 or later) for the Safety Analysis Set. Procedures will be 
classified by SOC, then by PT. Subjects will only be counted once within each SOC and PT. The SOCs 
and PTs will be sorted alphabetically by SOC and in decreasing frequency by PT using the numbers in 
the combined active arms column, and then alphabetically in the event of any ties (based on the total 
count in the analysis set). 
All concomitant procedures data will be presented in a listing based on the Safety Analysis Set for TDT 
and NTDT subjects. In addition, a listing of concomitant procedures that are reported on the Concomitant 
Procedures eCRF and categorized as “Disease Under Study” under the “Primary Reason Procedure was 
Performed”, based on the Safety Analysis Set for TDT and NTDT subjects, will be provided. 
13.5.4 Prior and Concomitant Iron Chelation Therapy 
Prior iron chelation therapies are defined as therapies that were started before the first dose of study drug 
that are reported on the Iron Chelation Therapy eCRF. Concomitant iron chelation therapies are therapies 
ongoing at the time of the first dose of study drug, or that started after first dose and within 30 days of the 
last dose of study drug, that are reported on the Iron Chelation Therapy eCRF. 
 
The number and percentage of subjects who took prior iron chelation therapies will be tabulated for each 
population by treatment arm, the combined active arms, and the total using the WHO-DD (01MAR2020 or 
later) standardized medication name for the Safety Analysis Set. Medications will be classified by ATC 
level 2 groups, then by preferred name within each ATC group. If the ATC level 2 group is missing, the 
next non-missing level will be used. Subjects will only be counted once within each ATC group and each 


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preferred name. ATC groups will be sorted alphabetically and preferred name will be sorted in 
descending frequency, using the numbers in the combined active arms column, and then alphabetically in 
the event of any ties. 
 
The number and percentage of subjects taking concomitant iron chelation therapies will be tabulated for 
each population by treatment arm and the combined active arms using the World Health Organization 
WHO-DD (01MAR2020 or later) standardized medication name for the Safety Analysis Set. Medications 
will be classified by Anatomical Therapeutic Chemical (ATC) level 2 groups, then by preferred name 
within each ATC group. If the ATC level 2 group is missing, the next non-missing level will be used. 
Subjects will only be counted once within each ATC group and each preferred name.  ATC groups will be 
sorted alphabetically and preferred name will be sorted in descending frequency, using the numbers in 
the combined active arms column, and then alphabetically in the event of any ties. 
All prior and concomitant iron chelation therapies data will be presented in a listing based on the Safety 
Analysis Set for TDT and NTDT subjects. 
13.6 Endpoint Analyses 
Endpoint analyses for TDT and NTDT populations will be reported separately. All efficacy endpoints will 
be conducted using the PP Analysis Set and may be repeated for the mITT Analysis Set (if applicable), 
and the ITT Analysis Set (where applicable). 
13.6.1 Hypothesis Testing Strategy and Multiplicity 
There will be no adjustment for multiple testing. 
13.6.2 Safety Analyses 
The below information regarding safety analyses is relevant for both the TDT and NTDT populations. The 
two populations will be summarized separately.  
IMR-687 safety and tolerability will be measured in both populations by: 
• 
Incidence and severity of AEs and SAEs 
• 
Incidence of subjects with a post-Baseline clinically significant worsening in the CTCAE 
laboratory grade for a lab parameter  
• 
Incidence of subjects with a post-Baseline clinically significant change in a vital signs parameter 
• 
Incidence of subjects meeting the clinically significant criteria for an electrocardiogram (ECG) 
parameter 
• 
Changes from Baseline in clinical laboratory tests (hematology, coagulation chemistry, urinalysis), 
vital signs (continuous parameters only) for any timepoint and 12-lead ECG parameters 
• 
Changes in physical examination findings relative to the Baseline physical examination 
13.6.2.1 Adverse Events 
MedDRA Coding 
AEs will be coded using MedDRA (v23.0 or higher).  
Treatment-emergent adverse event (TEAE) 
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges on or after the initiation of 
study drug, or an AE that existed pre-treatment and worsened in severity on or after the initiation of study 
drug, through 30 days after the last dose of study drug. A pre-treatment adverse event is an AE that 
emerges before the date of initiation of study drug. 


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Refer to Appendix 3 for handling of partial dates for AEs for the purpose of assigning treatment-emergent 
flags. In the case where it is not possible to define an AE as treatment emergent or not, the AE will be 
classified as treatment emergent. 
Severity  
Severity is classified as Grade 1: Mild, Grade 2: Moderate, Grade 3: Severe, Grade 4: Life Threatening, 
Grade 5: Death Related to AE, using the Common Terminology Criteria for Adverse Events, v5.0 (CTCAE 
v5.0). For the AE summary by CTCAE severity grade, an AE with missing CTCAE severity grade will not 
be imputed. Imputed values will not be included in data listings. 
Relationship to Study Treatment  
Relationship is classified as “Unlikely/Not related”, “Possible”, “Probably/Likely”, or “Certain/Related” by 
the Investigator. A “treatment-related TEAE” for the purpose of this summary is defined as a TEAE with 
relationship to study drug of “Possible”, “Probably/Likely” or “Certain/Related”. For the AE summary by 
relationship, an AE with a missing relationship to study drug will not be imputed. Imputed values will not 
be included in data listings. 
TEAEs Leading to Discontinuation of Study Treatment  
TEAEs leading to discontinuation of study treatment will be identified by action taken with study treatment 
being recorded as “Drug withdrawn” on the Adverse events CRF. 
Serious and Non-Serious TEAEs  
Serious adverse events (SAEs) are those events recorded as “Yes” for the question “Was the adverse 
event serious?” on the Adverse Event CRF. 
TEAEs Leading to Death  
TEAEs leading to death are those events which are recorded as “Yes” for the question “Did the adverse 
event result in death?”, or recorded CTCAE Toxicity Grade 5, or with outcome = “Fatal” on the Adverse 
Events CRF. 
TEAEs Leading to Study Discontinuation 
TEAEs leading to study discontinuation are those events which are recorded as “Yes” for the question 
“Did the adverse event cause the subject to be discontinued from the study?” on the Adverse events 
CRF. 
TEAEs Leading to Dose Reduction 
TEAEs leading to dose reduction will be identified by action taken with study treatment being recorded as 
“Dose Reduced” on the Adverse events CRF. 
A summary of TEAEs will be presented by treatment arm and the combined IMR-687 treatment arms for 
TDT and NTDT subjects. The number and percentage of subjects reporting any of the following 
categories will be provided: 
• 
Any pre-treatment adverse event 
• 
Any TEAE 
• 
Grade 3 or higher TEAEs 
• 
Treatment-related TEAEs 
• 
Treatment-related grade 3 or higher TEAEs 
• 
TEAEs with outcome of death 
• 
SAEs 
• 
Treatment-related SAEs 


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• 
Treatment-related grade 3 or higher SAEs 
• 
Treatment-related grade 2 or higher TEAEs 
• 
TEAEs leading to discontinuation of study drug 
• 
Treatment-related TEAEs leading to discontinuation of study drug 
• 
TEAEs leading to study discontinuation 
• 
Treatment-related TEAEs leading to study discontinuation 
• 
TEAEs leading to dose reduction 
• 
Treatment-related TEAEs leading to dose reduction 
The following AE tables will be summarized by treatment arm and the combined IMR-687 treatment arms, 
SOC and PT (according to the MedDRA dictionary version 23.0 or higher) for TDT and NTDT subjects. 
SOCs will be sorted alphabetically and PTs will be sorted by descending frequency, by the combined 
IMR-687 treatment arm column, and then alphabetically for ties. 
• 
The number and percentage of subjects reporting each TEAE. The AE count will be by subject, 
not event, and subjects are only counted once within each SOC or PT 
• 
The number and percentage of subjects reporting treatment-related TEAEs. Subjects with 
multiple events within a particular SOC or PT will be counted under the category of their most 
drug-related event within that SOC or PT. AEs will be considered related to study drug if they are 
reported as certain/related, probably/likely related, and possibly related. 
• 
The number and percentage of subjects reporting TEAEs, by severity (Grade 1, Grade 2, Grade 
3, Grade 4, Grade 5, all defined in Section 12.1.2.2.1 of the study protocol), will also be provided. 
Subjects with multiple events within a particular SOC or PT will be counted under the category of 
their most severe event within that SOC or PT. AE severity (intensity) will be graded using NCI 
CTCAE, version 5.0 
• 
The number and percentage of subjects reporting treatment-related TEAEs, by severity 
• 
The number and percentage of subjects reporting Grade 3 or higher TEAEs  
• 
The number and percentage of subjects reporting treatment-related Grade 3 or higher TEAEs  
• 
The number and percentage of subjects reporting treatment-related Grade 2 or higher TEAEs  
• 
The number and percentage of subjects reporting AEs leading to discontinuation of study drug 
• 
The number and percentage of subjects reporting treatment-related TEAEs, by relationship 
• 
SAEs  
• 
TEAEs leading to death  
The following AE tables will be summarized by treatment arm and the combined IMR-687 treatment arms, 
and PT for TDT and NTDT subjects. PTs will be sorted by descending frequency, by the combined IMR-
687 treatment arm column, and then alphabetically for ties. 
• 
The number and percentage of subjects reporting each TEAE. 
• 
The number and percentage of subjects reporting treatment-related TEAEs 
• 
The number and percentage of subjects reporting each TEAE with frequency ≥10% 
• 
The number and percentage of subjects reporting treatment-related TEAEs with frequency 
≥10% 


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All AEs (including non-treatment-emergent events) recorded on the CRF, all SAEs, and all deaths that 
occur following the first dose of study drug will be listed. All AE tables and listings will be reported using 
the Safety Analysis Set. 
13.6.2.2 Clinical Laboratory Evaluation 
Clinical laboratory tests (serum chemistry, central laboratory hematology, local laboratory hematology, 
and specialty hematology) will be summarized using the Safety Analysis Set and will be evaluated and 
presented using International System of Units (SI) unless otherwise stated. Clinical laboratory values will 
be graded from Grade 1 to Grade 4 using the NCI CTCAE, version 5.0. Post-Baseline laboratory values 
will only be compared to Baseline values from the same source.  For example, local laboratory post-
Baseline results can only be compared to local laboratory Baseline results. 
Hematology assessments include: RBC count (mean corpuscular volume [MCV], RDW, mean 
corpuscular Hb, and mean corpuscular Hb concentration), hematocrit, Hb, platelets, WBC count (with 
differential: basophils, eosinophils, neutrophils, monocytes, and lymphocytes), erythrocyte count, and 
reticulocyte count and reticulocyte percentage. Some of these assessments are also considered PD 
endpoints, further detailed in the exploratory endpoint section below. 
Specialty hematology assessments include: HbF and F-cells (%). 
Coagulation assessments include: PT, aPTT, and international normalized ratio (INR). 
Serum chemistry assessments include: alanine aminotransferase (ALT), albumin, alkaline phosphatase 
(ALP), aspartate aminotransferase (AST), bicarbonate, blood urea nitrogen (BUN), chloride, calcium, 
creatinine, glucose, lactate dehydrogenase (LDH), sodium, potassium, magnesium, phosphate, bilirubin 
(total, direct, and indirect), creatine kinase, total protein, glomerular filtration rate (GFR), and gamma-
glutamyl transferase (GGT). Follicle stimulating hormone (FSH) will be included as well, but this is only 
collected for post-menopausal women at screening. Some of these assessments are also considered PD 
endpoints, further detailed in the exploratory endpoint section below. 
Descriptive statistics (N, mean, SD, median, Q1, Q3, minimum, and maximum) for the observed, change 
from Baseline, and percent change from Baseline values will be summarized by visit, treatment arm, and 
the combined IMR-687 treatment arms, and presented separately for chemistry and hematology and for 
each population. Study Baseline defined in Section 10.1.2 will be used for change from baseline. Note 
that character urinalysis tests will only be listed. 
Urinalysis assessments include: appearance, color, pH, specific gravity, ketones, protein, glucose, 
bilirubin, and urobilinogen, including occult blood and microscopic examination of sediment (only if occult 
blood is detected). 
Shift tables will be used to summarize the shift from Baseline grade to maximum CTCAE grade (Grade 1 
to 4 and Missing) for selected hematology and chemistry parameters listed in Appendix 4, by treatment 
arm and the combined IMR-687 treatment arms and presented separately for each population. Any 
subject with a post-Baseline result meeting the criteria, including those collected at unscheduled visits, 
will be included in the tabulation. 
Potentially clinically significant (PCS) Criteria for hepatic function and renal function are shown in Table 5 
below. The number and percentage of subjects meeting these PCS criteria will be summarized for hepatic 
function parameters (ALT, AST, ALP, and total bilirubin), the renal function parameter (serum creatinine), 
and platelet count separately. Any subject with any post-baseline result (including “unscheduled” visits) 
meeting the criteria will be included in the tabulation. 
 
 
 
 


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Table 5  
PCS Criteria for Hepatic Function, Renal Function, and Platelet Count 
Hepatic Function 
Renal Function 
Platelet Count 
o Post-baseline Alanine Aminotransferase (ALT) 
≥ 3 x upper limit of normal (ULN) 
o Post-baseline Aspartate Aminotransferase 
(AST) ≥ 3 x ULN 
o Post-baseline Direct Bilirubin (BILDIR) ≥ 2 x 
ULN 
o Post-baseline ALT/AST and BILDIR (ALT≥ 3 x 
ULN or AST≥ 3x ULN) and BILDIR≥ 2 x ULN 
(Hy’s Law) 
o Post-baseline Creatinine 
Clearance (CREATCLR) < 0.5 x 
baseline 
o Post-baseline Serum Creatinine 
(CREAT) > 2 x baseline 
o Post-baseline 
Platelet Count 
>1000 x 109/L 
 
 
The following figures will be provided for the following hematology, chemistry, and coagulation results: 
MCV, platelets, neutrophils, reticulocyte (absolute and percent), GGT, LDH, creatinine, AST, ALT, indirect 
bilirubin, ACR. 
• 
Shift plot from baseline to post-baseline maximum value for each parameter by treatment arm 
and for the combined IMR-687 treatment arms; 
• 
Box and whisker plot for each lab parameter by visit for each treatment arm and the combined 
IMR-687 treatment arms. 
 
All laboratory parameters (serum chemistry, central laboratory hematology, local laboratory hematology, 
specialty hematology, coagulation, and urinalysis) will be displayed in individual subject data listings. In 
addition, a listing of only abnormal laboratory values will be provided. All lab tables and listings will be 
reported on the Safety Analysis Set. 
13.6.2.3 Vital Signs 
Descriptive statistics (N, mean, SD, median, Q1, Q3, minimum, and maximum) will be used to summarize 
vital sign parameters (body temperature, systolic blood pressure, diastolic blood pressure, heart rate, and 
respiratory rate) at Baseline, each post-Baseline visit, and change from Baseline to each post-Baseline 
visit, by treatment arm and the combined IMR-687 treatment arms, for both populations. Study Baseline 
as defined in Section 10.1.2 will be used. 
Potentially clinically significant (PCS) post-baseline vital signs can be identified using the criteria shown in 
the table below. The number and percentage of subjects with any post-baseline treatment-emergent 
potentially clinically significant vital sign value will be tabulated by treatment group for each criterion. Any 
subject with a post-baseline result meeting the criteria, including those collected at unscheduled visits, will 
be counted.  
Potentially clinically significant (PCS) post-baseline vital signs can be identified using the criteria shown 
Table 6 below. The number and percentage of subjects with any post-baseline treatment-emergent 
potentially clinically significant vital sign value will be tabulated by treatment arm and the combined IMR-
687 treatment arms and will be provided separately for each population for each criterion. Any subject with 
a post-baseline result meeting the criteria, including those collected at unscheduled visits, will be counted.  
 
 
 
 
 


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Table 6  
PCS Criteria for Vital Signs 
Vital Signs 
 
Parameter 
Criteria 
Heart Rate 
• 
≤ 50 and decrease ≥ 15 bpm 
• 
≥ 100 bpm and increase ≥ 15 bpm 
• 
≥ 120 and increase ≥ 15 bpm 
SBP 
• 
≤ 90 and decrease ≥ 20 mm Hg 
• 
< 140 mmHg and increase ≥ 20 mmHg 
• 
≥ 140 mmHg and increase ≥ 20 mmHg 
• 
≥ 160 and increase ≥ 20 mm Hg 
DBP 
• 
≤50 and decrease ≥15 mm Hg 
• 
< 100 mmHg and Increase ≥ 20 mmHg 
• 
≥ 100 mmHg and Increase ≥ 20 mmHg 
• 
≥100 mmHg and increase ≥15 mm Hg 
 
A plot will be presented to show the pattern of the SBP and DBP values over time by treatment arm and 
the combined IMR-687 treatment arms. Mean and SE will be presented in the plot. Additionally, spaghetti 
plots for SBP and DBP values over time will be provided for 1) individual subjects with maximum post-
baseline SBP increased ≥ 20 mmHg and SBP ≥ 150 mmHg and 2) maximum post-baseline DBP 
increased ≥ 20 mmHg and DBP ≥ 100 mmHg. A shift plot displaying shifts from Baseline heart rate ≤ 100 
to maximum heart rate >100 post-Baseline will be provided for each population. 
All vital signs will be listed in a data listing. All vital sign tables and listings will be reported on the Safety 
Analysis Set. 
13.6.2.4 12-lead ECGs 
The average of triplicate 12-lead ECGs will be performed to evaluate the change from Baseline in ECG 
parameters (heart rate, PR interval, RR interval, QRS duration, QT interval, and QTcF interval). 
Descriptive statistics (N, mean, SD, median, Q1, Q3, minimum, and maximum) of ECG parameters will be 
presented for Baseline, each post-Baseline visit, and change from Baseline to each post-Baseline visit by 
treatment arm, and the combined IMR-687 treatment arms, for both populations. Study Baseline defined 
in Section 10.1.2 will be used. At Baseline and Week 3 (TDT Population)/Week 4 (NTDT Population), 
descriptive statistics will also be presented for change from pre-dose to post-dose. All measurements, 
including those during unscheduled visits, will be provided in data listings, but only the scheduled 
measurements will be included in the summary.  
The average of the ECG results by visit and parameter will be calculated if two or more of the triplicate 
ECG values are reported at the visit for baseline or post-baseline visits. 
The number of subjects whose baseline or post-baseline QTcF values have exceeded the selected 
Criteria below, will be summarized with the number and percentage of subjects meeting each criterion, by 
treatment arm, and the combined IMR-687 treatment arms, and visit (baseline, post-baseline), separately 
for each population. Subjects with baseline or post-baseline (including unscheduled visits) results meeting 
any criteria will be counted.  
 
 
 


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Table 7  
PCS Criteria for ECGs 
ECGs 
 
Parameter 
Criteria 
QTcF Interval 
• 
> 450 msec (males only) 
• 
> 470 msec (females only) 
• 
> 500 msec 
QTcF Interval 
Increase from 
Baseline 
• 
≥ 30 msec 
• 
≥ 60 msec 
 
All ECG parameters will be listed in a data listing. All ECG tables and listings will be reported using the 
Safety Analysis Set. 
13.6.2.5 Physical Examinations 
All physical examination findings will be listed in by-subject listings on the Safety Analysis Set. No 
tabulation summaries will be provided.  
13.6.3 Imputation Methods for Endpoints 
Unless otherwise specified, no imputation of data relating to the primary endpoint of safety and 
tolerability, or for secondary or exploratory efficacy endpoints, will be performed.  
13.6.3.1 Pooling of Sites 
There will be no pooling of sites. 
13.6.4 Efficacy Analyses (Secondary Endpoints) 
The PP Analysis Set will be used for all efficacy endpoint analyses. Selected analyses will be repeated on 
the mITT and/or ITT Analysis Sets as sensitivity analyses, with mITT only used if different than the ITT. 
The TDT and NTDT populations will be summarized separately for all analyses. 
Table 8  
Secondary Endpoints – TDT Population 
Secondary Endpoints 
Time Points 
Secondary Endpoint Analysis  
Proportion of subjects with a ≥20% 
reduction in RBC transfusion burden with a 
reduction of at least 2 units of RBCs 
(hematological improvement)  
Fixed time 
periods of Week 
12 to Week 24, 
Week 24 to 
Week 36, and 
Week 12 to 
Week 36, 
compared to the 
12-week interval 
prior to Baseline 
(Day 1) 
• 
Cochran-Mantel Haenszel (CMH) analysis: 
Odds ratios (OR) (active arms vs. placebo), 2-
sided 95% CI, p-value  
• 
Summary of number and percentage of 
responders with difference in proportions 
(active arm-Placebo) and corresponding 2-
sided 95% CI 
• 
Forest plots of ORs, 2-sided 95% CIs, p-value 
– Higher dose vs. placebo, Lower dose vs. 
placebo 
Proportion of subjects with a ≥33% 
reduction in RBC transfusion burden with a 
reduction of at least 2 units of RBCs 
(hematological improvement) 
Proportion of subjects with a ≥50% 
reduction in RBC transfusion burden with a 
reduction of at least 2 units of RBCs 
(hematological improvement) 
 
Proportion of subjects with a ≥20% 
reduction in RBC transfusion burden with a 
Rolling 12-week 
time periods – 


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reduction of at least 2 units of RBCs 
(hematological improvement)  
 
Day 2 to 85, Day 
3 to 86, etc. 
through Day 170 
to Day 253 
(Week 36), 
compared to the 
12-week interval 
prior to Baseline 
(Day 1) 
 
Rolling 14-week 
time periods – 
Day 2 to 99, Day 
3 to 100, etc. 
through Day 156 
to Day 253 
(Week 36), 
compared to the 
12-week interval 
prior to Baseline 
(Day 1) 
Proportion of subjects with a ≥33% 
reduction in RBC transfusion burden with a 
reduction of at least 2 units of RBCs 
(hematological improvement) 
 
Proportion of subjects with a ≥50% 
reduction in RBC transfusion burden with a 
reduction of at least 2 units of RBCs 
(hematological improvement) 
Number of transfusion events  
  
 
Baseline to Week 
24, Baseline to 
Week 36  
• 
Summary statistics of the number of 
cumulative transfusions at every 3 weeks 
post-Baseline from Week 3 through Week 36.  
• 
Analysis of Covariance (ANCOVA) analysis 
with Baseline value as a covariate: LSMean 
(95% CI), LSMean difference (95% CI) 
between each active dose and placebo, and 
p-value.  
• 
Plots of the mean number of transfusions, 
mean number of units, and mean Hb by time 
periods (Weeks 1-12, Weeks 13-24, Weeks 
25-36) 
 
Change from Baseline for mean iron 
chelation therapy daily dose and mean 
serum ferritin 
 
Baseline to Week 
36 
• 
Analysis of Covariance (ANCOVA) analysis 
with Baseline value as a covariate: LSMean 
(95% CI), LSMean difference (95% CI) 
between each active dose and placebo, and 
p-value.  
 
The plasma PK profile of IMR-687after 
administration to subjects will be evaluated 
by determination of PK parameters (e.g., 
Cmax, tmax, AUC0-24) based on drug 
concentration levels in plasma obtained 
over time 
 
Baseline and 
Week 3 (TDT) 
Baseline and 
Week 4 (NTDT) 
Descriptive summary 
 
 
Table 9  
Secondary Endpoints – NTDT Population 
Secondary Endpoints 
Time Points 
Secondary Endpoint Analysis  
Change from Baseline for iron chelation 
therapy daily dose and serum ferritin 
 
Baseline to Week 
36 
• 
Analysis of Covariance (ANCOVA) analysis 
with Baseline value as a covariate: LSMean 
(95% CI), LSMean difference (95% CI) 


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between each active dose and placebo, and 
p-value.  
 
Change from Baseline in mean Hb values 
at Weeks 12 to 24 and Weeks 24 to 36 in 
the absence of transfusions  
[using Hb from Laboratory Hematology] 
Baseline to Week 
12-24, and Week 
24-36 
• 
Summary statistics for the Baseline, post-
Baseline, and change from Baseline Hb and 
HbF by treatment arm 
• 
Scatter box-whisker plots for mean change 
over continuous 12-week intervals 
• 
ANCOVA analysis with Baseline value as a 
covariate: LSMean (95% CI), LSMean 
difference (95% CI), and p-value. 
Change from Baseline in mean HbF values 
at Weeks 12 to 24 and Weeks 24 to 36 in 
the absence of transfusions 
Proportion of subjects with an increase 
from Baseline of ≥3% in mean HbF values 
at Weeks 12 to 24 and Weeks 24 to 36 in 
the absence of transfusions. 
 
Week 12 to 
Week 24, and 
Week 24 to 
Week 36 
 
• 
Cochran-Mantel Haenszel (CMH) analysis: 
Odds ratios (OR) (active arms vs. placebo), 2-
sided 95% CI, p-value  
• 
Summary of number and percentage of 
responders with difference in proportions 
(active arm-Placebo) and corresponding 2-
sided 95% CI 
• 
Forest plots of ORs, 2-sided 95% Cis, p-value 
– Higher dose vs. placebo, Lower dose vs. 
placebo 
Proportion of subjects with an increase 
from Baseline of ≥1.0 g/dL in mean Hb 
values at Weeks 12 to 24 and Weeks 24 to 
36 in the absence of transfusions. 
[using Hb from Laboratory Hematology] 
Week 12 to 
Week 24, and 
Week 24 to 
Week 36 
• 
Cochran-Mantel Haenszel (CMH) analysis: 
Odds ratios (OR) (active arms vs. placebo), 2-
sided 95% CI, p-value  
• 
Summary of number and percentage of 
responders with difference in proportions 
(active arm-Placebo) and corresponding 2-
sided 95% CI 
• 
Forest plots of ORs, 2-sided 95% Cis, p-value 
– Higher dose vs. placebo, Lower dose vs. 
placebo 
Proportion of subjects with an increase 
from Baseline of ≥1.5 g/dL in mean Hb 
values at Weeks 12 to 24 and Weeks 24 to 
36 in the absence of transfusions. 
[using Hb from Laboratory Hematology] 
Week 12 to 
Week 24, and 
Week 24 to 
Week 36 
• 
Cochran-Mantel Haenszel (CMH) analysis: 
Odds ratios (OR) (active arms vs. placebo), 2-
sided 95% CI, p-value  
• 
Summary of number and percentage of 
responders with difference in proportions 
(active arm-Placebo) and corresponding 2-
sided 95% CI 
• 
Forest plots of ORs, 2-sided 95% Cis, p-value 
– Higher dose vs. placebo, Lower dose vs. 
placebo 
The plasma PK profile of IMR-687 after 
administration to subjects will be evaluated 
by determination of PK parameters (e.g., 
Cmax, tmax, AUC0-24) based on drug 
concentration levels in plasma obtained 
over time 
 
Baseline and 
Week 3 (TDT) 
Baseline and 
Week 4 (NTDT) 
Descriptive summary 
 
 


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13.6.4.1 TDT Population 
Hematological Improvement Endpoints 
Hematological improvement is defined as a ≥20%, ≥33%, or a ≥50% reduction in pRBC units transfused, 
with a reduction of at least 2 units of RBCs, measured over a fixed period of 12 weeks (from Week 12 to 
Week 24 and from Week 24 to Week 36) or over 24 weeks (from Week 12 to Week 36) as compared to 
the 12-week period prior to the Baseline (Day 1) visit. The pRBC units are defined as the sum all pRBCs 
units for the specific 12- or 24-week period.  
Hematological improvement will also be assessed using any 12-week rolling time period – Day 2 to 85, 
Day 3 to 86, etc. through Day 170 to Day 253 (Week 36) – compared to the 12 weeks prior to Baseline 
(Day 1) – and any 14-week rolling time period – Day 2 to 99, Day 3 to 100, etc. through Day 156 to Day 
253 (Week 36) – compared to the 12 weeks prior to Baseline (Day 1). For the rolling time periods, a 
responder is defined as a subject who meets the hematological improvement criteria in at least one of the 
rolling time periods. 
The proportion of subjects with a ≥20% hematological improvement (a 20% or more reduction in pRBC 
units transfused, with a reduction of at least 2 units of RBCs) during Week 12 to Week 24 and Week 24 to 
Week 36, compared to the 12-week prior to Baseline (Day 1) timeframe, will be assessed using a CMH 
test. The estimate of the odds ratios and the associated 95% confidence intervals (CIs) and p-values from 
the CMH tests will be presented for each active arm vs. placebo at each timepoint. The difference in 
proportions (each active arm-Placebo and the combined active arms-Placebo) and corresponding 95% CI 
will be also provided. An odds ratio exceeding 1 indicates that the proportion of improved subjects in the 
treated arm is higher than in the placebo arm.   
The proportion of subjects with a ≥33% hematological improvement and the proportion of subjects with a 
≥50% hematological improvement for the Week 12 to Week 24 and Week 24 to Week 36 time periods will 
be analyzed similarly as for the proportion of subjects with ≥20% hematological improvement. 
The above analyses for the proportions of subjects with ≥20%, ≥33%, ≥50% hematological improvement 
will be repeated for the 24-week post-Baseline time period, Week 12 to Week 36.  
The proportion of subjects with a ≥20%, ≥33%, and ≥50% hematological improvement for the 12-week 
rolling and 14 week rolling time periods will be analyzed similarly as for the fixed time periods above.  
Bar plots will be provided. The proportion of subjects with a ≥20%, ≥33%, and ≥50% hematological 
improvement, odds ratios, 95% CIs, and p-values will be displayed by treatment arm for Week 12 to 
Week 24, Week 24 to Week 36, and Week 12 to Week 36, compared to the 12-week period prior to 
Baseline (Day 1). Separately, bar plots will be provided for the 12 week rolling time periods and for the 14 
week rolling time periods. 
Number of Transfusion Events Endpoint 
The number of transfusion events in IMR-687 arms from Baseline to Week 36 compared to placebo will 
be assessed using an ANCOVA model with baseline value as a covariate and treatment as a factor. 
Summary statistics of the number of cumulative transfusions at every 12 weeks post-Baseline from Week 
12 through Week 36 will be presented. All post-baseline assessments of number of transfusions will be 
cumulative from baseline. For example, the number of transfusions at Week 24 and Week 36 will include 
all transfusions from baseline through the Week 24 and Week 36 visits, respectively. The least squares 
mean (LSMean) estimates and 95% CIs will be presented for each active arm, the combined active arms, 
and placebo at Week 36. Additionally, the LSMean difference estimates and associated 95% CIs and p-
values at Week 36 will also be reported for each active arm vs. placebo and the combined active arms vs. 
Placebo. 
Box whisker plots of the mean number of transfusion events, mean number of units, and mean pre-
transfusion Hb with outliers over time will be provided by time periods (Weeks 1-12, Weeks 13-24, and 
Weeks 25-36) by treatment arm. 
Transfusion events data will be reported in a by-subject listing using the ITT Analysis Set. 


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Iron Chelation Therapy Endpoints] 
The mean changes from Baseline to Week 36 for iron chelation therapy daily (ICT) dose will be assessed 
using ANCOVA models with baseline value as a covariate on the Safety Analysis Set. The Baseline mean 
daily dose of ICT will be calculated during the 12 weeks prior to the first dose of study drug. The post-
baseline (Week 36) mean values will be calculated during the last 12 weeks of the 36-week treatment 
period, or the last 12 weeks of study drug for subjects who are discontinued early. Summary statistics for 
observed values at Baseline and Week 36 and change from Baseline to Week 36 of ICT will be 
presented. The change from baseline in mean daily dose of ICT at Week 36 will be analyzed using an 
ANCOVA model with baseline ICT mean daily dose as a covariate, including only subjects who did not 
change their ICT drug from Baseline to post-baseline and used only one ICT drug. LSMean estimates 
and 95% CIs will be presented for each active arm and placebo at Week 36. The LSMean difference 
estimates and associated 95% CIs and p-values at Week 36 will also be reported for each active arm vs. 
placebo and the combined active arms vs. Placebo. The values at Week 24 will be analyzed in a similar 
manner. Line plots will be provided for mean change from Baseline with 95% CI to Week 36 for ICT daily 
dose by treatment arm.  
The number and percentage of subjects who took monotherapy (i.e., only one ICT drug) vs. combo 
therapy (i.e., more than one ICT drug) will be summarized at Baseline and Week 36, by treatment arm. 
The percent change in mean daily dose of ICT from Baseline to Week 36 will be summarized with 
descriptive statistics, by treatment arm.  
For subjects that are stable on the same ICT drug(s) throughout the study, the change in mean daily dose 
will be calculated.  Subjects who switched drugs during the study will be excluded. For subjects on more 
than one drug, the change will be averaged for the drugs. 
Serum Ferritin Endpoint 
The mean changes from Baseline to Week 36 for serum ferritin will be assessed using ANCOVA models 
with baseline value as a covariate on the Safety Analysis Set. The Baseline mean serum ferritin will be 
calculated during the 12 weeks prior to the first dose of study drug. The post-baseline (Week 36) mean 
values will be calculated during the last 12 weeks of the 36-week treatment period, or the last 12 weeks of 
study drug for subjects who are discontinued early. Summary statistics for observed values at Baseline 
and Week 36 and change from Baseline to Week 36 of serum ferritin will be presented. The change from 
baseline in mean serum ferritin at Week 36 will be analyzed using an ANCOVA model with baseline 
serum ferritin mean as a covariate. LSMean estimates and 95% CIs will be presented for each active arm 
and placebo at Week 36. The LSMean difference estimates and associated 95% CIs and p-values at 
Week 36 will also be reported for each active arm vs. placebo and the combined active arms vs. Placebo.  
Line plots will be provided for mean change from Baseline with 95% CI to Week 36 for serum ferritin by 
treatment arm. The values at Week 24 will be analyzed in a similar manner.  
13.6.4.2 Imputation Methods for the Hb and HbF Endpoints for the NTDT Population 
The following imputation rules will be applied for the secondary efficacy endpoints related to Hb and HbF 
(Mean change from Baseline in mean Hb values at Weeks 12 to 24 and Weeks 24 to 36 in the absence of 
transfusions. Mean change from Baseline in mean HbF values at Weeks 12 to 24 and Weeks 24 to 36 in 
the absence of transfusions. Proportion of subjects with an increase from Baseline of ≥3% in mean HbF 
values at Weeks 12 to 24 and Weeks 24 to 36 in the absence of transfusions, and Proportion of subjects 
with an increase from Baseline of ≥1.0 g/dL in mean Hb values at Weeks 12 to 24 and Weeks 24 to 36 in 
the absence of transfusions): 
Hb : 
1. Subject will be treated as a non-responder for the Week 12 to 24 endpoint time period if they 
received an RBC Transfusion within the prior 8 weeks (from Week 4 to 24) and a non-responder 
for the Week 24 to 36 endpoint time period if they received an RBC Transfusion within the prior 8 
weeks (from Week 16 to 36). For the mean change from Baseline endpoints this means that the 
mean change from Baseline will be set to missing.  For the proportion of subjects with an 


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increase from Baseline endpoints, this means that the subject will not be included in the 
proportion of subjects with an increase. 
2. If some of the Hb values are missing during any of the time periods, the mean of the non-missing 
values during that time period will be used for the mean change from Baseline endpoints and the 
non- missing values during that time period will be used for the determination of the proportion of 
subjects with an increase from Baseline endpoints. 
HbF : 
1. If the subject received an RBC Transfusion during the time periods described above for Hb, 
regardless of the reason, the HbF will be imputed as the last assessment prior to transfusion 
2. If some of the HbF values are missing during any of the time periods, the mean of the non-
missing values during that time period will be used for the mean change from Baseline endpoints 
and the non- missing values during that time period will be used for the determination of the 
proportion of subjects with an increase from Baseline endpoints. 
The number of subjects with imputed values for the secondary efficacy endpoints and the reason for 
imputation will also be summarized. 
13.6.4.3 NTDT Population 
Responder Analyses 
Proportion of Subjects with an Increase from Baseline of ≥3% in Mean HbF Endpoint 
The proportion of subjects with increase from Baseline of ≥3% in mean HbF values (at Weeks 12 to 24 
and Weeks 24 to 36) will be assessed using a CMH test. The number and percentage of responders and 
non-responders at Weeks 12-24 and Weeks 24-36 will be presented for each treatment arm as well as 
ORs, 95% CIs, and p-values from the CMH tests. The difference in proportions (active arm-Placebo and 
and the combined active arms-Placebo) and corresponding 95% CI will be also provided. Bar plots will be 
provided. The proportion of subjects with response in HbF, where a responder has an increase of ≥3% at 
Weeks 12-24 and Weeks 24-36 compared to Baseline, Odds ratios, 95% CI, and p values will be 
displayed by treatment arm.  
Proportion of Subjects with an Increase from Baseline of ≥1.0 g/dL in Mean Hb Endpoint 
The proportion of subjects with increase from Baseline of ≥1.0 g/dL in mean Hb values (at Weeks 12 to 
24 and Weeks 24 to 36) will be evaluated using a Cochran-Mantel-Haenzel (CMH) test to compare the 
proportion of subjects who achieved improvement between the placebo group and each of the 2 active 
treatment arms (IMR-687 lower dose and IMR-687 higher dose) and the combined active arms. The 
number and percentage of responders and non-responders, ORs, 95% CIs, p-values from the CMH tests 
and the difference in proportions and corresponding 95% CI will be provided similarly to the HbF above.      
Mean Change Analyses 
Change from Baseline in Mean Hb and HbF Endpoints 
The Baseline value of Hb will be defined as the mean of the screening and baseline Hb values. The 
Baseline value of HbF will be defined in an analogous manner. Post-Baseline Hb is defined as the mean 
of all documented hemoglobin values collected during each 12-week interval. If there are any missing 
values at scheduled collected times, the mean will still be calculated from the remaining non-missing 
values. However, any Hb values collected within 8 weeks after a transfusion will not be included in the 
calculation of the mean. Post-Baseline HbF will be defined in an analogous manner. To estimate the 
change of Hb and HbF after dosing within each 12-week interval (Week 12-24, week 24-36), summary 
statistics for the Baseline, post-Baseline, and change from Baseline Hb and HbF will be provided by 
treatment arm.  
The number and percentage of subjects meeting the following selected change in Hb categories will be 
tabulated by treatment arm: 


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• 
Increase ≥1 g/dL 
• 
Increase ≥1.5 g/dL 
The number and percentage of subjects meeting the following selected change in HbF categories will be 
tabulated by treatment arm: 
• 
Increase ≥3% 
Scatter box-whisker plots for the mean change in Hb and HbF concentrations over continuous 12-week 
intervals from Week 12 to Week 24 and Week 24 to Week 36 in the absence of transfusions will be 
provided by treatment arm. 
In addition, the change in mean Hb and HbF concentrations over continuous 12-week intervals from 
Week 12 to Week 24, and Week 24 to Week 36 in the absence of transfusions will be assessed using 
ANCOVA models with Baseline value as a covariate. Summary statistics for observed values at Baseline, 
Weeks 12-24, and Weeks 24-36, and change from Baseline to Weeks 12-24 and 24-36 will be presented. 
LSMean estimates and 95% CIs will be presented for each active arm and placebo at Weeks 12-24 and 
Weeks 24-36. The LSMean difference estimates and associated 95% CIs and p-values at Weeks 12-24, 
and Weeks 24-36 will also be reported for each active arm compared to placebo and the combined active 
arms compared to Placebo. 
Iron Chelation Therapy and Serum Ferritin Endpoints 
The mean change from Baseline to Week 36 for iron chelation therapy daily (ICT) dose and serum ferritin 
will be assessed for the NTDT Population similar to above in section 13.6.4.1 for the TDT Population. 
13.6.4.4 Sensitivity Analyses 
All sensitivity analyses will be performed on the PP Analysis Set unless otherwise specified. 
13.6.4.4.1 NTDT Population 
Proportion of Subjects with an Increase from Baseline of ≥1.0 g/dL in Hb 
The proportion of subjects with increase from Baseline of ≥1.0 g/dL in Hb values (at Weeks 24 and 36) 
will be evaluated using a CMH test to compare the proportion of subjects who achieved improvement 
between the placebo group and each of the 2 active treatment arms (IMR-687 lower dose and IMR-687 
higher dose) and the combined active arms. The number and percentage of responders and non-
responders, ORs, 95% CIs, p-values from the CMH tests and the difference in proportions and 
corresponding 95% CI will be provided similarly to the secondary endpoint – Proportion of subjects with 
an increase from Baseline of ≥1.0 g/dL in mean Hb values. 
Proportion of Subjects with an Increase from Baseline of ≥3% in HbF 
The proportion of subjects with increase from Baseline of ≥3% in HbF values (at Weeks 24 and 36) will be 
assessed using a CMH test. The number and percentage of responders and non-responders at Weeks 
24 and 36 will be presented for each treatment group as well as ORs, 95% CIs, and p-values from the 
CMH tests. The difference in proportions (active arm-Placebo and the combined active arms-Placebo) 
and corresponding 95% CI will be also provided. The proportion of subjects with response in HbF, where 
a responder has an increase of ≥3% at Weeks 24 and 36 compared to Baseline, Odds ratios, 95% CI, 
and p values will be displayed by treatment arm. 
Mean Change from Baseline in Hb 
The mean change in Hb concentration at Week 24 in the absence of transfusions will be assessed using 
an ANCOVA model with Baseline value as a covariate. Summary statistics for observed values at 
Baseline and Week 24, and change from Baseline to Week 24 will be presented. LSMean estimates and 
95% CIs will be presented for each active arm and placebo at Week 24. The LSMean difference 
estimates and associated 95% CIs and p-values at Week 24 will also be reported for each active arm 
compared to placebo and the combined active arms-Placebo.  


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13.6.4.5 Subgroup Analyses 
Subgroup analyses will be performed for the secondary endpoints listed below using the categories listed 
below. All analyses performed on the secondary endpoints will be repeated for each subgroup level. 
Descriptive statistics will be provided. No inferential statistics will be performed. Summary tables and a 
forest plot will display descriptive statistics for each level of a subgroup for a population. 
Subgroup analyses will be performed for all secondary endpoints using the categories listed below. All 
analyses performed on the secondary endpoints will be repeated for each subgroup level for the following 
efficacy endpoints: 
• 
TDT: Transfusion burden proportion analyses –33% fixed and rolling 
• 
TDT: Transfusion burden – mean change from pre-treatment 
• 
NTDT: Mean change from baseline in Hb, HbF, and PRO scores (NTDT-PRO T/W domain and 
total score; SF-36 PCS and MCS)  
Subgroup analyses will also be performed for the following endpoints for the polymorphism genes (listed 
below – BCL11A and XMN1): 
• 
TDT: Transfusion burden proportion analyses –20% and 50% fixed and rolling 
• 
NTDT: Proportion of subjects with ≥1.0 g/dL increase from baseline in mean Hb in the absence of 
transfusions 
• 
NTDT: Proportion of subjects with 3% increase from baseline in mean HbF in the absence of 
transfusions 
Subgroups for the TDT population: 
• 
Region (Europe/North America, Asia/Africa) 
• 
Age (≤ median, > median) 
• 
Sex (male, female) 
• 
Mutation (β0/β0, non-β0/β0) 
• 
Pre-treatment transfusion burden (≤ median, > median) 
• 
Pre-treatment transfusion burden (units/12 weeks):  
o 
Low transfusion burden (≤ 5 units/12 weeks) 
o 
Medium transfusion burden (> 5 - ≤7 units/12 weeks) 
o 
High transfusion burden (> 7 units/12 weeks) 
• 
Splenectomy (yes, no)  
• 
Diagnosis (Major, Intermedia, BE/B+, BE/BO) (disease under history page)  
• 
Baseline serum ferritin (≤ median, > median of the total TDT population) 
• 
Pre-transfusion Hb (≤ median, > median of the total TDT population) 
• 
Baseline BCL11A 
• 
Baseline XMN1 
Subgroups for the NTDT population: 
• 
Age (≤ median, > median of the total population) 
• 
Sex (male, female) 


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• 
Region (Europe/North America, Asia/Africa)  
• 
Diagnosis (Major, Intermedia, BE/B+, BE/BO) (disease under history page) 
• 
Splenectomy (yes, no) 
• 
Baseline serum ferritin (≤ median, > median of the total NTDT population) 
• 
Baseline Hb (≤ median, > median of the total NTDT population) 
• 
Baseline HbF (≤ median, > median of the total NTDT population) 
• 
Baseline NTDT-PRO T/W domain (≤3, >3) 
• 
Baseline BCL11A 
• 
Baseline XMN1 
13.6.5 Pharmacokinetic Analyses 
Data from subjects who experience emesis within the PK sampling duration of IMR-687 at Study Day 1 or 
Week 3 (TDT) or Week 4 (NTDT) visits, will be evaluated on a case-by-case basis for exclusion from 
concentration-time data and PK analysis descriptive summaries. The individual subject data will be listed. 
 
If a quantifiable pre-dose concentration of IMR-687 is detected at Baseline (Study Day 1) and this 
concentration is greater than 5% of the corresponding Cmax, all subject data will be excluded from all 
concentration-time and PK analysis descriptive summaries but will be included in the subject data listings. 
 
All plasma concentration-time data will be reported to the same number of significant figures as displayed 
in the bioanalytical data. Lambdaz will be reported up to 4 decimal places and time-related PK parameters 
(T1/2, Tmax, and Tlast will be reported up to 3 decimal places. All other PK parameters will be reported to the 
same number of significant figures as displayed in the bioanalytical data. 
 
The concentration-time data from subjects with sparse PK sampling collected using the sampling 
schedule reflected in protocol version 5.0 (15 Mar2021) will be summarized descriptively and included in 
subject listings and analyzed for population PK. Noncompartmental analysis will not be performed with 
the PK data collected from these subjects. The concentration-time data from subjects with PK samples 
collected using the sampling schedule reflected in the prior protocol versions (up to version 4.0; 15 Jan 
2020) will be summarized descriptively and listed. The PK data from these subjects will be used for the 
estimation of PK parameters using noncompartmental analysis. All available PK data from this study will 
also be used to explore any relationship between IMR-687 exposure and clinical response, PD endpoints, 
or AEs, as data permit. These data will be analyzed together with PK data from other clinical studies for a 
population PK analysis, as appropriate. Population PK analysis and other exploratory PK/PD analyses 
are not within the scope of this SAP and will be detailed in a separate population PK analysis plan. 
 
No analysis visit windows will be applied for reporting of plasma concentration-time data and PK analysis, 
nominal visit times will be used (i.e., Study Day 1, Week 3 or Week 4). 
13.6.5.1 Plasma Concentrations 
Plasma concentrations of IMR-687 BLQ will be set to 0.01 ng/mL in the computation of mean 
concentration values. Descriptive statistics (number of subjects, mean, geometric mean, SD, coefficient of 
variation (%CV), geometric %CV, median, minimum, and maximum) will be used to summarize the 
plasma concentrations by treatment and by study visit (i.e., Study Day 1 and Week 3/Week 4) for each 
disease state (TDT and NTDT) at each scheduled timepoint. 
 
Linear and semi-logarithmic plots of the arithmetic mean (±SD) and geometric mean (±SD) plasma 
concentration by scheduled sampling time will be provided by dose, by study visit, and by disease state. 


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These plots will show time in hours. The plots will present all calculated means and will include a 
reference line for the lower limit of quantification (LLOQ). 
 
Linear and semi-logarithmic plots of the individual plasma concentration by scheduled sampling time will 
be provided by dose, by subject (one subject per page), and by study visit for each disease state. These 
plots will show time in hours. Individual plots will use the BLQ handling procedure described below for 
“Plasma Pharmacokinetic Parameters”. 
13.6.5.2 Plasma Pharmacokinetic Parameters Analyses 
Plasma PK parameters for IMR-687 will be estimated using non-compartmental methods with Phoenix® 
WinNonlin® Version 8.1 (Certara, USA). The PK parameters will be estimated from the concentration-time 
profiles, and all AUCs will be calculated using a linear up/log down method using actual sampling times. 
 
The apparent terminal elimination half-life, T1/2, where determinable, will be calculated as the natural log 
of 2 divided by the terminal phase rate constant, lambdaz. The number of data points included in the 
regression will be determined by visual inspection, but a minimum of 3 data points in the terminal phase, 
excluding Cmax, is required to estimate lambdaz. In order for lambdaz and lambdaz derived parameters 
(AUCinf, T1/2, Vz/F, CL/F, and Vz/F (steady state) to be reported, the adjusted r2 value reported in Phoenix® 
WinNonlin® must be ≥0.80. 
 
For the purposes of estimating the PK parameters, BLQ values will be set to zero prior to the first 
quantifiable concentration and set to missing thereafter, including embedded BLQs. Scheduled sampling 
times will be used for the interim analyses and actual sampling times will be used for the final analysis. 
 
Missing concentration-time data will be treated as missing except for the pre-dose plasma concentrations 
where a value of 0 will be imputed for Baseline for the purposes of PK parameter estimation. Similarly for 
the Week 3/4 visit, missing concentration-time data will be treated as missing except for the pre-dose 
concentration following steady state dosing where the lowest concentration value over the dosing interval 
(Cmin) will be used for imputation purposes. 
 
For the final analysis, if the actual time is missing, the scheduled time will be substituted and flagged. 
Subjects must have at least 4 consecutive non-zero post-dose plasma concentrations to be considered 
evaluable. Profiles that do not meet this criterion will be flagged for exclusion. 
 
Descriptive statistics (number of subjects, mean, geometric mean, SD, %CV, geometric %CV, median, 
minimum, and maximum) will be used to summarize the PK parameters by dose and by study visit for 
each disease state. Additional PK evaluations may be performed as needed. 
 
Ctrough concentrations for Study Day 1 and Week 3/4 will be summarized along with Ctrough concentrations 
at Week 1, Week 24, and Week 36. 
 
All individual subject PK parameters will be listed. 
 
The following PK parameters for IMR-687 may be computed, where feasible. Additional PK parameters 
may be determined: 
 
 
 
 
 
 


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Table 10 
PK Parameters 
Parameter 
Description 
Study Day 1 (Single Dose) 
Cmax 
Maximum plasma concentration postdose. Observed peak analyte concentration obtained 
directly from the experimental data without interpolation, expressed in concentration units. 
Tmax 
Time to maximum plasma concentration postdose. First observed time to reach peak analyte 
concentration obtained directly from the experimental data without interpolation, expressed in 
time units. 
Tlast 
Time of last measurable plasma concentration. 
Ctrough 
Concentration at the end of the dosing interval 
AUClast 
Area under the concentration-time curve from time 0 to the last measurable concentration 
postdose 
AUCinf 
Area under the concentration-time curve from time 0 to infinity, calculated as AUClast + 
(Clast/Lambdaz) 
Lambdaz 
Apparent terminal elimination phase rate constant 
T1/2 
Apparent terminal elimination half-life 
CL/F 
Apparent total body clearance from oral administration, calculated as Dose/AUCinf 
Vz/F 
Apparent volume of distribution from oral administration, calculated as Dose/lambdaz × AUCinf 
Week 3/4 (Steady State) 
Cmax,ss 
Maximum plasma concentration postdose at steady state. Observed peak analyte 
concentration obtained directly from the experimental data without interpolation, expressed in 
concentration units. 
Tmax,ss 
Time to maximum plasma concentration postdose at steady state. First observed time to reach 
peak analyte concentration obtained directly from the experimental data without interpolation, 
expressed in time units. 
Tlast 
Time of last measurable plasma concentration. 
Ctrough 
Concentration at the end of the dosing interval 
AUC0-24 
Area under the concentration-time curve from time 0 to 24 hours postdose. 
Lambdaz 
Apparent terminal elimination phase rate constant 
CLss/F 
Apparent total body clearance from oral administration at steady state, calculated as 
Dose/AUC0-24 
Vz/F 
Apparent volume of distribution from oral administration at steady state, calculated as 
Dose/lambdaz × AUC0-24 
RAUC 
Accumulation ratio, calculated as AUC0-24 (Week 3/4)/AUClast (Study Day 1; AUClast = 24 
hour) 
Clast = last observed measurable plasma concentration 
13.6.6 Exploratory Efficacy Analyses 
The PP Analysis Set will be used for all exploratory efficacy endpoint analyses. Selected analyses will be 
repeated on the ITT and/or mITT Analysis Sets as sensitivity analyses. 
 
 


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Table 11 
Exploratory Endpoints – TDT Population 
Exploratory Endpoints 
Time Points 
Exploratory Endpoint 
Analysis  
The PD effects as measured by the mean 
change from Baseline in serum PD markers 
of erythropoiesis, iron metabolism, and 
hemolysis. 
 
Baseline to week 36 (including 
all visits in between) 
Mixed Model Repeated Measures 
(MMRM) analysis: Mean (95% CI), 
Mean difference (95% CI), and p-
value will be provided. 
Mean change in transfusion burden (pRBC 
units) as a continuous variable  
Week 12 to Week 24, Week 24 
to Week 36, and Week 12 to 
Week 36, compared to the 12-
week prior to Baseline (Day 1) 
Descriptive summary 
 
Proportion of subjects who are transfusion-
free (independent) for ≥8 weeks during 
treatment 
 
Over treatment time  
CMH analysis: Odds ratios (active 
arm vs. placebo), 95% CI, p-value, 
difference in proportions (active 
arm-Placebo) and corresponding 
95% CI will be provided 
Proportion of subjects who are RBC 
transfusion-free (independent) over 36 
weeks and other variables of transfusion 
burden 
 
Over 36 weeks 
CMH analysis: Odds ratios (active 
arm vs. placebo), 95% CI, p-value, 
difference in proportions (active 
arm-Placebo) and corresponding 
95% CI will be provided 
Mean number of transfusion events 
 
Baseline to Week 36 
• 
Summary statistics of the 
number of cumulative 
transfusions at every 3 weeks 
post-Baseline from Week 3 
through Week 36.  
• 
Analysis of Covariance 
(ANCOVA) analysis with 
Baseline value as a covariate: 
LSMean (95% CI), LSMean 
difference (95% CI) between 
each active dose and placebo, 
and p-value.  
• 
Plots of the mean number of 
transfusions, mean number of 
units, and pre-transfusion 
mean Hb over time 
 
Change from Baseline in mean pre-
transfusion Hb values at Weeks 12 to 24, 
Weeks 24 to 36, and Weeks 12 to 36   
[using pre-transfusion Hb from the Historical 
Transfusion Burden and the Transfusion 
Burden CRFs] 
Baseline to Week 12 to Week 
24, Week 24 to Week 36, and 
Week 12 to Week 36 
• 
Summary statistics for the 
Baseline, post-Baseline, and 
change from Baseline    Hb by 
treatment arm 
• 
Scatter box-whisker plots for 
mean change over continuous 
12-week and 24-week intervals 
• 
ANCOVA analysis with 
Baseline  value as a covariate: 
LSMean (95% CI), LSMean 
difference (95% CI), and p-
value. 
Proportion of subjects with an increase from 
Baseline of ≥1.0 g/dL in mean pre-
transfusion Hb values or a Reduction in RBC 
Week 12 to Week 24, Week 24 
to Week 36, and Week 12 to 
Week 36 
• 
Cochran-Mantel Haenszel 
(CMH) analysis: Odds ratios 
(OR) (active arms vs. 


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Transfusion Burden (≥33% reduction) 
Endpoint at Weeks 12 to 24, Weeks 24 to 36, 
and Weeks 12 to 36 
[using pre-transfusion Hb from the Historical 
Transfusion Burden and the Transfusion 
Burden CRFs] 
placebo), 2-sided 95% CI, p-
value  
• 
Summary of number and 
percentage of responders with 
difference in proportions 
(active arm-Placebo) and 
corresponding 2-sided 95% CI 
• 
Forest plots of ORs, 2-sided 
95% Cis, p-value – Higher 
dose vs. placebo, Lower dose 
vs. placebo 
Mean change from Baseline in TranQOL 
quality of life tool  
 
Weeks, 12, 24, and 36  
Descriptive Summary 
Mean change from Baseline in SF-36 quality 
of life (PCS and MCS domains and 8 
sections) 
Weeks, 12, 24, and 36 
Descriptive Summary 
Pharmacogenomic analyses of genes that 
may affect treatment response (including α-
globin, gamma-globin XmnI polymorphism, 
and BLC11A) 
 
NA 
Descriptive Summary 
Average number of days between 
transfusions 
Over 36 weeks 
Descriptive Summary 
 
Table 12 
Exploratory Endpoints – NTDT Population 
Exploratory Endpoints 
Time Points 
Exploratory Endpoint 
Analysis  
Proportion of subjects who are transfusion-
free (independent) for ≥8 weeks during 
treatment 
 
Over treatment time  
CMH analysis: Odds ratios (active 
arm vs. placebo), 95% CI, p-
value, difference in proportions 
(active arm-Placebo) and 
corresponding 95% CI will be 
provided 
Proportion of subjects who are RBC 
transfusion-free (independent) over 36 weeks 
and other variables of transfusion burden 
 
Over 36 weeks 
CMH analysis: Odds ratios (active 
arm vs. placebo), 95% CI, p-
value, difference in proportions 
(active arm-Placebo) and 
corresponding 95% CI will be 
provided 
Mean change from Baseline in SF-36 quality 
of life (PCS and MCS domains and 8 
sections) 
 
Weeks, 12, 24, and 36 
Descriptive Summary 
Pharmacogenomic analyses of genes that 
may affect treatment response (including α-
globin, gamma-globin XmnI polymorphism, 
and BLC11A) 
 
NA 
• 
Descriptive Summary 
• 
Subgroup analysis 
Proportion of subjects who have an Hb 
increase of ≥1.0 g/dL from Baseline for ≥14 
days in the absence of RBC transfusions 
 
Any consecutive 14-day period 
through Week 36 
CMH analysis: Odds ratios (active 
arm vs. placebo), 95% CI, p-
value, difference in proportions 
(active arm-Placebo) and 
corresponding 95% CI will be 
provided 


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Proportion of subjects who have an increase 
from Baseline of ≥1.0 g/dL in Hb in the 
absence of transfusions  
 
Week 24, Week 36 
Descriptive Summary 
Proportion of subjects who have an increase 
from Baseline of ≥1.5 g/dL in Hb in the 
absence of transfusions 
 
Week 24, and Week 36 
Descriptive Summary 
Duration of the Hb increase from Baseline of 
≥1.0 g/dL over 36 weeks 
 
Over 36 weeks from Baseline 
Descriptive Summary 
Mean change from Baseline in NTDT-PRO 
total score and domain scores including T/W 
and SOB domain scores over a continuous 
12-week interval  
 
Week 12 to Week 24, and 
Week 24 to Week 36. 
Descriptive Summary 
Mean change from Baseline in NTDT-PRO 
total score and domain scores including T/W 
and SOB domain scores  
 
Week 24, Week 36 
Analysis of Covariance 
(ANCOVA) analysis with Baseline 
value as a covariate: LSMean 
(95% CI), LSMean difference 
(95% CI) between each active 
dose and placebo, and p-value. 
Rolling 12-week analysis for Proportion of 
subjects with an increase in Hb 
Rolling time periods – Day 2 to 
85, Day 3 to 86, etc. through 
Day 170 to Day 253 (Week 36) 
• 
Cochran-Mantel Haenszel 
(CMH) analysis: Odds ratios 
(OR) (active arms vs. 
placebo), 2-sided 95% CI, p-
value  
• 
Summary of number and 
percentage of responders with 
difference in proportions 
(active arm-Placebo) and 
corresponding 2-sided 95% CI 
• 
Forest plots of ORs, 2-sided 
95% Cis, p-value – Higher 
dose vs. placebo, Lower dose 
vs. placebo 
Time to first Hb increase (≥1.0 g/dL) 
Over 36 weeks from Baseline 
• 
Kaplan-Meier methods - log 
rank test and hazard ratios 
(and 95% CIs) will be 
estimated from a Cox 
regression model 
• 
Kaplan-Meier for the time to 
first Hb increase with 
separate curves for each 
treatment arm 
 
13.6.6.1 TDT Population 
PD Effects of Erythropoiesis, Iron Metabolism, and Hemolysis Endpoints 
The mean changes from Baseline in serum PD markers of erythropoiesis, iron metabolism, and hemolysis 
will each be analyzed with an ANCOVA model with the corresponding Baseline value as a covariate. 
LSMean estimates and 95% CIs will be presented for each active arm and placebo at Week 36. The 


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LSMean difference estimates and associated 95% CIs and p-values at Week 36 will also be reported for 
each active arm vs. placebo and the combined active arms vs. Placebo. 
Transfusion Burden Endpoints 
Summary statistics of transfusion burden during the 12-week period prior to Baseline (Day 1) and the 24-
week post-Baseline time period will be provided. 
Boxplots illustrating the observed pRBC of transfused RBCs at Baseline, Week 12 to Week 24, Week 24 
to Week 36, and Week 12 to Week 36 will be presented by treatment arm. Additionally, separate boxplots 
showing the change from the 12-week prior to Baseline (Day 1) timeframe to the Week 12 to Week 24 
and Week 24 to Week 36 time periods and from the estimated 24-week period prior to Baseline (Day 1) to 
the Week 12 to Week 36 time period will be presented by treatment group. The estimated 24-week period 
prior to Baseline (Day 1) is the same estimate as calculated for the hematological improvement 
secondary endpoint.  
Proportion of Subjects who are Transfusion Independent for ≥8 Weeks During Treatment Endpoint 
The number and percentage of subjects who remain transfusion independent for at least 8 weeks during 
treatment will be tabulated, along with summary statistics of the duration of transfusion independence in 
weeks. The proportion of subjects who are transfusion independent for at least 8 weeks during treatment 
will also be analyzed using CMH tests. ORs, 95% CIs, and p-values will be reported. The difference in 
proportions (active arm-Placebo and the combined active arms-Placebo) and corresponding 95% CI will 
be also provided. 
Number of Transfusion Events Endpoint 
The mean number of transfusion events in IMR-687 arms from Baseline to Week 36 compared to placebo 
will be assessed using an ANCOVA model with baseline value as a covariate and treatment as a factor. 
Summary statistics of the number of cumulative transfusions at every 3 weeks post-Baseline from Week 3 
through Week 24 will be presented. All post-baseline assessments of number of transfusions will be 
cumulative from baseline. For example, the number of transfusions at Week 24 and Week 36 will include 
all transfusions from baseline through the Week 24 and Week 36 visits, respectively. The least squares 
mean (LSMean) estimates and 95% CIs will be presented for each active arm and placebo at Week 24. 
Additionally, the LSMean difference estimates and associated 95% CIs and p-values at Week 36 will also 
be reported for each active arm vs. placebo and the combined active arms vs. Placebo. 
Box whisker plots of the number of units, and pre-transfusion Hb with outliers over time will be provided by 
treatment arm. 
Transfusion events data will be reported in a by-subject listing using the ITT Analysis Set. 
Change from Baseline in Mean Pre-transfusion Hb Endpoint 
The Baseline value of pre-transfusion Hb will be defined as the mean of the screening and baseline pre-
transfusion Hb values from the Historical Transfusion Burden CRF. Post-Baseline pre-transfusion Hb is 
defined as the mean of all documented pre-transfusion hemoglobin values collected during each 12-week 
interval on the Transfusion Burden CRF. If there are any missing values at scheduled collected times, the 
mean will still be calculated from the remaining non-missing values. To estimate the pre-transfusion 
change of Hb after dosing within each 12-week interval (Week 12-24, week 24-36) and the 24-week 
interval (Week 12-36), summary statistics for the Baseline, post-Baseline, and change from Baseline pre-
transfusion Hb will be provided by treatment arm.  
Scatter box-whisker plots for the mean change in pre-transfusion Hb concentrations over continuous 12-
week intervals from Week 12 to Week 24, Week 24 to Week 36, and Week 12 to 36 will be provided by 
treatment arm. 
In addition, the change in mean pre-transfusion Hb concentrations over continuous 12-week intervals 
from Week 12 to Week 24, and Week 24 to Week 36 and 24-week intervals from Week 12 to Week 36 
will be assessed using ANCOVA models with Baseline value as a covariate. Summary statistics for 
observed values at Baseline, Weeks 12-24, Weeks 24-36, and Weeks 12-36, and change from Baseline 


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to Weeks 12-24, 24-36, and 12-36 will be presented. LSMean estimates and 95% CIs will be presented 
for each active arm and placebo at Weeks 12-24, Weeks 24-36, and Weeks 12-36. The LSMean 
difference estimates and associated 95% CIs and p-values at Weeks 12-24, Weeks 24-36, and Weeks 
12-36 will also be reported for each active arm compared to placebo and the combined active arms 
compared to Placebo. 
Proportion of Subjects with an Increase from Baseline of ≥1.0 g/dL in Mean Pre-transfusion Hb or a 
Reduction in RBC Transfusion Burden Endpoint 
The number and percentage of subjects meeting the following selected change in pre-transfusion Hb 
categories will be tabulated by treatment arm: 
• 
Increase ≥1 g/dL 
• 
Increase ≥1 g/dL OR ≥33% reduction in RBC transfusion burden with a reduction of at least 2 
units of RBCs (hematological improvement) 
The proportion of subjects in meeting each criteria above (at Weeks 12 to 24, Weeks 24 to 36, and 
Weeks 12 to 36) will be evaluated using a Cochran-Mantel-Haenzel (CMH) test to compare the proportion 
of subjects who achieved improvement between the placebo group and each of the 2 active treatment 
arms (IMR-687 lower dose and IMR-687 higher dose) and the combined active arms. The number and 
percentage of responders and non-responders at Weeks 12-24, Weeks 24-36, and Weeks 12-36 will be 
presented for each treatment arm as well as ORs, 95% CIs, and p-values from the CMH tests. The 
difference in proportions (active arm-Placebo and and the combined active arms-Placebo) and 
corresponding 95% CI will be also provided. Bar plots will be provided. The proportion of subjects with 
response in pre-transfusion Hb or hematological improvement at Weeks 12-24, Weeks 24-36, and Weeks 
12-36 compared to Baseline, Odds ratios, 95% CI, and p values will be displayed by treatment arm. 
Mean Change from Baseline in TranQOL and SF-36 Quality of Life Tools 
Subjects in the TDT Population will complete two questionnaires, TranQOL and SF-36, at Baseline and at 
Weeks 12, 24, and 36.  
The TranQOL includes 36 questions spanning five domains. Questions 1 – 10 will be used to calculate 
Physical Health domain scores, questions 11 – 24 will be used to calculate the Emotional Health domain 
score, question 25 will be used to calculate the Sexual Activity domain score, questions 26 – 30 will be 
used to calculate the Family Functioning domain score, and questions 31 – 36 will be used to calculate 
the School and Career Functioning domain score. Each of the 36 questions has five possible responses 
which will be coded numerically. For all questions except for items 2, 4, 9, 16, 17, 25, 26, and 27, 
responses and corresponding numerical values are: 
• 
5 = Always 
• 
4 = Often 
• 
3 = Sometimes 
• 
2 = Almost Never 
• 
1 = Never 
• 
-1 = Not Applicable 
For the remaining 8 questions, responses and corresponding numerical values are: 
• 
1 = Always 
• 
2 = Often 
• 
3 = Sometimes 
• 
4 = Almost Never 


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• 
5 = Never 
• 
-1 = Not Applicable 
Domain scores are calculated using the equation 100 x (1 – [(Sum of all scores in the domain – number 
of valid responses in the domain) / (number of valid responses in the domain x 4)]). Scores of -1 are 
excluded from the calculation. Domain scores can only be calculated if <25% of the total number of 
questions in that domain are missing. Domain scores range from 0 to 100 where higher scores indicate 
higher QoL.  
Descriptive statistics for the five domain scores will be reported at Baseline and Weeks 12, 24, and 36. 
Change from Baseline to each post-Baseline assessment will also be presented for each domain score.  
The SF-36 includes 36 questions spanning 8 scales which are weighted sums of the questions in their 
section. Optum Health scoring software will be used to transform individual question responses to the 
scales which range from 0 to 100 where higher scores indicate less disability. The scales include Physical 
Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional, and 
Mental Health. The software will also calculate two overall scores, the Physical Component Score and the 
Mental Component Score. 
Descriptive statistics for the eight scale scores and the two component scores will be tabulated at 
Baseline and at Weeks 12, 24, and 36. Change from Baseline to each post-Baseline assessment will also 
be presented for each scale and component score.  
By-subject listings of TranQOL data and SF-36 data will be presented on the ITT Analysis Set. 
Average Number of Days Between Transfusions Endpoint 
Descriptive statistics for the average number of days between transfusions over 36 weeks will be 
tabulated with the ITT Analysis Set. Tabulations will be repeated on the mITT (if available) and PP 
Analysis Sets. 
13.6.6.2 Imputation Methods for the Hb Endpoints for the NTDT Population 
The following imputation rules will be applied for the exploratory efficacy endpoints related to Hb 
(Proportion of subjects who have an Hb increase of ≥1.0 g/dL from Baseline for ≥14 days in the absence 
of RBC transfusions, Number of subjects with increase from Baseline of 1.0 g/dL in mean Hb values at 
Week 24 and Week 36 compared to Baseline in the absence of transfusions, Duration of the mean Hb 
increase from Baseline of ≥1.0 g/dL over 36 weeks, and Proportion of subjects who have an increase 
from Baseline of ≥1.5 g/dL in mean of Hb values in the absence of transfusions): 
1. For the number of subjects with increase from Baseline of 1.0 g/dL in mean Hb values at Week 
24 and Week 36 compared to Baseline in the absence of transfusions endpoint, and the 
proportion of subjects who have an increase from Baseline of ≥1.5 g/dL in mean of Hb values in 
the absence of transfusions endpoints, subjects will be treated as non-responders for the Week 
24 or Week 36 time point if they received an RBC Transfusion within the prior 8 weeks for that 
time point (Weeks 16-24 for the Week 24 time point, Weeks 28-36 for the Week 36 time point). 
For the duration of the mean Hb increase from Baseline of ≥1.0 g/dL over 36 weeks endpoint, an 
8 week period following any transfusion will be excluded from the duration total. For the number 
of subjects and the proportion of subjects with an increase from Baseline endpoints, this means 
that the subject will not be included in the number or proportion of subjects with an increase. 
2. If the subject received an RBC Transfusion during the time periods described above the Hb will 
be imputed as the last assessment prior to transfusion 
3. If some of the Hb values are missing during any of the time periods, the duration of the non-
missing values during that time period will be used for the duration of the mean increase from 
Baseline endpoint and the non-missing values during that time period will be used for the 
determination of the number or proportion of subjects with an increase from Baseline endpoints. 


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The number of subjects with imputed values for the exploratory efficacy endpoints and the reason for 
imputation will also be summarized. 
13.6.6.3 NTDT Population 
Proportion of Subjects who have an Hb Increase of ≥1.0 g/dL Endpoints 
The number and percentage of subjects who have an Hb increase of ≥1.0 g/dL from Baseline for ≥14 
days in the absence of RBC transfusions will be calculated at all post-Baseline Hb collection time points. 
All Hb values, including those collected at unscheduled visits but excluding values collected within 8 
weeks after a RBC transfusion, will be sorted by date. For each value and the next subsequent value in 
time, the values and the time between values will be compared.  If both values are increased ≥1.0 g/dL 
from Baseline and are ≥14 days apart, the subject will be counted as a yes in the proportion. The 
proportion of subjects who have an Hb increase of ≥1.0 g/dL from Baseline for ≥14 days, in the absence 
of RBC transfusions, in active arms will be compared to the placebo group using CMH tests. ORs, 95% 
CIs, and p-values will be reported. The difference in proportions (active arm-Placebo and the combined 
active arms-Placebo) and corresponding 95% CI will be also provided 
The number and percentage of subjects who have an Hb increase of ≥1.0 g/dL from Baseline will be 
calculated at all post-Baseline Hb collection time points. For Week 24 and Week 36 data, the proportion 
of subjects with increases from Baseline of ≥1.0 g/dL in active arms will be compared to the placebo 
group using CMH tests. ORs, 95% CIs, and p-values will be reported. The difference in proportions (active 
arm-Placebo and the combined active arms-Placebo) and corresponding 95% CI will be also provided.  
Proportion of Subjects who are RBC Transfusion-Free Over 36 Weeks Endpoint 
The number and percentage of subjects who remain RBC transfusion free throughout the 36-week 
treatment period will be reported. Additionally, the number and percentage of subjects who have 
remained transfusion free since Baseline at each post-Baseline timepoint prior to Week 36 will be 
reported. Transfusion burden data will also be listed on the ITT Analysis Set. 
Duration of the Mean Hb Increase from Baseline of ≥1.0 g/dL Over 36 Weeks 
Duration of Hb increase from Baseline of ≥1.0 g/dL over 36 weeks will be summarized descriptively by 
treatment arm. The duration will be calculated according to the following: 
1. Sort all post-baseline non-missing laboratory Hb values for a subject, including unscheduled, 
chronologically. 
2. For any Hb change from baseline values that are ≥1.0 g/dL, compute the following: 
a. Date of Hb change from baseline value ≥1.0 g/dL – (Date of previous non-missing 
laboratory Hb value) 
b. Note: The date of the previous non-missing laboratory Hb value may include baseline 
values. 
3. For each subject, sum up all values from #2 above. 
Mean Change from Baseline in NTDT-PRO and SF-36 Quality of Life Tools 
Subjects in the NTDT Population will complete two questionnaires, SF-36 and NTDT-PRO, at Baseline 
and Weeks 12, 24, and 36. 
Similar to the TDT Population, descriptive statistics for the eight scale scores and the two component 
scores of the SF-36 will be tabulated at Baseline and at Weeks 12, 24, and 36. Change from Baseline to 
each post-Baseline assessment will also be presented for each scale and component score.  
The NTDT-PRO consists of eight items. Questions 1 and 2 assess tiredness with and without physical 
activity. Questions 3 and 4 assess weakness with and without physical activity. Questions 5 and 6 assess 
shortness of breath with and without physical activity. The final two items assess the overall severity and 
progression of thalassemia symptoms. Items 1 – 4 are grouped into the Tiredness/Weakness Domain 
and Items 5 – 6 are grouped into the Shortness of Breath Domain. 


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Scores for the 6 domain related questions range from 0 (no tiredness/weakness/shortness of breath) to 
10 (extreme tiredness/weakness/shortness of breath). 
The Tiredness/Weakness domain score will be calculated by averaging the responses to questions 1-4. 
The Shortness of Breath domain score will be calculated by averaging the responses to questions 5-6. If 
any responses are missing in questions 1-4 or 5-6 for the timepoint of evaluation, then the 
Tiredness/Weakness and Shortness of Breath domain scores cannot be calculated, respectively. 
The total score will be calculated by averaging the responses to questions 1-6. If any responses are 
missing at the time point in question, then the total score cannot be calculated. 
Descriptive statistics of the Tiredness/Weakness and Shortness of Breath domain scores and total score, 
and changes from Baseline, will be reported at Baseline and at Weeks 12, 24, and 36 by treatment group, 
as well as changes from the last assessment, i.e., from Week 12 to Week 24 and Week 24 to Week 36.  
The mean change from Baseline in the NTDT-PRO total score will be assessed using an ANCOVA model 
with Baseline value as a covariate. Summary statistics for observed values at Baseline and Week 24 and 
change from Baseline to Week 24 will be presented. LSMean estimates and 95% CIs will be presented 
for each active arm and placebo at Week 24. The LSMean difference estimates and associated 95% CIs 
and p-values at Week 24 will also be reported for each active arm compared to placebo and the 
combined active arms-Placebo. The Week 36 NTDT-PRO total score will be analyzed with a similar 
model, as will the NTDT-PRO T/W and SOB domain scores at Weeks 24 and 36. 
By-subject listings of SF-36 data and NTDT-PRO data will be presented on the ITT Analysis Set. 
Proportion of Subjects with an Increase from Baseline of ≥3% in Mean HbF Over 12 Week Rolling Time 
Periods Endpoint 
The proportion of subjects with increase from Baseline of ≥3% in mean HbF values measured over 12-
week intervals (from Day 2 to 85, Day 3 to 86, etc. through Day 170 to Day 253 (Week 36)) will be 
assessed using a CMH test. The number and percentage of responders and non-responders at each of 
the rolling time periods will be presented for each treatment group as well as ORs, 95% CIs, and p-values 
from the CMH tests. The difference in proportions (active arm-Placebo and the combined active arms-
Placebo) and corresponding 95% CI will be also provided. Bar plots will be provided. The proportion of 
subjects with response in HbF, where a responder has an increase of ≥3% at each of the rolling time 
periods compared to Baseline, Odds ratios, 95% CI, and p values will be displayed by treatment arm.  
Proportion of Subjects with an Increase from Baseline of ≥1.0 g/dL in Mean Hb Over 12 Week Rolling 
Time Periods Endpoint 
The proportion of subjects with increase from Baseline of ≥1.0 g/dL in mean Hb values measured over 12 
week intervals (from Day 2 to 85, Day 3 to 86, etc. through Day 170 to Day 253 (Week 36)) will be 
evaluated using a Cochran-Mantel-Haenzel (CMH) test to compare the proportion of subjects who 
achieved improvement between the placebo group and each of the 2 active treatment arms (IMR-687 
lower dose and IMR-687 higher dose) and the combined active arms. The number and percentage of 
responders and non-responders, ORs, 95% CIs, p-values from the CMH tests and the difference in 
proportions and corresponding 95% CI will be provided similarly to the HbF above.  
Time to First Hb Increase (≥1.0 g/dL) 
The time to first Hb increase will be analyzed using Kaplan-Meier methods. Time in months to the first Hb 
increase can be calculated as ([date of first Hb increase – date of first dose + 1] / 30.4375).  
Subjects who experience no Hb increase during the study will be censored at their study end date (or 
data cut-off date if the study end date is not available). The number and percentage of subjects with 
events (subjects who experienced at least 1 Hb increase on-study) and censored (subjects who did not 
experience any Hb increase on-study) will be presented. The 25th, 50th (median), and 75th percentiles, 
along with associated 2-sided 95% CIs based on the Brookmeyer and Crowley method will be presented. 
The p-values from a log rank test and hazard ratios (and 95% CIs) estimated from a Cox regression 


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model will be presented for comparison of each treatment arm to placebo. Kaplan-Meier figures will be 
produced for the time to first Hb increase with separate curves for each treatment arm. 
13.6.6.4 Sensitivity Analyses 
All sensitivity analyses will be performed on the PP Analysis Set unless otherwise specified. 
13.6.6.4.1 TDT Population 
Proportion of subjects who are transfusion-free (independent) for ≥12 weeks during treatment 
The number and percentage of subjects who remain transfusion independent for at least 12 weeks during 
treatment will be tabulated, along with summary statistics of the duration of transfusion independence in 
weeks. The proportion of subjects who are transfusion independent for at least 12 weeks during treatment 
will also be analyzed using CMH tests. ORs, 95% CIs, and p-values will be reported. The difference in 
proportions (active arm-Placebo and the combined active arms-Placebo) and corresponding 95% CI will be 
also provided. A bar plot will be provided, including both the proportions of subjects who are transfusion-
free for ≥ 8 weeks and ≥12 weeks. 
13.6.6.4.2 NTDT Population 
Proportion of subjects who are transfusion-free (independent) for ≥12 weeks during treatment 
The number and percentage of subjects who remain transfusion independent for at least 12 weeks during 
treatment will be tabulated, along with summary statistics of the duration of transfusion independence in 
weeks. The proportion of subjects who are transfusion independent for at least 12 weeks during treatment 
will also be analyzed using CMH tests. ORs, 95% CIs, and p-values will be reported. The difference in 
proportions (active arm-Placebo and the combined active arms-Placebo) and corresponding 95% CI will be 
also provided. A bar plot will be provided, including both the proportions of subjects who are transfusion-
free for ≥ 8 weeks and ≥12 weeks. 
13.6.7 Specialty Hematology Endpoints 
Specialty hematology laboratory assessments will be summarized and listed using the ITT and Per-
Protocol Analysis sets similarly but separately for each population. Assessments will include: 
 
• 
HbF 
• 
F-cells (%) 
 
Descriptive statistics (N, mean, SD, median, Q1, Q3, minimum, and maximum) for the observed and 
change from Baseline values will be presented at Baseline and each post-Baseline collection.  
Specialty hematology tabulations will be repeated stratified by genotype (concomitant alpha gene deletion 
vs. concomitant alpha gene duplication vs. concomitant alpha gene triplication). 
The following figures will be provided for all specialty hematology parameters:  
• 
Shift plot from Baseline to post-Baseline maximum for each specialty hematology parameter by 
treatment arm and for the combined IMR-687 treatment arms; 
• 
Box and whisker plot for each specialty hematology parameter by visit for each treatment arm 
and the combined IMR-687 treatment arms 
13.6.8 Pharmacodynamic Endpoints 
Pharmacodynamic laboratory assessments will be summarized and listed using the Per Protocol, ITT, 
and mITT Analysis sets, for the TDT population. Assessments will include: 
 
• 
Iron Metabolism 


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o 
Serum ferritin 
o 
Hepcidin-25 
o 
Serum iron and total iron binding capacity (TIBC) for calculated transferrin saturation 
• 
Erythropoiesis 
o 
Erythropoietin 
o 
Soluble transferrin receptor (STFR) 
• 
Hemolysis 
o 
Haptoglobin 
o 
LDH 
o 
Indirect Bilirubin 
o 
Reticulocytes (absolute and %) 
• 
Cardiac/inflammation 
o 
Serum N-terminal pro-B-type natriuretic peptide (serum NT-proBNP) 
o 
High-sensitivity C-reactive protein (hsCRP) 
• 
Adhesion 
o 
Soluble E-selectin 
o 
Soluble P-selectin 
o 
Soluble intercellular adhesion molecule 1 (ICAM-1) 
o 
Vascular cell adhesion molecule 1 (VCAM-1) 
• 
Hematology 
o 
RDW 
o 
MCV 
o 
Hb 
Descriptive statistics (N, mean, SD, median, Q1, Q3, minimum, and maximum) for the observed and 
change from Baseline values will be presented at Baseline and each post-Baseline collection.  
PD tabulations will be repeated stratified by genotype (concomitant alpha gene deletion vs. concomitant 
alpha gene duplication vs. concomitant alpha gene triplication) and Beta-Thalassemia Major (B0 / B0, B0 
/ B+), Beta-Thalassemia Intermedia (B+ / B+, B0 / B+, B+ / B, B0 / B, B0 / B0), and HbE/Beta-
Thalassemia (BE / B+, BE / B0). 
The following figures will be provided for all PD parameters:  
• 
Shift plot from Baseline to post-Baseline maximum for each PD parameter and treatment arm and 
for the combined IMR-687 treatment arms; 
• 
Box and whisker plot of PD parameters by visit and treatment arm and the combined IMR-687 
treatment arms. 
13.7 Other Data 
Pregnancy test results will be listed on the Safety Analysis Set. 
Virology available data will be summarized and listed by treatment group on the Safety Analysis Set. 
Blood samples will be collected for serum virology (screening assessment) only if clinically indicated. 
Testing will be performed through a central laboratory and may include hepatitis B surface antigen 
(HBsAg), hepatitis A immunoglobulin M (IgM), and hepatitis C virus (HCV) antibody, as well as HIV 
testing. 
 
 


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 References 
FDA, ICH. (2013, January) Guidance for Industry E3 Structure and Content of Clinical Study Reports 
Questions and Answers (R1). https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/e3-structure-and-content-clinical-study-reports-questions-and-answers-r1. 
 
ICH. (2005, May 12) The Clinical Evaluation of QT/QTC Interval Prolongation and Proarrhythmic Potential 
for Nonantiarrhythmic Drugs E14. https://database.ich.org/sites/default/files/E14_Guideline.pdf. 
 
Klaassen RJ, Barrowman N, Merelles-Pulcini M, Vichinsky EP, Sweeters N, et al. Validation 
and reliability of a disease-specific quality of life measure (the TranQol) in adults and children 
with thalassaemia major. Br J Haematol. 2014 Feb;164(3):431-7 (PubMed Abstract) 
Taher A, Viprakasit V, Cappellini MD, Sutcharitchan P, Ward R, Mahmoud D, et al. 
Development of a patient-reported outcomes symptom measure for patients with 
nontransfusion-dependent thalassemia (NTDT-PRO©). Am J Hematol. 2019 Feb;94(2):171-6. 
Cappellini et al., Health-related quality of life outcomes for patients with transfusion-dependent beta-
thalassemia treated with luspatercept in the BELIEVE trial. American Society of Hematology. 2020 Nov 
12. https://acceleronpharma.com/wp-content/uploads/2020/12/Cappellini-ASH-2020-BELIEVE-HRQoL-
Oral_Nov-12-1.pdf 
 
 


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 Glossary of Abbreviations 
Glossary of Abbreviations: 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomic Therapeutic Classification 
AUC0-24 
Area Under the Concentration-Time Curve from Time 0 to 24 Hours Postdose 
AUCinf 
Area Under the Concentration-Time Curve from Time 0 to Infinity 
AUClast 
Area Under the Concentration-Time curve from Time 0 to the Last Measurable 
Concentration Postdose 
BLQ 
Below the Limit of Quantification 
CI 
Confidence Interval 
Clast 
Last Observed Measurable Plasma Concentration 
CL/F 
Apparent Total Body Clearance from Oral Administration after Single Dose 
CLss/F 
Apparent Total Body Clearance from Oral Administration at Steady State 
Cmax 
Maximum Plasma Concentration Postdose after Single Dose 
Cmax,ss 
Maximum Plasma Concentration Postdose at Steady State 
Cmin 
Minimum Plasma Concentration over the Dosing Interval 
Ctrough 
Concentration at the End of the Dosing Interval 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
Hb 
Hemoglobin 
HbF 
Fetal Hemoglobin 
IXRS/IVRS 
Interactive Voice Response System 
Lambdaz 
Apparent Terminal Elimination Phase Rate Constant 
LLOQ 
Lower Limit of Quantification 
LSMean 
Least squares mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model Repeated Measures 
NTDT 
Non-transfusion dependent 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PP 
Per Protocol 


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pRBC 
Packed red blood cells 
PT 
Preferred Term 
QD 
Once daily 
QoL 
Quality of Life 
RAUC 
Accumulation Ratio 
RBC 
Red blood cells 
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SI 
International System of Units 
SOC 
System Organ Class 
T1/2 
Apparent Terminal Elimination Half-life 
Tlast 
Time of Last Measurable Plasma Concentration 
Tmax 
Time to Maximum Plasma Concentration Postdose after Single Dose 
Tmax,ss 
Time to Maximum Plasma Concentration Postdose at Steady State 
TDT 
Transfusion dependent 
TEAE 
Treatment-Emergent Adverse Event 
Vz/F 
Apparent Total Body Clearance from Oral Administration after Single Dose or 
Steady State 


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 Appendices 
Appendix 1 Schedule of Assessments – TDT Population 


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Statistical Analysis Plan 
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Page 67 of 82 
 
Screening 
Baseline 
Double-blind, Placebo-controlled Treatment 
EOTa / ET 
End of Study 
(Safety FU) 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Study Week(s) 
-4 to 0 
NA 
1 
2 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
40 
Study Day(s) 
-28 
to -1 
1b 
7 
±2 
14 
±2 
21 
±7 
42 
±7 
63 
±7 
84 
±7 
105 
±7 
126 
±7 
147 
±7 
168 
±7 
189 
±7 
210 
±7 
231±7 
252±7 
280±7 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Transfusion burdenh 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examinationi 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECGj 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Hematology and 
Chemistry 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Coagulation studies 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Urinalysis 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Pregnancy testingk 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Specialty hematologyl 
X 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
PD markersm 
X 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
IMR-687 plasma PKn 
 
X 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
QOL assessmentso 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Study drug dispensing 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Study drug admin at 
sitep 
 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Study drug admin 
 
Oral administration of IMR-687 or placebo qd 
 
AEs and concomitant 
medications 
Continuousq 
AE = adverse event; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; ET= early termination; EOT = end of treatment; FU = follow-up; 


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Hb = hemoglobin; HbF = fetal hemoglobin; HIV = human immunodeficiency virus; hsCRP = highly sensitive C-reactive protein; ICAM-1 = intercellular adhesion 
molecule 1; ICF = informed consent form; NT-proBNP = N-terminal pro B-type natriuretic peptide; PD = pharmacodynamics; PE = physical examination; PGx = 
pharmacogenomics; 
PK = pharmacokinetic; pRBC = packed red blood cells; QOL = quality of life; SD = standard deviation; SF-36 = Short Form (36) Health Survey; TEAE = treatment-
emergent adverse event, TIBC = total iron binding capacity; TranQOL = Transfusion-dependent QoL Questionnaire; VCAM-1 = vascular cell adhesion molecule 1. 
Note: Unless otherwise specified, all assessments should be completed prior to dosing at any given timepoint. 
Note: Unscheduled visits may occur, limited to visits resulting from potential TEAEs, drug dispensation, or other urgent study-related procedures 
a The last day of dosing will be at Week 36 visit; subject should consume their last dose of study drug on site, after pre-dose assessments have been completed. The 
Week 36 visit will also be the ET visit. During the study visit, assessments should be collected from any subject who discontinues study drug or study prematurely. 
Early termination visits will have the same procedures as the Week 36 visit, except that study drug will not be administered and trough PK will not be collected. 
b The first day study drug is taken is considered Baseline (Day 1). Day 1 assessments should be performed prior to study drug administration. If a subject requires a 
transfusion on this day, the transfusion may occur only after all study assessments are completed. 
c Qualified site personnel will contact the subject by telephone at Week 2 to capture potential TEAEs and concomitant medications. Subjects will also be reminded of 
compliance with drug and the next visit schedule. If any AEs of significant clinical concern are identified during the telephonic visit, the subject will be requested 
to come into the site to be assessed. 
d Pharmacogenomic evaluation is optional and may be performed at screening if subject provides informed consent. 
e Disease history should contain a confirmed diagnosis of β-thalassemia or hemoglobin E/β-thalassemia. Concomitant alpha gene deletion, duplication, or 
triplication is allowed. f After obtaining signed informed consent, the subject’s transfusion history for the 12 weeks prior to Baseline (Day 1) visit date should be 
recorded. In order to be eligible for the 
study, the dates of transfusion events and the number of pRBC units per event within the 12 weeks prior to the Baseline (Day 1) visit must be available. If 
available, the following data should also be collected for each transfusion event: volume and hematocrit of each pRBC unit, pre-transfusion Hb, and pre-
transfusion weight. 
g Vital signs include heart rate, respiratory rate, blood pressure, and body temperature. At Day 1 and Week 3, vital signs will be taken pre-dose and 2 hours (± 20 
minutes) 
post-dose, during the PK assessments. At all other timepoints, vital signs can be taken irrespective of taking study drug. Vital signs should be consistently 
measured in either the sitting or semi-supine position. 
h Transfusion burden will be assessed using the following variables: dates of transfusion events, number of pRBC units per event, volume and hematocrit of 
each pRBC unit, pre-transfusion Hb, and pre-transfusion weight. 
i Complete PEs will be performed at Screening, Week 24, and Week 36 and will include a general examination of the body including the abdomen, heart, lungs, 
lymph nodes, back/neck, neurological system, skin, extremities, head, eyes, nose, and throat. At all other visits, symptom-directed PEs will be obtained after 
identification of AEs deemed by the investigator to be of significant clinical concern. 
j All ECGs to be performed in triplicate. At Baseline and Week 3, ECGs will be obtained at pre-dose and 2 hours (±30 minutes) post-dose. At all other timepoints, 
ECGs will be taken pre-dose. 
k Females of childbearing potential only. A serum pregnancy test will be performed at screening via a central laboratory; all subsequent tests will be urine 
performed locally (with test kits provided by the central laboratory). 
l Includes HbF and percent F cells. Blood samples should be obtained prior to administration of study drug. 
m Includes serum ferritin, soluble transferrin receptor, hepcidin-25, haptoglobin, E-selectin, P-selectin, ICAM-1, VCAM-1, hsCRP, serum NT-proBNP, serum iron and 
TIBC for calculated transferrin saturation, and erythropoietin. Blood samples should be obtained prior to administration of study drug. PD markers will need to 
be collected prior to RBC transfusion (if applicable). 
n At Baseline and Week 3, serial blood samples for IMR-687 and concentrations of metabolite(s) will be drawn pre-dose (within 30 minutes) and at 15 minutes (±5 
minutes), 30 minutes (±5 minutes), and 3 hours (±20 minutes) after administration of study drug. A trough blood sample will be drawn pre-dose at Week 1, Week 
24, and Week 36. The date/time of the previous dose will be recorded. If a subject requires a transfusion on the day of a PK draw, the transfusion can only be 
performed after the final PK sampling. For ET visits, a trough blood sample will not be collected. Patients dosed prior to protocol version 5.0 (15 Mar 2021) used 


Statistical Analysis Plan 
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the following PK sampling schedule: At Baseline and Week 3, serial blood samples for IMR-687 and concentrations of metabolite(s) were drawn pre-dose (within 
30 minutes) and at 30 minutes (± 5 minutes), 1.5 hours (±15 minutes), 4 hours (±15 minutes), 6 hours (±1 hour) and 24 hours (± 2 hours) after administration of 
study drug. On these full profile PK days, food details were also recorded at the clinical sites. A trough blood sample was drawn pre-dose at Week 1, Week 24, and 
Week 36. Transfusion should not have coincided with Baseline (Day 1) or the Week 3 visit, due to the PK assessment that day. For ET visits, a trough blood sample 
was not collected. 
o Quality of life assessments will be assessed by the TranQOL and SF-36 QoL tools. The QoL assessments will be administered at Baseline and at Weeks 12, 24, and 
36. Baseline QoL assessments should be completed before administration of study drug. 
p On days when study drug is taken in the clinic, food details will also be recorded. 
q Adverse events and concomitant medications, including iron chelation therapy and hydroxyurea use, will be recorded at each visit throughout the study from 
Screening (after signing the ICF) through the end of study visit (Week 40). 
 
 


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Appendix 2 Schedule of Assessments – NTDT Population 
 


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Screenin 
g 
Baseline 
Double-blind, Placebo-controlled Treatment 
EOTa / 
ET 
End of Study 
(Safety FU) 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Study Week(s) 
-4 to 0 
NA 
1 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
Study Day(s) 
-28 to -1 
1b 
7±2 
14±2 
28±5 
56±7 
84±7 
112±7 
140±7 
168±7 
196±7 
224±7 
252±7 
280±7 
Physical examinationi 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECGj 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology and 
chemistry 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation studies 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
Urinalysis 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
Pregnancy testingk 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Specialty hematologyl 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
PD markersm 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
IMR-687 plasma PKn 
 
X 
X 
 
X 
 
 
 
 
X 
 
 
X 
QOL assessmentso 
X 
X 
X 
X 
Study drug admin at 
sitep 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug dispensing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug admin 
Oral administration of IMR-687 or placebo qd 
AEs and concomitant 
medications 
Continuousq 
AEs = adverse events; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; ET= early termination; EOT = end of treatment; FU = follow-up; Hb = 
hemoglobin; HIV = human immunodeficiency virus; hsCRP = highly sensitive C-reactive protein; ICAM-1 = intercellular adhesion molecule 1; ICF = informed consent 
form; NTDT-PRO = non- -thalassemia patient reported outcome; NT-proBNP = N-terminal pro B-type natriuretic peptide; PD = pharmacodynamics; PE = physical 


Statistical Analysis Plan 
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Page 72 of 82 
 
examination; PGx = pharmacogenomics; PK = pharmacokinetic; pRBC = packed red blood cells; QOL = quality of life; RBC = red blood cell; SD = standard deviation; SF-36 
= Short Form (36) Health Survey; TEAE = treatment-emergent adverse event; TIBC = total iron binding capacity; VCAM-1 = vascular cell adhesion molecule 
1. 
Note: Unless otherwise specified, all assessments should be completed prior to dosing at any given timepoint. 
Note: In the case of a subject receiving a transfusion after signing the ICF, but prior to randomization, the investigator would inform the medical monitor. The intent is to 
avoid transfusions within the 2-week period leading to randomization. Approval could be obtained for the screening period to be extended by a maximum of 14 days. 
Note: Unscheduled visits may occur, limited to visits resulting from potential TEAEs, drug dispensation, or other urgent study-related procedures. 
a The last day of dosing will be at Week 36 visit; subject should consume their last dose of study drug on site, after pre-dose assessments have been completed. The 
Week 36 visit will also be the ET visit. During the study visit, assessments should be collected from any subject who discontinues study drug or study prematurely. Early 
termination visits will have the same procedures as the Week 36 visit, except that study drug will not be administered and trough PK will not be collected. 
b The first day study drug is taken is considered Baseline (Day 1). Day 1 assessments should be performed prior to study drug administration. If a subject requires a 
transfusion on this day, the transfusion may occur only after all study assessments are completed. 
c Qualified site personnel will contact the subject by telephone at Week 2 to capture potential TEAEs and concomitant medications. Subjects will also be reminded of 
compliance with drug and the next visit schedule. If any AEs of significant clinical concern are identified during the telephonic visit, the subject will be requested to come 
into the site to be assessed. 
d Pharmacogenomic evaluation is optional and may be performed at screening if subject provides informed consent. 
e Disease history should contain a confirmed diagnosis of β-thalassemia or hemoglobin E/β-thalassemia. Concomitant alpha gene deletion, duplication, or triplication is 
allowed. 
f After obtaining signed informed consent, the subject’s transfusion history for the 12 weeks prior to Baseline (Day 1) visit date should be recorded. In order to be 
eligible for the study, the dates of transfusion events and the number of pRBC units per event within the 12 weeks prior to the Baseline (Day 1) visit must be available. If 
available, the following data should also be collected for each transfusion event: volume and hematocrit of each pRBC unit, pre-transfusion Hb, and pre-transfusion 
weight. 
g Vital signs include heart rate, respiratory rate, blood pressure, and body temperature. At Day 1 and Week 4, vital signs will be taken pre-dose and 2 hours (± 20 
minutes) post-dose, during the PK assessments. At all other timepoints, vital signs can be taken irrespective of taking study drug. Vital signs should be consistently 
measured in either the sitting or semi-supine position. 
h Transfusion burden will be assessed using the following variables: dates of transfusion events, number of pRBC units per event, volume and hematocrit of each pRBC 
unit, pre-transfusion Hb, and pre-transfusion weight. 
i Complete PEs will be performed at Screening, Week 24, and Week 36 and will include a general examination including the abdomen, hear 
neurological system, skin, extremities, head, eyes, nose, and throat. At all other visits, symptom-directed PEs will be obtained after identification of AEs deemed by the 
investigator to be of significant clinical concern. 
j All ECGs to be performed in triplicate. At Baseline and Week 4, ECGs will be obtained at pre-dose and 2 hours (±30 minutes) post-dose. At all other timepoints, ECGs 
will be taken pre-dose. 
k Females of childbearing potential only. A serum pregnancy test will be performed at screening via central laboratory; all subsequent tests will be urine performed 
locally (with test kits provided by the central laboratory). 
l Includes HbF and percent F cells. Blood samples should be obtained prior to administration of study drug. 
m Includes serum ferritin, soluble transferrin receptor, hepcidin-25, haptoglobin, E-selectin, P-selectin, ICAM-1, VCAM-1, hsCRP, serum NT-proBNP, serum iron and TIBC 
for calculated transferrin saturation, and erythropoietin. Blood samples should be obtained prior to administration of study drug. PD markers will need to be collected 
prior to RBC transfusion (if applicable). 
n At Baseline and Week 4, serial blood samples for IMR-687 and concentrations of metabolite(s) will be drawn pre-dose (within 30 minutes) and at 15 minutes (±5 
minutes), 30 minutes (±5 minutes), and 3 hours (±20 minutes) after administration of study drug. A trough blood sample will be drawn pre-dose at Week 1, Week 24, 
and Week 36. The date/time of the previous dose will be recorded. If a subject requires a transfusion on the day of a PK draw, the transfusion can only be performed 
after the final PK sampling. For ET visits, a trough blood sample will not be collected. Patients dosed prior to protocol version 5.0 (15 Mar 2021) used the following PK 


Statistical Analysis Plan 
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sampling schedule: At Baseline and Week 4, serial blood samples for IMR-687 and concentrations of metabolite(s) were drawn predose (within 30 minutes) and at 30 
minutes (± 5 minutes), 1.5 hours (± 15 minutes), 4 hours (±15 minutes), 6 hours (±1 hour), and 24 hours (±2 hours) after administration of study drug. On these full 
profile PK days, food details was also recorded at the clinical sites. A trough blood sample was drawn predose at Week 1, Week 24, and Week 36. Transfusion should not 
have coincided with Baseline (Day 1) or the Week 4 visit, due to the PK assessment that day. For ET visits, a trough blood sample was not collected. 
o Quality of life assessments will be performed by the NTDT-PRO and SF-36 QoL tools. The QoL assessments will be administered at Baseline and at Weeks 12, 24, and 
36. Baseline QoL assessments should be completed before administration of study drug. 
p On days when study drug is taken in the clinic, food details will also be recorded. 
q Adverse events and concomitant medications, including iron chelation therapy and hydroxyurea use, will be recorded at each visit throughout the study from 
Screening (after signing the ICF) through the end of study visit (Week 40). 
 


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Appendix 3 Data Handling Rules 
 
Category 
Description 
Data Handling Rule 
1. Age (years) 
Age (years) 
Age is collected from Demographics CRF page. 
2. First Dose 
Date/Time of 
Study Drug  
date/time of first dose of 
study drug 
The date and time (24 hr. clock) of the first dose of study 
drug will be taken from the Study Drug Administration 
CRF.  
3. Last Dose Date 
of Study Drug  
date of last dose of study 
drug 
The date of the last dose of study drug will be the Date of 
last dose from the End of Treatment CRF.  
 
If it is missing for the IA, DMC, and final analyses use the 
data cutoff date. 
 
If it is missing at the database lock, the date of the last 
dose of study drug will be imputed as the later of last visit 
date, last dispensing date (from Drug Accountability 
CRF), date of Completion/Discontinuation, and death 
date. 
4. Last Visit Date 
Date of Last Visit 
Date of last visit according to the Clinic Visit CRF. 
5. Last Study 
Participation Date 
(STDM variable, 
typically named 
RFPENDTC) 
Last Study Participation 
Date (STDM variable, 
RFPENDTC), where SDTM 
denotes Study Data 
Tabulation Model 
Last study participation date is defined as last known 
date of contact which would be the later of the following 
dates: last visit date, date of the last dose, date of 
Completion/Discontinuation, date of clinical study follow-
up, or death date. 
6. Study Day 
Definitions 
Study Day for an 
assessment/event which 
occurred on or after the start 
of study drug 
Study Day = Date of assessment/event – date of the first 
dose of study drug + 1. 
Study Day for an 
assessment/event which 
occurred on a day prior to 
the first dose of study drug 
in the study 
Study Day = date of assessment/event – first dose date 
of study drug in the study. 
Study Day of 
Randomization 
Study Day of Randomization = date of randomization – 
date of the first dose of study drug in the study + 1. 
Study Day is 1 if Baseline is on the day of randomization. 
First Dose Day 
First Dose Day in the study is defined as the study day 
of the first dose of study drug in the study (Study Day 1). 
Last Dose Day 
Last Dose Day in the study is defined as the study day 
of the last dose of study drug in the study. 
7. Duration of an 
event  
The duration of an event  
The duration of an event is defined as (stop date – start 
date + 1). 
8. Multiple 
assessments for 
the same visit 
Vital Sign, ECG and 
Laboratory assessments 
• 
All ECG assessments are to be performed in 
triplicate. Valid assessments will be averaged to get 
the analysis value for that visit. 
• 
Other than for ECG assessments, the last 
non-missing measurement taken prior to the 
date/time of first study drug (including unscheduled 
assessments) will be the analysis Baseline.  
• 
Windowing will be applied for by-visit analyses. 
Unscheduled or Screening visits that occurred 
before the Baseline visit will not be assigned an 
analysis visit. The early discontinuation visit will be 
eligible for allocation to an analysis visit.  


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Category 
Description 
Data Handling Rule 
• 
If one or more results for a variable are assigned to 
the same analysis visit, the result with the date 
closest to the protocol scheduled day will be used in 
the analysis. If 2 measurements in the same 
analysis visit window are equidistant from the 
protocol scheduled study day, the earliest 
measurement will be used in the analysis.  
• 
If multiple assessments are available on the same 
day (or for the same time point for ECG 
assessments), then the average of the assessments 
will be used in the analysis.  
• 
If both central and local assessments of the same 
lab test are available on the same day, the central 
result will take precedence over the local result. 
• 
All data will be listed in data listings. 
 
9. 
Special Lab 
Value Handling  
Lab values with a prefix 
such as: ‘>’, ‘<’, ‘+’ and ‘Less 
than’ Etc. 
 
• 
‘>’: use the available original value +0.001 in the 
analyses. 
• 
‘<’: use the available original value –0.001 in the 
analyses. 
• 
‘+’: use the available original value without the prefix 
in the analyses. 
• 
‘≥’: use the available original value in the analyses. 
• 
‘≤’: use the available original value in the analyses. 
10. Prior and 
concomitant, 
medication / 
treatment 
Prior, concomitant, and post-
treatment 
medication/treatment 
• 
Any medication that was used at any time prior to 
the date of first study drug is a Prior Medication. 
• 
Any medication that was used at any time on or after 
the date of first study drug and within 30 days of the 
last dose of study drug is a Concomitant Medication.  
• 
If the date of first study medication is missing, then 
the date of randomization is used (as long as the 
subject is known to have received study drug on at 
least one day during the study). Otherwise, in the 
case of missing dates, any period (Prior and 
Concomitant) that is possible based on the available 
information should be applied. 
11. Adverse event 
Missing CTCAE severity 
(toxicity grade) 
For the AE summary by CTCAE severity grade, an AE 
with missing CTCAE severity grade will not be imputed. 
Imputed values will not be listed in data listings. 
Missing relationship to study 
drug 
For the AE summary by relationship, an AE with a 
missing relationship to study drug will not be imputed. 
Imputed values will not be listed in data listings.  
Treatment-emergent 
adverse event  
An adverse event is considered treatment-emergent if 
emerges on or after initiation of study drug, or an AE that 
existed pre-treatment and worsened in severity on or 
after initiation of study drug, through 30 days after the 
last dose of study drug. 
 
An adverse event that begins on the same date as the 
first dose of study drug is treatment-emergent if the AE 
begins after the time of first dose or if the time of AE 
onset is unknown.  
 


Statistical Analysis Plan 
Version Date: 14-Oct-2021  
 
Sponsor: Imara, Inc. 
 
Protocol no: IMR-BTL-201 
 
Page 76 of 82 
 
Category 
Description 
Data Handling Rule 
If the AE start date is partial/missing, then 
• 
If AE start date is completely missing, then the AE is 
considered as treatment-emergent. 
• 
If both AE start month and day are missing and AE 
start year is the same or after the first dose year, 
then the AE is considered as treatment-emergent. 
• 
If AE start day is missing and AE start year and 
month are the same or after the first dose year and 
month, then the AE is considered as treatment-
emergent. 
 
Missing/incomplete (partial) AE start and end dates will 
not be imputed for data listings. 
12. Treatment 
Duration (days) 
Treatment Duration (days) 
Treatment duration is defined as Date of last dose of a 
study drug - Date of first dose of a study drug +1.  
13. Duration of 
Exposure (days) 
Duration of Exposure (days) 
Exposure is defined as (Date of the last dose of the 
study drug – Date of first dose of the study drug + 1).  
14. General 
Conversion of Duration in 
Days to Duration in 
Years/Months/Days 
Duration in Years = Duration in Days/365.25 
 
Duration in Months = Duration in Days/30.4375 
 
Duration in Weeks = Duration in Days/7 
 
15. Hard coding 
Hard coding for data 
analysis 
Hard Coding is not allowed during data analysis unless if 
agreed in writing by Imara. 
 
 
 
 


Statistical Analysis Plan 
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Sponsor: Imara, Inc. 
 
Protocol no: IMR-BTL-201 
 
Page 77 of 82 
 
Appendix 4 Clinical Laboratory CTCAE Grading 
 
Investigations 
Grade 
Laboratory 
Analyte 
1 
2 
3 
4 
aPTT (activated 
partial 
thromboplastin time) 
prolonged 
>ULN - 1.5 x ULN 
>1.5 – 2.5 x ULN 
>2.5 x ULN 
- 
Alanine 
aminotransferase 
increased 
>ULN – 3.0 x ULN if 
baseline was normal; 
1.5 - 3.0 x baseline if 
baseline was 
abnormal  
 
>3.0 – 5.0 x ULN if 
baseline was 
normal; >3.0 - 5.0 x 
baseline if baseline 
was abnormal  
 
>5.0 – 20.0 x ULN if 
baseline was 
normal; >5.0 - 20.0 x 
baseline if baseline 
was abnormal  
 
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if baseline 
was abnormal  
 
Alkaline 
phosphatase 
increased 
>ULN – 2.5 x ULN if 
baseline was 
normal; 2.0 - 2.5 x 
baseline if baseline 
was abnormal  
 
>2.5 – 5.0 x ULN if 
baseline was 
normal; >2.5 - 5.0 x 
baseline if baseline 
was abnormal  
 
>5.0 – 20.0 x ULN if 
baseline was 
normal; >5.0 - 20.0 x 
baseline if baseline 
was abnormal  
 
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if baseline 
was abnormal  
 
Aspartate 
aminotransferase 
increased 
>ULN – 3.0 x ULN if 
baseline was 
normal; 1.5 - 3.0 x 
baseline if baseline 
was abnormal  
 
>3.0 – 5.0 x ULN if 
baseline was 
normal; >3.0 - 5.0 x 
baseline if baseline 
was abnormal  
 
>5.0 – 20.0 x ULN if 
baseline was 
normal; >5.0 - 20.0 x 
baseline if baseline 
was abnormal  
 
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if baseline 
was abnormal  
 
Blood bilirubin 
increased 
>ULN – 1.5 x ULN if 
baseline was 
normal; > 1.0 - 1.5 x 
baseline if baseline 
was abnormal  
 
>1.5 – 3.0 x ULN if 
baseline was 
normal; >1.5 - 3.0 x 
baseline if baseline 
was abnormal  
 
>3.0 – 10.0 x ULN if 
baseline was 
normal; >3.0 - 10.0 x 
baseline if baseline 
was abnormal  
 
>10.0 x ULN if 
baseline was 
normal; >10.0 x 
baseline if baseline 
was abnormal  
 
Creatinine 
increased 
>ULN -1.5 x ULN 
>1.5 – 3.0 x 
baseline; >1.5 -3.0 x 
ULN 
>3.0 baseline; >3.0 – 
6.0 xULN 
>6.0 x ULN 
GGT (gamma-
glutamyl 
transferase) 
increased 
>ULN – 2.5 x ULN if 
baseline was 
normal; 2.0 - 2.5 x 
baseline if baseline 
was abnormal  
 
>2.5 – 5.0 x ULN if 
baseline was 
normal; >2.5 - 5.0 x 
baseline if baseline 
was abnormal  
 
>5.0 – 20.0 x ULN if 
baseline was 
normal; >5.0 - 20.0 x 
baseline if baseline 
was abnormal  
 
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if baseline 
was abnormal  
 
Hemoglobin 
increased (a) 
Increase in >0 – 2 
gm/dL above ULN 
(a) 
Increase in >2 – 4 
gm/dL above ULN 
(a) 
Increase in >4 
gm/dL above ULN 
(a) 
n/a 


Statistical Analysis Plan 
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Sponsor: Imara, Inc. 
 
Protocol no: IMR-BTL-201 
 
Page 78 of 82 
 
Investigations 
Grade 
Laboratory 
Analyte 
1 
2 
3 
4 
Anemia 
(hemoglobin 
decreased) 
LLN- 10g/dL;  
<LLN – 6.2 mmol/L; 
<LLN – 100 g/L 
<10.0 – 8.0 g/dL;  
<6.2 – 4.9 mmol/L;  
<100 – 80g/L 
<8.0 g/dL; <4.9 
mmol/L; <80 g/L; 
transfusion indicated 
Life-threatening 
consequences; 
urgent intervention 
indicated 
INR increased 
>1.2 – 1.5; >1 -1.5 x 
baseline if on 
anticoagulation (use 
of anticoagulation 
identified using the 
B01A ATC code) 
>1.5 – 2.5; >1.5 – 
2.5 x baseline if on 
anticoagulation (use 
of anticoagulation 
identified using the 
B01A ATC code) 
>2.5; >2.5 x baseline 
if on anticoagulation 
(use of 
anticoagulation 
identified using the 
B01A ATC code) 
- 
Neutrophil count 
decreased 
<LLN - 1500/mm3; 
<LLN - 1.5 x 10e9 /L 
<1500 - 1000/mm3; 
<1.5 - 1.0 x 10e9 /L 
<1000 - 500/mm3; 
<1.0 - 0.5 x 10e9 /L 
<500/mm3; <0.5 x 
10e9 /L 
Lymphocyte count 
decreased 
<LLN - 800/mm3; 
<LLN - 0.8 x 10e9/L 
<800 - 500/mm3; 
<0.8 - 0.5 x 10e9 /L 
<500 - 200/mm3; 
<0.5 - 0.2 x 10e9 /L 
<200/mm3; <0.2 x 
10e9 /L 
Lymphocyte count 
increased 
 - 
>4000/mm3 - 
20,000/mm3 
>20,000/mm3 
 - 
Platelet count 
decreased 
<LLN - 75,000/mm3;  
<LLN - 75.0 x 109/L 
<75,000 - 
50,000/mm3;  
<75.0 - 50.0 x 109/L 
<50,000 - 
25,000/mm3; <50.0 - 
25.0 x 109/L 
<25,000/mm3; 
 <25.0 x 109/L 
White blood cell 
decreased 
<LLN – 3000/mm3; 
<LLN – 3.0 x 109/L 
<3000 – 2000/mm3; 
 <3.0 – 2.0 x 109 /L 
<2000 – 1000/mm3; 
<2.0 – 1.0 x 109 /L 
<1000/mm3;  
<1.0 x 109 /L 
(a) Definition: A finding based on laboratory test results that indicate increased levels of hemoglobin above normal – 
i.e. above ULN. 
 


Statistical Analysis Plan 
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Protocol no: IMR-BTL-201 
 
Page 79 of 82 
 
Metabolism and Nutrition Disorders 
 
Grade 
Adverse Event 
1 
2 
3 
4 
Hypercalcemia 
(Calcium Increased) 
Corrected serum 
calcium of >ULN - 
11.5 mg/dL; >ULN - 
2.9 mmol/L; Ionized 
calcium >ULN - 1.5 
mmol/L 
Corrected serum 
calcium of >11.5 - 
12.5 mg/dL; >2.9 - 
3.1 mmol/L; Ionized 
calcium >1.5 - 1.6 
mmol/L; 
symptomatic 
Corrected serum 
calcium of >12.5 - 
13.5 mg/dL; >3.1 - 
3.4 mmol/L; Ionized 
calcium >1.6 - 1.8 
mmol/L; 
hospitalization 
indicated 
Corrected serum 
calcium of >13.5 
mg/dL; >3.4 
mmol/L; Ionized 
calcium >1.8 
mmol/L; life-
threatening 
consequences 
Hyperkalemia 
(Potassium Increased) 
>ULN - 5.5 mmol/L 
>5.5 - 6.0 mmol/L; 
intervention initiated 
>6.0 - 7.0 mmol/L; 
hospitalization 
indicated 
>7.0 mmol/L; life-
threatening 
consequences 
Hypermagnesemia 
(Magnesium 
Increased) 
>ULN - 3.0 mg/dL; 
>ULN - 1.23 mmol/L 
n/a 
>3.0 - 8.0 mg/dL; 
>1.23 - 3.30 mmol/L 
>8.0 mg/dL; >3.30 
mmol/L; life-
threatening 
consequences 
Hypernatremia 
(Sodium Increased) 
>ULN - 150 mmol/L 
>150 - 155 mmol/L; 
intervention initiated 
>155 - 160 mmol/L; 
hospitalization 
indicated 
>160 mmol/L; life-
threatening 
consequences 
Hypoalbuminemia 
(Albumin Decreased) 
<LLN - 3 g/dL; <LLN 
- 30 g/L 
<3 - 2 g/dL; <30 - 20 
g/L 
<2 g/dL; <20 g/L 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Hypocalcemia 
(Calcium Decreased) 
Corrected serum 
calcium of <LLN - 
8.0 mg/dL; <LLN - 
2.0 mmol/L; Ionized 
calcium<LLN - 1.0 
mmol/L 
Corrected serum 
calcium of  <8.0 - 
7.0 mg/dL; <2.0 - 
1.75 mmol/L; 
Ionized calcium 
<1.0- 0.9 mmol/L; 
symptomatic 
Corrected serum 
calcium of  <7.0 - 
6.0 mg/dL; <1.75 - 
1.5 mmol/L; Ionized 
calcium <0.9- 0.8 
mmol/L; 
hospitalization 
indicated 
Corrected serum 
calcium of <6.0 
mg/dL; <1.5 
mmol/L;Ionized 
calcium <0.8 
mmol/L;life-
threatening 
consequences 
Hypoglycemia 
(Glucose Decreased) 
<LLN - 55 mg/dL; 
<LLN - 3.0 mmol/L 
<55 - 40 mg/dL; 
<3.0 - 2.2 mmol/L 
<40 - 30 mg/dL; 
<2.2 - 1.7 mmol/L 
<30 mg/dL; <1.7 
mmol/L; life-
threatening 
consequences; 
seizures 
Hypokalemia 
(Potassium 
Decreased) 
<LLN - 3.0 mmol/L 
Symptomatic with 
<LLN - 3.0 mmol/L; 
intervention 
indicated 
<3.0 - 2.5 mmol/L; 
hospitalization 
indicated 
<2.5 mmol/L; life-
threatening 
consequences 
Hypomagnesemia 
(Magnesium 
Decreased) 
<LLN - 1.2 mg/dL; 
<LLN - 0.5 mmol/L 
<1.2 - 0.9 mg/dL; 
<0.5 - 0.4 mmol/L 
<0.9 - 0.7 mg/dL; 
<0.4 - 0.3 mmol/L 
<0.7 mg/dL; <0.3 
mmol/L; life-
threatening 
consequences 
Hyponatremia 
(Sodium Decreased) 
<LLN - 130 mmol/L 
125-129 mmol/L 
and asymptomatic 
125-129 mmol/L 
symptomatic; 120-
124 mmol/L 
regardless of 
symptoms 
<120 mmol/L; life-
threatening 
consequences 
 
 
 


Statistical Analysis Plan 
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Sponsor: Imara, Inc. 
 
Protocol no: IMR-BTL-201 
 
Page 80 of 82 
 
Renal and Urinary 
Disorders 
 
 
Grade 
Adverse Event 
1 
2 
3 
4 
Chronic kidney 
disease 
eGFR (estimated 
Glomerular 
Filtration Rate) or 
CrCl (creatinine 
clearance) <LLN -
60 ml/min/1.73 m2 
or proteinuria 2+ 
present; urine 
protein/creatinine 
>0.5 
eGFR or CrCl 59 - 
30 ml/min/1.73 m2 
eGFR or CrCl 29 - 
15 ml/min/1.73 m2 
eGFR or CrCl <15 
ml/min/1.73 m2; 
dialysis or renal 
transplant indicated 
 
 
 


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Protocol no: IMR-BTL-201 
 
Page 81 of 82 
 
Appendix 5 Regions 
 
The following geographic regions include the countries listed below: 
 
Europe/North America: 
Denmark  
France  
Italy  
Greece 
Netherlands 
Georgia  
Turkey 
UK 
US 
 
Asia/Africa: 
Israel 
Lebanon 
Malaysia 
Tunisia 
Morocco  
 
 
 
 


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Protocol no: IMR-BTL-201 
 
Page 82 of 82 
 
Appendix 6 Shell Column Headers 
For shells with all treatment arms and a total column, the column headers will be displayed as: 
 
Placebo 
(N=XX) 
IMR-687 200/300 mg 
(N=XX) 
IMR-687 300/400 mg 
(N=XX) 
 
 
IMR-687 Pooled Dose 
(N=XX) 
Total 
(N=XX) 
 
For shells with all treatment arms and a pooled active arms column, the column headers will be displayed as: 
 
Placebo 
(N=XX) 
IMR-687 200/300 mg 
(N=XX) 
IMR-687 300/400 mg 
(N=XX) 
IMR-687 Pooled 
Dose 
(N=XX)