A Phase 2a, Randomised, Double-Blind, Placebo-Controlled Study of IMR-687 in Adult Patients With Sickle Cell Anaemia (Homozygous HbSS or Sickle-β0 Thalassemia)
Phase: PHASE2
Conditions: Sickle Cell Disease
Sponsor: Cardurion Pharmaceuticals, Inc.

A Phase 2a, Randomised, Double-Blind, Placebo-Controlled 
Study of IMR-687 in Adult Patients with Sickle Cell 
Anaemia (Homozygous HbSS or Sickle-β0 Thalassemia) 
Unique Protocol ID: 
NCT Number: 
EudraCT Number:  
Date of Protocol:  
IMR-SCD-102 
NCT03401112 
2017-000653-39 
28 June 2019 

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CLINICAL TRIAL PROTOCOL 
 
Study Title: 
A Phase 2a, Randomised, Double-Blind, Placebo-Controlled Study of 
IMR-687 in Adult Patients with Sickle Cell Anaemia (Homozygous 
HbSS or Sickle-β0 Thalassemia) 
Study Number: 
IMR-SCD-102 
Study Phase: 
2a 
Product Name: 
IMR-687 
IND Number: 
130549 
EudraCT Number: 
2017-000653-39 
Protocol Version: 
United States: 008 
United Kingdom: 011 
Protocol Date: 
28 June 2019 
Indication: 
Sickle Cell Anaemia (Homozygous sickle HbSS or Sickle-β0 
Thalassemia) 
Sponsor: 
Imara 
700 Technology Square, 3rd Floor 
Cambridge, MA 02139 
Sponsor Contact: 
 Imara 
 
 
 
 
 
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. 
PPD
PPD

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SIGNATURE PAGE 
Sponsor's Approval 
The protocol has been approved by Imara, Inc. 
Sponsor's Authorized Officer: 
Imara, Inc. 
Date 
Proprietary and Confidential 
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Oimara 
PPD
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INVESTIGATOR’S AGREEMENT 
 
I have read the Protocol IMR-SCD-102 and agree to conduct the study in compliance with the 
approved protocol and will adhere to Good Clinical Practice (GCP) and all applicable laws and 
regulatory requirements. I agree to maintain the confidentiality of all information received or 
developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 
 

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KEY ROLES AND RESPONSIBILITIES 
Emergency Contact Information 
Role in Study 
Name 
Telephone number 
Responsible Physician 
Medical Advisor 
Safety Review Committee 
A Safety Review Committee (SRC) will review all available clinical safety data approximately 
every 2 weeks (with additional ad hoc meetings, if necessary) throughout the study. The SRC must 
approve any intra-patient dose escalations as well as the initiation of treatment in Population B 
(patients receiving a stable dose of hydroxyurea). The minutes from all SRC meetings will be 
documented in writing and retained in the study files. 
The composition of the SRC as well as specific governing procedures (e.g., convening meetings, 
executing responsibilities) will be described in the SRC charter, which is maintained as a separate 
document.  
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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Name of Sponsor/Company: Imara 
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 2a, Randomised, Double-Blind, Placebo-Controlled Study of IMR-687 in Adult Patients 
with Sickle Cell Anaemia (Homozygous HbSS or Sickle-β0 Thalassemia) 
Study centre(s): This study will be conducted at approximately 10 study sites in the United States (US) and up 
to 10 study sites in the United Kingdom (UK). 
Studied period (years):  
Estimated date first patient enrolled: January 2018 
Estimated date last patient completed: December 
2019 
Phase of development: 2a 
Objectives:  
Primary Objectives: 
• 
To assess the safety and tolerability of IMR-687 in adult patients with sickle cell anaemia (SCA), defined 
as homozygous sickle haemoglobin (HbSS) or sickle-β0 thalassemia, who are not receiving hydroxyurea 
(HU) and in adult SCA patients who are receiving a stable dose of HU 
Secondary Objectives: 
 
• 
To characterise the pharmacokinetic (PK) profile of IMR-687 in adult patients with SCA who are/are 
not receiving a stable dose of HU  
• 
To characterise the PK profile of HU in adult patients with SCA before and after receiving IMR-687 to 
determine whether there is a clinically relevant PK interaction. 
Exploratory Objectives:  
• 
To assess the pharmacodynamic (PD) effects of IMR-687 in adult patients with SCA who are/are not 
receiving stable HU 
• 
To assess the potential efficacy of IMR-687 on SCA-related clinical outcome measures in adult patients 
with SCA who are/are not receiving stable HU 
Methodology:  
This is a randomised, double-blind, placebo-controlled study to evaluate the safety, tolerability, PK, and 
exploratory PD and clinical outcomes of the phosphodiesterase (PDE) type 9 (PDE9) inhibitor, IMR-687, 
administered once daily for 16 to 24 weeks in 2 populations of patients with SCA: those who are not receiving 
HU (Populations A and A1) and those who are currently receiving a stable dose of HU according to standard of 
care (Populations B and B1). Approximately 60 patients will be enrolled in Populations A and A1 combined and 
approximately 30 patients will be enrolled in Population B and B1 combined. 
Population A is composed of those patients already enrolled at the time of this amendment who are not receiving 
HU. These patients will attend site visits at the time points specified in the Schedule of Assessments (SOA) 
provided in Table 1 (Population A). Population A1 is composed of patients who are not receiving HU and will be 
enrolled after this amendment. These patients will attend site visits at the time points specified in the SOA 
provided in Table 2. Population B consists of those patients already enrolled at the time of this amendment who 
are receiving stable doses of HU. These patients will attend site visits at time points specified in the SOA provided 
in Table 3. Population B1 consists of patients who are receiving stable doses of HU and will be enrolled after this 
amendment. These patients will attend site visits at the time points specified in the SOA provided in Table 4. In 
addition, for the first 4 weeks for each population, patients will be seen in person once a week for an abbreviated 
physical examination and collection of adverse events (AEs) and vital signs; thereafter, telephone-based check-

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ins may be performed on weeks where there are no scheduled assessments. Safety and concomitant medications 
will be monitored throughout the study, while PK, PD, and clinical outcome measures will be performed at 
selected site visits.  
All available clinical data from all patients in all populations will be collated and submitted to a Safety Review 
Committee (SRC) for review approximately every 2 weeks throughout the course of the entire study. 
The study designs for Populations A, A1, B, and B1 are depicted graphically in Figure 1, Figure 2, Figure 3, 
and Figure 4, respectively. 
Population A 
Following a Screening period of up to 4 weeks, eligible patients in Population A (i.e., those enrolled prior to this 
amendment and not receiving HU) will receive either IMR-687 or placebo for a total of 24 weeks. On Day 1, 
patients will be randomised 1:1:1 to receive oral IMR-687 50 mg, IMR-687 100 mg, or placebo daily for the first 
12 weeks; for the second 12 weeks (Weeks 13-24), each patient’s dose may be doubled (i.e., from 50 mg to 100 
mg; from 100 mg to 200 mg; or placebo). (Note: Because placebo and all dose levels of IMR-687 are the same in 
appearance, dose escalation will not affect study medication blinding.)  
Throughout the study, all available clinical data will be reviewed approximately every 2 weeks by the SRC, and 
dose escalation will occur on an individual-patient basis on Day 85 only if approved by the SRC based on review 
of each patient’s individual clinical safety data.  
Safety, PK, PD, and efficacy assessments will be performed at the time points shown in Table 1. 
Population A1 
Following a Screening period of up to 4 weeks, eligible patients in Population A1 (i.e., those enrolled after this 
amendment and not receiving HU) will receive either IMR-687 or placebo for a total of 24 weeks. On Day 1, 
patients will be randomised 2:1 to receive oral IMR-687 100 mg or placebo daily for 4 weeks; for the subsequent 
20 weeks (Weeks 5-24), each patient’s dose may be doubled (i.e., from 100 mg to 200 mg; or placebo). (Note: 
because placebo and all dose levels of IMR-687 are the same in appearance, dose escalation will not affect study 
medication blinding.)  
Throughout the study, all available clinical data will be reviewed approximately every 2 weeks by the SRC, and 
dose escalation will occur on an individual-patient basis on Day 29 only if approved by the SRC based on review 
of each patient’s individual clinical safety data.  
Safety, PK, PD, and efficacy assessments will be performed at the time points shown in Table 2. 
Population B 
Following a Screening period of up to 4 weeks, eligible patients in Population B (i.e., those enrolled prior to this 
amendment and receiving stable HU) will enter an approximately 8-week lead-in period and will have blood 
samples drawn to characterise the PK profile of the patient’s prescribed dose of HU in the absence of IMR-687 
(i.e., to characterise the patient’s baseline HU PK profile). Two full baseline HU PK profile (with blood samples 
drawn over a 10-hour period ) will be determined. 
IMR-687 dosing in Population B will not begin until at least 4 weeks of safety data from 6 patients in 
Population A have been reviewed by the SRC and the SRC has determined that it is safe and appropriate to begin 
dosing in Population B. Following SRC approval to initiate dosing in Population B and once the baseline HU PK 
blood draw are complete, patients will be randomised 2:1 on Day 1 to receive oral IMR-687 50 mg or placebo for 
16 weeks. For the first 4 weeks (Weeks 1-4), patients will receive study medication according to their randomised 
treatment assignment; for the following 12 weeks (Weeks 5-16), each patient’s dose may be doubled (i.e., from 
50 mg to 100 mg; or placebo). Dose escalation will occur on Day 29 only if approved by the SRC based on review 
of each patient’s individual clinical safety data. (Note: because placebo and all dose levels of IMR-687 are the 
same in appearance, dose escalation will not affect study medication blinding.) 
Safety, PK, PD, and efficacy assessments will be performed at the time points shown in Table 3. 

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Population B1 
Following a Screening period of up to 4 weeks, eligible patients in Population B1 (i.e., those enrolled after this 
amendment and receiving stable HU) will enter an approximate 4-week lead-in period and will have a single set 
of blood samples drawn to characterise the patient’s baseline HU PK profile. 
Once the baseline HU PK blood draw is complete, patients will be randomised 2:1 on Day 1 to receive oral 
IMR-687 or placebo for 24 weeks. For the first 4 weeks (Weeks 1-4), patients will receive study medication 
according to their randomised treatment assignment (i.e., 50 mg or placebo); for the following 20 weeks 
(Weeks 5-24), each patient’s dose may be doubled (i.e., from 50 mg to 100 mg; or remain on placebo). Dose 
escalation will occur on Day 29 only if approved by the SRC based on review of each patient’s individual clinical 
safety data. (Note: because placebo and all dose levels of IMR-687 are the same in appearance, dose escalation 
will not affect study medication blinding.) 
Safety, PK, PD, and efficacy assessments will be performed at the time points shown in Table 4. 
Study Design Rationale 
This is the first study in a patient population (patients with SCA), and as such, is designed to examine the safety, 
tolerability, and PK, as well as the potential PD effects and clinical efficacy, of IMR-687 across a range of doses 
in adult patients with SCA. Given the possibility that IMR-687, if approved, could be administered as a single 
agent or co-administered with HU, the effects of IMR-687 will be evaluated in SCA patients who are not receiving 
HU or any other treatment known to modulate foetal haemoglobin (HbF) levels (Populations A and A1), as well 
as in those who are currently receiving a stable dose of HU (Populations B and B1).  
Available nonclinical and healthy volunteer clinical data suggest that IMR-687 will be safe and well tolerated at 
once daily doses of 50, 100, and 200 mg and that a potentially clinical beneficial PD effect is likely to be observed 
when a dose of at least 100 mg is administered for at least 24 weeks. Therefore, Populations A and A1 are designed 
to explore the PD dose response in patients as well as the tolerability of the 200 mg dose level in sickle cell 
patients who have tolerated the 100 mg dose well.   
Results from Populations B and B1 are intended to provide information on IMR-687 when administered 
concomitantly with HU, both of which increase HbF levels through alternative biochemical pathways that increase 
intracellular cyclic guanosine monophosphate (cGMP). Because there are no clinical data to support 
administration of IMR-687 concomitantly with HU, patients in Population B will initiate IMR-687 dosing at the 
low dose (50 mg) and will only escalate to the 100 mg dose if the 50 mg dose has been safe and tolerated for 
4 weeks. In addition, although available nonclinical data do not suggest that concomitant administration of HU 
with IMR-687 would increase IMR-687 exposure, dosing in Population B will not initiate until 4 weeks of safety 
data are available from Population A in2 patients each at 50 mg (starting dose in Population B) and at 100 mg 
(twice the starting dose) as well as placebo.  
Number of patients (planned):  
A total of approximately 90 evaluable patients are expected to enroll in this study. 
• 
In Populations A and A1, approximately 60 adult patients with a confirmed diagnosis of SCA who have 
not received HU for at least 90 days prior to Screening and who are not planning to take HU within the 
next 6 months will be enrolled. 
• 
In Populations B and B1, approximately 30 adult patients with a confirmed diagnosis of SCA who have 
received HU for at least 6 months, have been on a stable dose for at least 60 days prior to Screening, and 
are not planning to change the dose or discontinue HU within the next 6 months will be enrolled. 
Diagnosis and main criteria for inclusion:  
Inclusion Criteria: 
Each patient must meet all of the following criteria to be enrolled in the study: 
1. Male or female ≥18 or ≤55 years of age. 
2. Confirmed diagnosis of SCA (HbSS or sickle-B0 thalassemia). Note: If not already documented in the 

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patient’s record, the diagnosis of SCA must be confirmed via electrophoresis, high-performance liquid 
chromatography (HPLC), and/or genotyping.  
3. Use of HU: 
• 
For patients in Populations A and A1: Have not received HU within 90 days prior to Screening and 
are not planning to take HU while on the study.  
• 
For patients in Populations B and B1: Have received HU for at least 6 months, have been on a stable 
dose for at least 60 days prior to Screening, and are not planning to change the dose level, dose 
regimen, or discontinue HU within the next 6 months.  
4. Female patients must not be pregnant and be highly unlikely to become pregnant. Male patients must be 
unlikely to impregnate a partner. Male or female patients must meet at least one of the following criteria: 
• 
A female patient who is not of reproductive potential is eligible without requiring the use of 
contraception. A female patient who is not of reproductive potential is defined 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 local 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 male patient who is not of reproductive potential is eligible without requiring the use of 
contraception. A male patient 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 patient 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 patient. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the 
duration of the trial and withdrawal are not acceptable methods of contraception. Acceptable 
methods of highly effective birth control are combined or progestogen-only hormonal contraception 
that is associated with inhibition of ovulation, intrauterine device, and intrauterine hormone-
releasing system.  
5. Be capable of giving informed consent and reading and signing the informed consent form after the 
nature of the study has been fully explained by the investigator or investigator designee. 
6. Be willing and able to complete all study assessments and procedures and to communicate effectively 
with the investigator and site staff. 
Exclusion Criteria: 
Patients who meet any of the following criteria will be excluded from the study: 
1. Total haemoglobin (Hb) at Screening >12.5 g/dL or <6 g/dL. 
2. Reticulocyte count <100 x 109/L for Populations A and A1, or <80 x 109/L for Populations B and B1. 
3. Greater than 7 hospitalizations (for at least 24 hours) for vaso-occlusive crises (VOC), including acute 
chest syndrome and priapism, within the prior year. 
4. (Intentionally left blank.)  
5. Blood transfusion or donation of blood or any blood product within 60 days of Day 1 or on chronic 
transfusion therapy regimen. 
6. Positive for human immunodeficiency virus (HIV), hepatitis C (HCV) antibodies (unless the patient has 
successfully completed drug therapy that results in cure/clearance of HCV), or hepatitis B surface 
antigen. 
7. For female patients of childbearing potential, a positive serum human chorionic gonadotropin (hCG) test 

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(Screening) or a positive urine hCG test on Day 1. 
8. Estimated glomerular filtration rate (eGFR) <50 mL/min as calculated by the equation from the 
Modification of Diet in Renal Disease Study using creatinine, age, sex, and ethnicity. 
9. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3x the upper limit of normal 
(ULN). 
10. Body mass index (BMI) <17.5 or >35 kg/m2; a total body weight <50 kg.  
11. Use of PDE type 5 (PDE5) inhibitors (including but not limited to sildenafil, tadalafil, vardenafil) within 
7 days prior to the first dose of study drug, or planning to use any time during study. 
12. A history of drug or alcohol abuse as judged by the investigator within the past 1 year, or a positive 
alcohol (breathalyser) test (Screening or Day -1). 
13. A cancer that has not been in complete remission for at least 5 years. Patients with squamous cell or 
basal cell carcinoma of the skin, localised cervical cancer, or localised prostate cancer are eligible if, in 
the opinion of the investigator, the condition has been adequately diagnosed, and is determined to be 
clinically in remission, and the patient’s participation in the study would not represent a safety concern. 
14. 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. 
15. On electrocardiogram (ECG), a corrected QT interval, Fridericia’s formula (QTcF) >450 ms in men and 
>470 ms in women or the presence of clinically significant abnormalities as determined by the 
investigator. 
16. A history of major surgery within 4 weeks or minor surgery within 2 weeks of Day 1. 
17. Any flu-like syndrome or other respiratory infection within 2 weeks of Day 1 or vaccination with 
attenuated live virus within 4 weeks of Day 1. 
18. Participation in an investigational drug or device study within 30 days prior to Day 1. 
19. Use within 30 days prior to Day 1, or planning to use during the study, of any drugs or substances that 
are known to strongly inhibit or induce cytochrome P450 (CYP) enzymes, including but not limited to 
cimetidine, cyclosporine, erythromycin, omeprazole, rifampin, ritonavir, and St. John’s wort. If there is 
any question as to whether a substance is permitted, please review the product labelling (if applicable) 
and consult the Sponsor. 
20. Consumption of grapefruit, grapefruit juice, or grapefruit products within 24 hours prior to Day 1 or 
planning to consume grapefruit products during the study. 
21. Use within 30 days prior to Day 1, or planning to use during the study, of any CYP3A-sensitive 
substrates (excluding opioids), including but not limited to alfentanil, avanafil, budesonide, buspirone, 
conivaptan, darifenacin, darunavir, dasatinib, dronedarone, ebastine, eletriptan, eplerenone, everolimus, 
felodipine, ibrutinib, indinavir, lomitapide, lurasidone, maraviroc, midazolam, naloxegol, nisoldipine, 
quetiapine, saquinavir, sirolimus, tacrolimus, ticagrelor, tipranavir, tolvaptan, and triazolam. If there is 
any question as to whether a substance is permitted, please review the product labelling (if applicable) 
and consult the Sponsor. 
22. Use within 30 days prior to Day 1, or planning to use during the study, of any drugs or substances known 
to be significant substrates or inhibitors of P-glycoprotein (P-gp), including but not limited to 
cyclosporine, lovastatin, propranolol, quinidine, and simvastatin. If there is any question as to whether a 
substance is permitted, please review the product labelling (if applicable) and consult the Sponsor.  
23. Other prior or ongoing medical condition, physical findings, or laboratory abnormality that, in the 
investigator's opinion, could adversely affect the safety of the patient, make it unlikely that the course of 
treatment or follow-up would be completed, or impair the assessment of study results. 
24. In the opinion of the investigator, the patient is unable to meet the requirements of the study. 
Investigational product, dosage and mode of administration:  
IMR-687 will be supplied as 50, 100, or 200 mg white tablets and will be administered orally with food. The 
different doses of IMR-687 are visually identical in tablet form.  

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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. Placebo will be administered orally with food.  
Duration of study participation and treatment:  
The total duration of the study is approximately 32 weeks for Populations A and A1, including a Screening period 
of up to 4 weeks, a treatment period of 24 weeks, and a 4-week safety follow-up assessment after the last dose of 
study drug is administered.  
The total duration of the study is approximately 32 weeks for Population B, including a Screening period of up to 
4 weeks, a lead-in period of approximately 8 weeks, a treatment period of 16 weeks, and a 4-week safety follow-
up assessment after the last dose of study drug is administered.  
The total duration of the study is approximately 36 weeks for Population B1, including a Screening Period of up 
to 4 weeks, a lead-in period of approximately 4 weeks, a treatment period of 24 weeks, and a 4-week safety follow-
up assessment after the last dose of study drug is administered. 
Endpoints:   
The endpoints for Populations A, A1, B, and B1 are the same except where noted otherwise. 
Primary Endpoints 
• 
IMR-687 safety and tolerability as measured by: 
o 
Incidence and severity of adverse events (AEs) and serious adverse events (SAEs); 
o 
Change from baseline in 12-lead ECG parameters, clinical laboratory tests (chemistry, 
haematology, coagulation, urinalysis), and vital signs 
o 
Physical examination findings 
Secondary Endpoints 
• 
The plasma PK profile of IMR-687 after oral administration to adult patients with SCA (Populations A, 
A1, B, and B1) 
• 
The plasma PK profile of HU before and after oral administration of IMR-687 to adult patients with 
SCA (Populations B and B1 only) 
Exploratory Endpoints 
• 
IMR-687 PD as measured by the following (additional exploratory biomarkers may also be tested): 
o 
Total Hb levels 
o 
HbF value (%) 
o 
Percent erythrocytes containing HbF (%F cells) 
o 
Indices of red cell haemolysis (unconjugated bilirubin, reticulocyte count, lactase 
dehydrogenase [LDH], and haptoglobin levels) 
o 
Soluble E-selectin (sE-sel), soluble P-selectin (sP-sel), and soluble intercellular adhesion 
molecule 1 (sICAM-1) 
o 
High-sensitivity C-reactive protein (hs-CRP) 
• 
IMR-687 clinical outcomes as measured by pain-related measures (frequency, severity, and duration of 
pain; impact of pain/fatigue on work/school and on activities of daily living; need for/use of pain 
medication; SCA-related events requiring professional medical or health care, including events requiring 
hospitalization or therapies, such as transfusions) and in the physical, social, and emotional impact of 
SCA as measured by the Adult Sickle Cell Quality-of-Life Measurement Information System (ASCQ-
Me) 
In addition, a separate blood sample will be collected for confirmation of diagnosis by electrophoresis, HPLC, 
and/or deoxyribonucleic acid (DNA) sequencing (as needed) as well as for possible pharmacogenomic analyses 
of genes that may affect treatment response (including but not limited to alpha globin and BCL11A).  
 

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Statistical Methods: 
General Considerations: 
Descriptive summary statistics will be provided for demographics, disposition, and IMR-687 exposure (and HU 
for patients in Populations B and B1). The number and percentage of patients who discontinue from the study, 
along with reasons for discontinuations will be tabulated and described in listings. 
Continuous data will be summarised using descriptive statistics (number of patients, mean, standard deviation 
[SD], median, minimum, and maximum) and, where appropriate, coefficient of variation (%CV) and graphic 
representation. Categorical data will be summarised by sample size and proportions. Data will be summarised by 
population (A, A1, B, and B1) and dose cohort at each time point as appropriate. Graphs of actual values and 
changes over time may also be created as appropriate. 
Analysis Datasets: 
The safety analysis set, defined as all patients who have received any amount of study drug and from whom 
informed consent has been obtained, will be used to summarise all safety and tolerability data. 
The PK concentration set, defined as a subset of the safety analysis set that includes all patients who are enrolled 
in the study, have received one dose of IMR-687, and have any measurable IMR-687 concentration-time data, 
will be used to generate IMR-687 (and HU for patients in Populations B and B1) PK concentration profiles.  
The PK evaluable set, defined as a subset of the PK concentration set that includes all patients who have provided 
sufficient concentration data without protocol deviations or events that would be expected to affect the PK 
analysis, will be used to generate IMR-687 (and HU for patients in Populations B and B1) PK parameter data.  
The PD evaluable set, defined as a subset of the safety analysis set that includes all patients who have provided 
samples for PD analysis sufficient to obtain at least one valid PD observation and who are without protocol 
deviations or events that would be expected to affect the PD analysis, will be used to generate PD observation 
and parameter data. 
The per protocol set, defined as a subset of the safety analysis set that includes all patients who have completed 
at least one valid clinical outcomes assessment without protocol deviations or events that would be expected to 
affect the analysis, will be used to generate clinical outcomes data. 
Safety Analyses: 
Descriptive statistics will be computed for safety parameters, as appropriate. The number and percentage of 
patients who discontinued from the study because of AEs will be tabulated; severity and frequency of AEs and 
SAEs will also be summarised. Absolute and, where appropriate, change from baseline in clinical laboratory 
values, vital signs, and ECG results will also be summarised. All safety data will be provided in listings. 
Further statistical evaluations will be applied for select safety endpoints, if warranted. 
Pharmacokinetic Analyses: 
PK analysis parameters will be estimated using non-compartmental analysis methods. Graphs of individual and 
mean IMR-687 (and HU for patients in Populations B and B1) plasma concentrations over time will be generated 
by population and dose cohort as appropriate. The following PK parameters will be determined, as appropriate: 
maximum concentration (Cmax); time to maximum concentration (tmax); apparent terminal half-life (t½); and area 
under the concentration-time curve (AUC) from time 0 to 12 hours (AUC0-12), from 0 to 24 hours (AUC0-24), from 
0 to the last measurable time point (AUClast), and extrapolated to infinity (AUC0-∞). Other PK parameters may be 
determined as appropriate. PK parameters will be summarised descriptively using the number of non-missing 
values (n), mean, median, SD, minimum, maximum, %CV, geometric mean, and geometric %CV. Dose 
proportionality will be assessed. 
To assess the potential drug interaction for HU with IMR-687 (test) and HU without IMR-687 (reference) in 
Populations B and B1, log-transformed PK parameters (Cmax, AUC) will be analysed using analysis of variance 
(ANOVA), including terms for visit as a fixed effect and patient as a random effect. Based on this analysis, point 
estimates and two-sided 90% confidence intervals (CI) for the ratios “IMR-687+HU/HU” will be calculated by 
back-transformation of the logarithmic data. Within-subject variability will be estimated.   
 

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Analyses of Exploratory Endpoints: 
Exploratory PD and clinical outcomes data for each time point will be listed by patient and summarised by 
population and dose cohort as appropriate. Correlations between PK and the exploratory endpoints may be 
assessed. Descriptive statistics will be computed as appropriate. 

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1.2. 
Protocol Schema 
The study design for Populations A, A1, B, and B1 are depicted graphically in Figure 1, Figure 2, 
Figure 3, and Figure 4, respectively. 
Figure 1: 
Study Design Schema for Population A 
 
HU = hydroxyurea; QD = once daily; SRC = Safety Review Committee 
Note: The SRC reviews all available collated and individual data every other week throughout the study and has 
jurisdiction over decisions to continue dosing, dose escalate individual patients, initiate dosing in Populations B and 
B1, and to terminate dosing. 
 
Figure 2: 
Study Design Schema for Population A1 
 
HU = hydroxyurea; QD = once daily; SRC = Safety Review Committee 
Note: The SRC reviews all available collated and individual data every other week throughout the study and has 
jurisdiction over decisions to continue dosing, dose escalate individual patients, initiate dosing in Populations B and 
B1, and to terminate dosing. 

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Figure 3 
Study Design Schema for Population B 
 
HU = hydroxyurea; QD = once daily; SRC = Safety Review Committee 
Note: The SRC reviews all available collated and individual data every other week throughout the study and has 
jurisdiction over decisions to continue dosing, dose escalate individual patients, initiate dosing in Populations B and 
B1, and to terminate dosing. 
 
Figure 4 
Study Design Schema for Population B1 
 
 
HU = hydroxyurea; QD = once daily; SRC = Safety Review Committee 
Note: The SRC reviews all available collated and individual data every other week throughout the study and has 
jurisdiction over decisions to continue dosing, dose escalate individual patients, initiate dosing in Populations B 
and B1, and to terminate dosing. 
1.3. 
Schedule of Assessments 
The Schedule of Assessments is provided in Table 1, Table 2, Table 3, and Table 4 below for 
Populations A, A1, B, and B1, respectively. 
 

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Table 1: 
Schedule of Assessments: Population A (not receiving HU) 
Screening 
Double-Blind, Placebo-Controlled Treatment 
End of Study 
(Safety FU) 
Study Week(s) 
 
1 
2 
3 
4 
5 
9 
13 
14 
15 
16 
17 
21 
25b 
(EOT) 
29 (EOS) 
Study Day(s) 
-28 to -1 
1a 
8 ± 2 15 ± 2 22 ± 2 29 ± 2 57 ± 2 85 ± 2 92 ± 2 99 ± 2 106 ± 2 113 ± 2 141 ± 2 
169 ± 2 
197± 5 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic Information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Disease History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Dx Confirmation & 
Pharmacogenomicsc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Telephonic Visits d 
 
 
 
X 
X 
 
 
 
 
X 
X 
 
 
 
 
Vital Signse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
 
 
 
X 
X 
X 
 
 
 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECGg 
 
X 
 
 
 
 
 
X 
X 
 
 
X 
X 
X 
 
Safety Laboratory Assessments  
X 
X 
X 
 
 
X 
X 
X 
 
 
 
X 
X 
X 
X 
Pregnancy Testingh 
X 
X 
 
 
 
X 
X 
X 
 
 
 
X 
X 
X 
X 
Exploratory PD Markersi 
 
X 
 
 
 
X 
X 
X 
 
 
 
X 
X 
X 
 
IMR-687 Plasma PKj 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
QOL Assessments (ASCQ-Me) 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
App-based Pain Questionnaire 
 
Daily 
 
Study Drug Administration 
 
Once Daily Oral Administration IMR-687k 
 
AEs & Concomitant Medications 
Continuousl 
Abbreviations: % F cells = percent of red blood cells containing foetal haemoglobin; AEs = adverse events; ASCQ-Me = Adult Sickle Cell Quality-of-Life Measurement Information 
System; BL = baseline; Dx = disease; FU = follow-up; ECG = electrocardiogram; EOT = end of treatment; PD = pharmacodynamics; PE = physical examination; PK = pharmacokinetic; 
QOL = quality of life; SFU = safety follow-up. 
Note: Unless otherwise specified, all assessments should be completed prior to dosing at any given time point. 
a  The first day study drug is taken is considered “Day 1”.  
b  The last day of dosing will be the end of Week 24 (Day 169 ± 2); patient should consume their last dose of study drug on site, after pre-dose assessments have been completed. 
During the study visit Day 169 ± 2, assessments should be collected from any patient who discontinues study drug or study prematurely. The week 25 visit will also be the 
EOT visit.   
c  Pharmacogenomic evaluation is optional and may be performed at any point during the study if patient provides informed consent. 

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d  Site will contact the patient telephonically during Weeks 3, 4, 15, and 16. If any AEs of significant clinical concern are identified during the telephonic visit, the patient will 
be requested to come into the site to be assessed by targeted PE and vital sign measurements. Physical examinations and vital signs will not be assessed at these time points 
if patients do not have AEs of concern.   
e  On Days 1, 85, and the last day of dosing (End of Week 24 [Day 169 ± 2]), vital signs will be taken pre-dose and 2 hours (± 15 minutes) post-dose. At all other time points, 
vital signs will be taken pre-dose only. Vital sign measurements on Weeks 3, 4, 15, and 16 are obtained only if the patient is brought into the site after identification of AEs 
of significant clinical concern during the telephonic visits. Vital signs should be measured in the sitting or semi-supine position.  
f  At the Screening and Day 1 visits, the PE will include a general examination of the body including the abdomen, heart, chest, lungs, lymph nodes, dentition, back/neck, 
neurological system, skin, extremities, head, ears, eyes, nose, and throat. Subsequent PEs will be symptom directed; symptom-directed PEs on Weeks 3, 4, 15, and 16 are 
obtained only if the patient is brought into the site after identification of AEs of significant clinical concern during the telephonic visits. 
g On Days 1, 85, and the last day of dosing (End of Week 24 [Day 169 ± 2]), ECGs will be obtained in triplicate at pre-dose and 2 hours (± 30 minutes) post-dose.  
h Females of childbearing potential only. A serum pregnancy test will be performed at screening; all subsequent tests will be urine. 
i Includes total haemoglobin (Hb), haemoglobin F (% HbF levels and % F cells), indices of red cell haemolysis (unconjugated bilirubin, reticulocyte counts, lactate 
dehydrogenase [LDH], haptoglobin, soluble E-selectin [sE-sel], soluble P-selectin [sP-sel], soluble intercellular adhesion molecule 1 [sICAM-1], and high-sensitivity 
C-reactive protein [hsCRP]). Blood samples should be obtained within 30 minutes prior to administration of study drug. 
j  On Days 1, 85, and the last day of dosing (End of Week 24 [Day 169 ± 2]), serial blood samples for IMR-687 plasma concentrations will be drawn pre-dose (within 30 minutes); 
at 0.5, 1, 1.5, 2, 4, 6, and 8 hours (± 5 minutes) after administration of study drug; and at 24 hours (± 1 hour) after administration of study drug.  
k At each study visit, patients should be reminded to bring their study medication to their next site visit and to not take study drug on the day of the next visit until instructed to 
do so by the site during the visit. The last day of dosing will be the end of Week 24 (Day 169 ± 2); patient should consume the last dose on site after pre-dose assessments have 
been completed.  
l Adverse events will be recorded throughout the study from Screening through the safety follow-up. In addition to the specified study time points in the Schedule of 
Assessments, patients will be followed weekly by the investigator for safety. Telephone-based check-ins may be performed on weeks where there are no scheduled site visits.  
 

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Table 2 
Schedule of Assessments: Population A1 (not receiving HU) 
Screening 
Double-Blind, Placebo-Controlled Treatment 
End of Study 
(Safety FU) 
Study Week(s) 
 
1 
2 
3 
4 
5 
9 
13 
14 
15 
16 
17 
21 
25b 
EOT 
29 (EOS) 
Study Day(s) 
-28 to -1 
1a 
8 ± 2 15 ± 2 22 ± 2 29 ± 2 57 ± 2 85 ± 2 92 ± 2 99 ± 2 106 ± 2 113 ± 2 
141 ± 2 
169 ± 2 
197± 5 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic Information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Disease History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Dx Confirmation & 
Pharmacogenomicsc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Telephonic Visits d 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
 
 
Vital Signse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
 
 
 
X 
X 
X 
 
 
 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECGg 
 
X 
 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
 
Safety Laboratory Assessments  
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
Pregnancy Testingh 
X 
X 
 
 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
Exploratory PD Markersi 
 
X 
 
 
 
X 
X 
X 
 
 
 
X 
X 
X 
 
IMR-687 Plasma PKj 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
QOL Assessments (ASCQ-Me) 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
App-based Pain Questionnaire 
 
Daily 
 
Study Drug Administration 
 
Once Daily Oral Administration IMR-687k 
 
AEs & Concomitant Medications 
Continuousl 
Abbreviations: % F cells = percent of red blood cells containing foetal haemoglobin; AEs = adverse events; ASCQ-Me = Adult Sickle Cell Quality-of-Life Measurement Information 
System; BL = baseline; Dx = disease; FU = follow-up; ECG = electrocardiogram; EOT = end of treatment; PD = pharmacodynamics; PK = pharmacokinetic; QOL = quality of life; SFU 
= safety follow-up. 
Note: Unless otherwise specified, all assessments should be completed prior to dosing at any given time point. 
a  The first day study drug is taken is considered “Day 1”.  
b  The last day of dosing will be the end of Week 24 (Day 169 ± 2); patient should consume their last dose of study drug on site, after pre-dose assessments have been completed. 
During the study visit Day 169 ± 2, assessments should be collected from any patient who discontinues study drug or study prematurely.    
c  Pharmacogenomic evaluation is optional and may be performed at any point during the study if patient provides informed consent. 
d  Site will contact the patient telephonically during Weeks 3, , 15, and 16. If any AEs of significant clinical concern are identified during the telephonic visit, the patient will 
be requested to come into the site to be assessed by targeted PE and vital sign measurements. Physical examinations and vital signs will not be assessed at these time points 
if patients do not have AEs of concern.   

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e   On Days 1, 29, and the last day of dosing (End of Week 24 [Day 169 ± 2]), vital signs will be taken pre-dose and 2 hours (± 15 minutes) post-dose. At all other time points, 
vital signs will be taken pre-dose only. Vital sign measurements on Weeks 3,  15, and 16 are obtained only if the patient is brought into the site after identification of AEs of 
significant clinical concern during the telephonic visits. Vital signs should be measured in the sitting or semi-supine position.  
f  At the Screening and Day 1 visits, the PE will include a general examination of the body including the abdomen, heart, chest, lungs, lymph nodes, dentition, back/neck, 
neurological system, skin, extremities, head, ears, eyes, nose, and throat. Subsequent PEs will be symptom directed; symptom-directed PEs on Weeks 3,  15, and 16 are 
obtained only if the patient is brought into the site after identification of AEs of significant clinical concern during the telephonic visits. 
g  On Days 1, 29, and the last day of dosing (End of Week 24 [Day 169 ± 2]), ECGs will be obtained in triplicate at pre-dose and 2 hours (± 30 minutes) post-dose. 
h  Females of childbearing potential only. A serum pregnancy test will be performed at screening; all subsequent tests will be urine. 
i  Includes total haemoglobin (Hb), haemoglobin F (% HbF levels and % F cells), indices of red cell haemolysis (unconjugated bilirubin, reticulocyte counts, lactate 
dehydrogenase [LDH], haptoglobin, soluble E-selectin [sE-sel], soluble P-selectin [sP-sel], soluble intercellular adhesion molecule 1 [sICAM-1], and high-sensitivity 
C-reactive protein [hsCRP]). Blood samples should be obtained within 30 minutes prior to administration of study drug. 
j  On  Days 1, 29, and the last day of dosing (End of Week 24 [Day 169 ± 2]), serial blood samples for IMR-687 plasma concentrations will be drawn pre-dose (within 
30 minutes); at 0.5, 1, 1.5, 2, 4, 6, and 8 hours (± 5 minutes) after administration of study drug; and at 24 hours (± 1 hour) after administration of study drug. If well-tolerated, 
dose escalation from 100 mg to 200 mg will occur after 4 weeks of treatment. 
k At each study visit, patients should be reminded to bring their study medication to their next site visit and to not take study drug on the day of the next visit until instructed to 
do so by the site during the visit. The last day of dosing will be the end of Week 24 (Day 169 ± 2); patient should consume the last dose on site after pre-dose assessments have 
been completed.  
l Adverse events will be recorded throughout the study from Screening through the safety follow-up. In addition to the specified study time points in the Schedule of 
Assessments, patients will be followed weekly by the investigator for safety. Telephone-based check-ins may be performed on weeks where there are no scheduled site visits.  
 

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Table 3: 
Schedule of Assessments: Population B (receiving stable dose of HU) 
 
Screening 
Perioda 
Lead-in 
Periodb 
Double-Blind, Placebo-Controlled Treatment 
End of Study 
(Safety FU) 
Study Week(s) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
13 
17d 
(EOT) 
21(EOS) 
Study Day(s) 
1c 
8 ± 2 15 ± 2 22 ± 2 29 ± 2 36 ± 2 43 ± 2 50 ± 2 57 ± 2 85 ± 2 113 ± 2 
141 ± 5 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic Information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Disease History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Dx Confirmation & 
Pharmacogenomicse 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Telephonic Visitsf 
 
 
 
 
X 
X 
 
X 
X 
X 
 
 
 
 
Vital Signsg 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationh 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECGi 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
Safety Laboratory Assessments 
X 
 
X 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
Pregnancy Testingj 
X 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
 
Exploratory PD Markersk 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
 
IMR-687 Plasma PKl 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
HU PKm 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
QOL Assessments (ASCQ-Me) 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
App-based Pain Questionnaire 
 
 
Daily 
 
Study Drug Administration 
 
 
Once Daily Oral Administration IMR-687 and HUn 
 
AEs & Concomitant 
Medications 
 
 
Continuouso 
Abbreviations: % F cells = percent of red blood cells containing foetal haemoglobin; AEs = adverse events; App = application; BL = baseline; Dx = disease; ECG = electrocardiogram; 
EOS = end of study; EOT = end of treatment; FU = follow-up; HU = hydroxyurea; PD = pharmacodynamic; PE = physical examination; PK = pharmacokinetic; QOL = quality of life; 
SRC = safety review committee. 
Note: Unless otherwise specified, all assessments should be completed prior to dosing. 
a Screening should occur within a 4-week period and can begin approximately 12 weeks prior to the anticipated first dose of study medication in Population B.  
b Once all Screening assessments have been performed and the patient is eligible for the study, the patient will enter the lead-in period and will have serial blood samples drawn 
for 2 complete baseline HU PK profiles. For each profile, samples will be drawn pre-dose (within 30 minutes); at 0.5, 1, 1.5, 3, 6, 8, and 10 hours (± 5 minutes) after self-
administration of the prescribed dose of HU. The duration of the lead-in period is up to approximately 8 weeks, depending on when at least 4 weeks of safety data from at least 
6 patients in Population A are available for SRC review. 

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c The first day study drug is taken is considered “Day 1”; unless otherwise specified. Administration of study medication (Day 1) in Population B will not begin until at least 
4 weeks of safety data from at least 6 patients in Population A have been reviewed by the SRC and the SRC has determined that it is safe and appropriate to begin dosing in 
Population B. 
d  The last day of dosing will be the end of Week 16 (Day 113 ± 2), patient should consume the last dose on site after pre-dose assessments have been completed. During study visit 
Day 113 ± 2, assessments should be collected from any patient who discontinues study drug or study prematurely. 
e Assessments are optional and may be performed at any point during the study if the patient consents. 
f Site will contact the patient telephonically during study week 3, 4, 6, 7, and 8. If any AEs of significant clinical concern are identified during the telephonic visit, the patient 
will be requested to come into the site to be assessed by targeted PE and vital sign measurements. Physical examinations and vital signs will not be assessed at these time 
points if patients do not have AEs of concern.  
g On Days 1, 29, and the last day of dosing [End of Week 16 (Day 113 ± 2)], vital signs will be taken pre-dose and 2 hours (± 15 minutes) post-dose. At all other time points, 
vital signs will be taken pre-dose only. Vital sign measurements on Weeks 3, 4, 6, 7, and 8 are obtained only if the patient is brought into the site after identification of AEs of 
significant clinical concern during the telephonic visits. Vital signs should be measured in the sitting or semi-supine position. 
h At the Screening and Day 1 visits, the PE will include a general examination of the body including the abdomen, heart, chest, lungs, lymph nodes, dentition, back/neck, 
neurological system, skin, extremities, head, ears, eyes, nose, and throat. Subsequent PEs will be symptom-directed; symptom-directed PEs on Weeks 3, 4, 6, 7, and 8 are 
obtained only if the patient is brought into the site after identification of AEs of significant clinical concern during the telephonic visits. 
i On Days 1, 29, and the last day of dosing (End of Week 16 [Day 113 ± 2]), ECGs will be obtained in triplicate at pre-dose and 2 hours (± 30 minutes) post-dose. 
j  Females of childbearing potential only; a serum pregnancy test will be performed at screening; all subsequent tests will be urine. 
k Includes total haemoglobin (Hb), haemoglobin F (% HbF levels and % F cells), indices of red cell haemolysis (unconjugated bilirubin, reticulocyte counts, lactate 
dehydrogenase [LDH], haptoglobin, soluble E selectin [sE-sel], soluble P-selectin [sP-sel], soluble intercellular adhesion molecule 1 [sICAM-1], and high-sensitivity C-reactive 
protein [hsCRP]). Blood samples should be obtained within 30 minutes prior to administration of study drug. 
l On Days 1, 29, and 113, serial blood samples for IMR-687 PK will be drawn pre-dose (within 30 minutes); at 0.5, 1, 1.5, 2, 4, 6, and 8 hours (± 5 minutes) after administration 
of study drug; and at 24 hours (± 1 hour) after administration of study drug.  
m Baseline blood samples for HU PK will be drawn as described in footnote ‘b’. On Days 29 and 113, serial blood samples for HU PK will be drawn pre-dose (within 30 minutes) 
and at 0.5, 1, 1.5, 3, 6, 8, and 10 hours (± 5 minutes) after self-administration of the prescribed dose of HU.  
n At each study visit, patients should be reminded to bring their study medication and their HU to their next site visit and to not take either medication on the day of the next visit 
until instructed to do so by the site during the visit. 
o Adverse events will be recorded throughout the study from Screening to end of Follow-up. In addition to the specified study time points in the Schedule of Assessments, 
patients will be followed weekly by the investigator for safety. Telephone-based check-ins may be performed on weeks where there are no scheduled site visits. 
 
 

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Table 4 
Schedule of Assessments: Population B1 (receiving stable dose of HU) 
 
Screening 
Perioda 
Lead-in 
Periodb 
Double-Blind, Placebo-Controlled Treatment 
End of 
Study 
(Safety FU) 
Study Week(s) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
13 
17 
21 
25d 
(EOT)  29 (EOS) 
Study Day(s) 
1c 
8 ± 2 15 ± 2 22 ± 2 29 ± 2 36 ± 2 43 ± 2 50 ± 2 57 ± 2 85 ± 2 113 ± 2 141 ± 2 169 ± 2 
197± 5 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic Information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Disease History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Dx Confirmation & 
Pharmacogenomicse 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Telephonic Visitsf 
 
 
 
 
X 
X 
 
X 
X 
X 
 
 
 
 
 
 
Vital Signsg 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationh 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECGi 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Safety Laboratory Assessments 
X 
 
X 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Pregnancy Testingj 
X 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
Exploratory PD Markersk 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
IMR-687 Plasma PKl 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
HU PKm 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
QOL Assessments (ASCQ-Me) 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
App-based Pain Questionnaire 
 
 
Daily 
 
Study Drug Administration 
 
 
Once Daily Oral Administration IMR-687 and HUn 
 
AEs & Concomitant 
Medications 
 
 
Continuouso 
Abbreviations: % F cells = percent of red blood cells containing foetal haemoglobin; AEs = adverse events; App = application; BL = baseline; Dx = disease; ECG = electrocardiogram; 
EOS = end of study; EOT = end of treatment; FU = follow-up; HU = hydroxyurea; PD = pharmacodynamic; PE = physical examination; PK = pharmacokinetic; QOL = quality of life; 
SRC = safety review committee. 
Note: Unless otherwise specified, all assessments should be completed prior to dosing. 
a Screening should occur within a 4-week period and can begin approximately 8 weeks prior to the anticipated first dose of study medication in Population B.  

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b Once all Screening assessments have been performed and the patient is eligible for the study, the patient will enter the lead-in period and will have serial blood samples drawn 
for 1 complete baseline HU PK profile. For the baseline HU PK profile, samples will be drawn pre-dose (within 30 minutes); at 0.5, 1, 1.5, 3, 6, 8, and 10 hours (± 5 minutes) 
after self-administration of the prescribed dose of HU. The duration of the lead-in period is approximately 4 weeks. 
c The first day study drug is taken is considered “Day 1”; unless otherwise specified.  
d  The last day of dosing will be the end of Week 24 (Day 169 ± 2); patient should consume the last dose on site after pre-dose assessments have been completed. During study visit 
Day 169 ± 2, assessments should be collected from any patient who discontinues study drug or study prematurely. 
e Assessments are optional and may be performed at any point during the study if the patient consents. 
f Site will contact the patient telephonically during study week 3, 4, 6, 7, and 8. If any AEs of significant clinical concern are identified during the telephonic visit, the patient 
will be requested to come into the site to be assessed by targeted PE and vital sign measurements. Physical examinations and vital signs will not be assessed at these time 
points if patients do not have AEs of concern.  
g On Days 1, 29, and the last day of dosing (End of Week 24 [Day 169 ± 2]), vital signs will be taken pre-dose and 2 hours (±15 minutes) post-dose. At all other time points, vital 
signs will be taken pre-dose only. Vital sign measurements on Weeks 3, 4, 6, 7, and 8 are obtained only if the patient is brought into the site after identification of AEs of 
significant clinical concern during the telephonic visits. Vital signs should be measured in the sitting or semi-supine position. 
h At the Screening and Day 1 visits, the PE will include a general examination of the body including the abdomen, heart, chest, lungs, lymph nodes, dentition, back/neck, 
neurological system, skin, extremities, head, ears, eyes, nose, and throat. Subsequent PEs will be symptom-directed; symptom-directed PEs on Weeks 3, 4, 6, 7, and 8 are 
obtained only if the patient is brought into the site after identification of AEs of significant clinical concern during the telephonic visits. 
i On Days 1, 29, and the last day of dosing (End of Week 24 [Day 169 ± 2]), ECGs will be obtained in triplicate at pre-dose and 2 hours (±30 minutes) post-dose. 
j  Females of childbearing potential only; a serum pregnancy test will be performed at screening; all subsequent tests will be urine. 
k Includes total haemoglobin (Hb), haemoglobin F (% HbF levels and % F cells), indices of red cell haemolysis (unconjugated bilirubin, reticulocyte counts, lactate 
dehydrogenase [LDH], haptoglobin, soluble E selectin [sE-sel], soluble P-selectin [sP-sel], soluble intercellular adhesion molecule 1 [sICAM-1], and high-sensitivity C-reactive 
protein [hsCRP]). Blood samples should be obtained within 30 minutes prior to administration of study drug. 
l On Days 1, 29, and 169, serial blood samples for IMR-687 PK will be drawn pre-dose (within 30 minutes); at 0.5, 1, 1.5, 2, 4, 6, and 8 hours (± 5 minutes) after administration 
of study drug; and at 24 hours (± 1 hour) after administration of study drug.  
m Baseline blood samples for HU PK will be drawn as described in footnote ‘b’. On Days 29 and 169, serial blood samples for HU PK will be drawn pre-dose (within 30 minutes) 
and at 0.5, 1, 1.5, 3, 6, 8, and 10 hours (± 5 minutes) after self-administration of the prescribed dose of HU.  
n At each study visit, patients should be reminded to bring their study medication and their HU to their next site visit and to not take either medication on the day of the next visit 
until instructed to do so by the site during the visit. 
o Adverse events will be recorded throughout the study from Screening to end of Follow-up. In addition to the specified study time points in the Schedule of Assessments, 
patients will be followed weekly by the investigator for safety. Telephone-based check-ins may be performed on weeks where there are no scheduled site visits

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2. 
TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
KEY ROLES AND RESPONSIBILITIES ......................................................................................4 
Emergency Contact Information ......................................................................................................4 
Safety Review Committee ...............................................................................................................4 
1. 
PROTOCOL SUMMARY ............................................................................................5 
1.1. 
Synopsis ........................................................................................................................5 
1.2. 
Protocol Schema .........................................................................................................13 
1.3. 
Schedule of Assessments ............................................................................................14 
2. 
TABLE OF CONTENTS ...........................................................................................23 
LIST OF TABLES .........................................................................................................................27 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................28 
4. 
INTRODUCTION ......................................................................................................31 
4.1. 
Background .................................................................................................................31 
4.1.1. 
IMR-687 .....................................................................................................................32 
4.1.2. 
Nonclinical Data .........................................................................................................32 
4.1.3. 
Clinical Data ...............................................................................................................33 
4.1.3.1. 
Phase 1a Study of IMR-687 in Healthy Adult Volunteers (IMR-SCD-101) ..............33 
4.1.3.2. 
Phase 2 Study of IMR-687 in Adult Patients with Sickle Cell Anaemia 
(IMR-SCD-102) ..........................................................................................................35 
4.2. 
Rationale for Conducting the Study ...........................................................................37 
4.3. 
Benefit/Risk Assessment ............................................................................................37 
4.3.1. 
Potential Benefits ........................................................................................................37 
4.3.2. 
Potential Risks ............................................................................................................38 
4.3.2.1. 
Gastrointestinal ...........................................................................................................38 
4.3.2.2. 
Central Nervous System .............................................................................................38 
4.3.2.3. 
Cardiovascular ............................................................................................................38 
5. 
OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS .................................39 
5.1. 
Primary Objective and Endpoint(s) ............................................................................39 

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5.2. 
Secondary Objectives and Endpoints .........................................................................39 
5.3. 
Exploratory Objectives and Endpoints .......................................................................39 
6. 
STUDY DESIGN .......................................................................................................40 
6.1. 
Overall Design ............................................................................................................40 
6.1.1. 
Population A ...............................................................................................................40 
6.1.2. 
Population A1 .............................................................................................................41 
6.1.3. 
Population B ...............................................................................................................41 
6.1.4. 
Population B1 .............................................................................................................42 
6.2. 
Dose Selection Rationale ............................................................................................42 
6.3. 
Scientific Rationale for Study Design ........................................................................43 
6.4. 
End of Study Definition ..............................................................................................44 
6.4.1. 
Participant Completion ...............................................................................................44 
6.4.2. 
Study Completion .......................................................................................................44 
7. 
STUDY POPULATION .............................................................................................44 
7.1. 
Patient Inclusion Criteria ............................................................................................44 
7.2. 
Patient Exclusion Criteria ...........................................................................................45 
7.3. 
Screen Failures ............................................................................................................47 
8. 
STUDY INTERVENTION ........................................................................................47 
8.1. 
Name and Description ................................................................................................47 
8.1.1. 
Test Therapy (IMR-687) .............................................................................................47 
8.1.2. 
Reference Therapy (Placebo) .....................................................................................48 
8.2. 
Packaging and Labelling .............................................................................................48 
8.3. 
Preparation, Handling, Storage, and Accountability ..................................................48 
8.4. 
Randomization and Blinding ......................................................................................49 
8.4.1. 
Randomization ............................................................................................................49 
8.4.2. 
Blinding ......................................................................................................................49 
8.4.3. 
Emergency Unblinding ...............................................................................................50 
8.5. 
Administration ............................................................................................................50 
8.6. 
Compliance/Adherence ...............................................................................................50 
8.7. 
Concomitant Medications/Therapies ..........................................................................50 
8.7.1. 
Non-investigational Medicinal Products ....................................................................51 

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8.7.2. 
Prohibited Concomitant Medications/Therapies ........................................................51 
8.8. 
Dose Modification ......................................................................................................51 
9. 
STUDY, SITE, OR PARTICIPANT DISCONTINUATION ....................................52 
9.1. 
Criteria for Study or Site Termination or Study Suspension ......................................52 
9.2. 
Treatment Discontinuation/Stopping Rules ................................................................53 
9.3. 
Participant Discontinuation/Withdrawal ....................................................................54 
9.4. 
Lost to Follow-up .......................................................................................................54 
9.5. 
Patient Replacement ...................................................................................................55 
9.6. 
Patient Telephonic Visits ............................................................................................55 
10. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................55 
10.1. 
Pharmacokinetic and Pharmacodynamic Assessments ..............................................56 
10.1.1. 
Blood Sample Collection ............................................................................................56 
10.1.2. 
Analytical Methodology .............................................................................................56 
10.2. 
Exploratory Clinical Outcome Assessments ..............................................................56 
10.2.1. 
Pain-related Measures .................................................................................................56 
10.2.2. 
Quality of Life Measurement ......................................................................................57 
10.3. 
Disease Confirmation and Pharmacogenomics ..........................................................57 
10.4. 
Safety Assessments .....................................................................................................57 
10.4.1. 
Adverse Event and Serious Adverse Event Collection ...............................................57 
10.4.1.1. 
Time Period Adverse Event Collection ......................................................................57 
10.4.1.2. 
Follow-up ....................................................................................................................58 
10.4.2. 
Adverse Event Recording and Reporting ...................................................................58 
10.4.2.1. 
Definitions ..................................................................................................................58 
10.4.2.2. 
Evaluation of Adverse Events / Serious Adverse Events ...........................................59 
10.4.2.3. 
Recording and Reporting Adverse Events and Serious Adverse Events ....................61 
10.4.2.4. 
Regulatory Reporting Requirements ..........................................................................62 
10.4.2.5. 
Exposure During Pregnancy .......................................................................................62 
10.4.3. 
Other Safety Parameters .............................................................................................62 
10.4.3.1. 
Clinical Laboratory Tests ...........................................................................................62 
10.4.3.2. 
Vital Signs ..................................................................................................................63 
10.4.3.3. 
Electrocardiograms .....................................................................................................63 

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10.4.3.4. 
Physical Examinations ................................................................................................64 
11. 
STATISTICS ..............................................................................................................64 
11.1. 
General Considerations ...............................................................................................64 
11.2. 
Analysis Datasets: .......................................................................................................65 
11.3. 
Safety Analyses ..........................................................................................................65 
11.4. 
Pharmacokinetic Analyses ..........................................................................................65 
11.5. 
Analyses of Exploratory Endpoints ............................................................................66 
11.6. 
Interim Analysis ..........................................................................................................66 
11.7. 
Determination of Sample Size ....................................................................................66 
11.8. 
Computer Systems ......................................................................................................67 
12. 
DATA MANAGEMENT ...........................................................................................67 
12.1. 
Data Collection Tools and Source Document Identification ......................................67 
12.1.1. 
Source Data .................................................................................................................67 
12.1.2. 
Source Documents ......................................................................................................67 
12.1.3. 
Case Report Forms .....................................................................................................67 
12.2. 
Audits and Inspections ................................................................................................67 
12.3. 
Archiving ....................................................................................................................68 
12.4. 
Data Monitoring ..........................................................................................................68 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................68 
13.1. 
Compliance .................................................................................................................68 
13.2. 
Serious Breaches to GCP or the Protocol ...................................................................69 
13.3. 
Written Informed Consent ..........................................................................................69 
13.4. 
Data Protection and Patient Confidentiality ...............................................................70 
13.5. 
Financial Disclosure ...................................................................................................70 
14. 
LIST OF REFERENCES ............................................................................................71 
15. 
APPENDICES ............................................................................................................73 

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LIST OF TABLES 
Table 1: 
Schedule of Assessments: Population A (not receiving HU) .....................................15 
Table 2 
Schedule of Assessments: Population A1 (not receiving HU) ...................................17 
Table 3: 
Schedule of Assessments: Population B (receiving stable dose of HU) ....................19 
Table 4 
Schedule of Assessments: Population B1 (receiving stable dose of HU) ..................21 
Table 5 
Summary of PK Parameters in Fed Patients After a Single Dose of IMR-687 
(IMR-SCD-102 Part A Interim Analyses) ..................................................................36 
Table 6: 
IMR-687 Active Investigational Medicinal Product ..................................................48 
Table 7: 
Accepted Time Window for PK and PD Blood Draws ..............................................56 
Table 8: 
Safety Laboratory Parameters to be Measured ...........................................................63 
LIST OF FIGURES 
Figure 1: 
Study Design Schema for Population A .....................................................................13 
Figure 2: 
Study Design Schema for Population A1 ...................................................................13 
Figure 3 
Study Design Schema for Population B .....................................................................14 
Figure 4 
Study Design Schema for Population B1 ...................................................................14 
Figure 5 
Individual Pharmacokinetic Concentrations After a Single Dose of IMR-687 
(IMR-SCD-102 Part A Interim Analysis) ...................................................................37 

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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADL 
activities of daily living 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
API 
active pharmaceutical ingredient 
ARC 
absolute reticulocyte count 
ASCQ-Me 
Adult Sickle Cell Quality-of-Life Measurement Information System 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-12 
area under the concentration-time curve from time 0 to 12 hours 
AUC0-24 
area under the concentration-time curve from time 0 to 24 hours 
AUC0-inf  
area under the concentration-time curve extrapolated to infinity 
AUClast  
area under the concentration-time curve from time 0 to the last 
measurable time point 
cGMP 
cyclic guanosine monophosphate 
CI 
confidence interval 
CIOMS 
Council for International Organisations of Medical Sciences 
Cmax  
maximum concentration 
CNS 
central nervous system 
CRO 
contract research organisation 
CTCAE 
Common Terminology Criteria for Adverse Events 
%CV 
coefficient of variation 
CYP 
cytochrome P450 
DNA 
deoxyribonucleic acid 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
eGFR 
estimated glomerular filtration rate 
FE 
food effect 

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Abbreviation 
Definition 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
Hb 
haemoglobin 
HbF 
foetal haemoglobin 
HbSS 
homozygous sickle haemoglobin 
hCG 
human chorionic gonadotropin  
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HPLC 
high-performance liquid chromatography 
HU 
hydroxyurea 
IC50 
concentration that produces 50% of maximal response 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
LDH 
lactate dehydrogenase 
MAD 
multiple ascending dose 
MDR1 
multidrug-resistant protein 1 
MHRA 
Medicines and Healthcare Products Regulatory Agency 
MPO 
myeloperoxidase 
mRNA 
messenger ribonucleic acid 
NIMP 
non-investigational medicinal product 
NO 
nitric oxide 
NOAEL 
no-observed-adverse-effect level 
OECD 
Organisation for Economic Cooperation and Development 
PD 
pharmacodynamic(s) 
PDE 
phosphodiesterase 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 

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Abbreviation 
Definition 
QTc 
corrected QT interval 
QTcF 
corrected QT interval, Fridericia’s formula 
RBC 
red blood cell 
REC 
Research Ethics Committee 
SAD 
single ascending dose 
SAE 
serious adverse event 
SCA 
sickle cell anaemia 
SCD 
sickle cell disease 
SD 
standard deviation 
sE-sel 
soluble E-selectin 
sICAM-1 
soluble intercellular adhesion molecule-1 
sP-sel 
soluble P-selectin 
SRC 
Safety Review Committee 
SUSAR 
suspected unexpected serious adverse reaction 
sVCAM 
soluble vascular cell adhesion molecule 
t½  
apparent terminal half-life 
TEAE 
treatment-emergent adverse event 
tmax  
time to maximum concentration 
ULN 
upper limit of normal 
US 
United States 
VOC 
vaso-occlusive crisis 
WBC 
white blood cell 
 

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4. 
INTRODUCTION 
4.1. 
Background 
The Sponsor is developing IMR-687 for the treatment of patients with the most severe forms of 
sickle cell disease (SCD), which include homozygous sickle haemoglobin (HbSS) and sickle-β0 
thalassemia, collectively referred to as sickle cell anaemia (SCA).   
With a neonatal incidence of 294,000 to 330,000 patients worldwide (Piel 2013), SCA is a rare 
inherited disorder of red blood cells (RBCs) that is both serious and life threatening. The most 
common manifestations of SCA include vaso-occlusive crisis (VOC), chronic and acute severe 
pain, acute chest syndrome, stroke, priapism, acute anaemia (particularly from aplastic crisis and 
splenic sequestration), increased susceptibility to infection, and progressive damage to major 
organs including the spleen, brain, kidney, heart, lung, skin, retina, vestibular cochlear systems, 
and bone. In developed countries where there is prenatal screening and widespread access to 
prophylactic and acute interventions, the median age of death remains in the 40s to 50s, though 
many patients succumb to the disease much earlier (Platt 1994; Lanzkron 2013; Paulukonis 2016). 
SCA is caused by a specific point mutation in the gene encoding haemoglobin subunit beta that 
results in the substitution of a hydrophobic valine residue for glutamic acid in the 6th position from 
the N terminus of the β chain and leads to the production of abnormal haemoglobin (“sickle 
haemoglobin” or HbS), which polymerises when in the deoxygenated conformation. Under 
conditions of hypoxia, acidity, and/or dehydration, the intracellular concentration of deoxyHbS 
increases thereby favouring polymerization and causing RBCs to deform (i.e., sickle) or become 
rigid, leading to a complex cascade of haemolysis, inflammation, elevated cell adhesion, 
leucocytosis, oxidative stress, and endothelial dysfunction that culminates in the vascular 
obstruction and ischemia responsible for much of the observed morbidity.  
Prior to July 2017, the only drug specifically approved for the treatment of SCA was hydroxyurea 
(HU), a small molecule inhibitor of ribonucleotide reductase that was originally developed for the 
treatment of myeloproliferative disorders. HU is also known as hydroxycarbamide and has been 
approved to treat SCA since 1998 in the United States (US) and since 2001 in Europe. In SCA, 
HU reduces painful crises and the need for blood transfusions (Charache 1995), at least in part by 
increasing levels of foetal haemoglobin (HbF), which reduces RBC sickling and improves blood 
flow. These effects are mediated, at least in part, by increased nitric oxide (NO) and cyclic 
guanosine monophosphate (cGMP) production (Erard 1981; Platt 1984; Cokic 2003). 
Unfortunately, HU is often poorly tolerated and its widespread use is limited by concerns about its 
potential impact on fertility and reproduction, challenges achieving and maintaining an efficacious 
dose due to its hematologic toxicities, and requirements for monthly monitoring (Heeney 2008).  
In July 2017, L-glutamine oral powder (Endari™) was approved in the US to reduce complications 
of SCD; however, the data available to date are limited primarily to the results from 230 patients 
(158 who received L-glutamine oral powder and 78 who received placebo) in the phase 3 pivotal 
trial. In this study, the median number of sickle cell crises through Week 48 (primary endpoint) 
was 3 in patients who received L-glutamine oral powder compared with 4 in patients who received 
placebo. Thus, additional novel, safe, and effective treatments to prevent the morbid complications 
of SCA in patients of all ages are still urgently needed. 

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4.1.1. 
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) type 9 (PDE9); PDE9 mediates cellular signalling pathways 
by degrading 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 HbF, which reduces the cellular concentration of abnormal haemoglobin within 
RBCs and its associated sequelae. The importance of increasing HbF in treating SCD is evidenced 
by large studies like the Cooperative Study of Sickle Cell Disease 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 haematological parameters of SCA (Akinsheye 2011; Alsultan 2013; Barbosa 2013; Sheehan 
2013). 
PDE9 is highly expressed in hematopoietic cells and is also widely distributed in brain, with the 
highest expression measured in cerebellar Purkinje cells of rodents (van Staveren 2002). A 
potential advantage of IMR-687 for the SCA 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). 
4.1.2. 
Nonclinical Data 
The IMR-687 nonclinical program supports its potential safety and efficacy for the treatment of 
SCA. 
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 SCA 
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 Good Laboratory Practice (GLP)/Organisation for Economic Cooperation and Development 
(OECD)-compliant safety pharmacology studies, IMR-687 had no test article-related adverse 
effects on respiratory function in the rat at doses <1000 mg/kg, no test article-related adverse 
effects on CNS/behavioural function in the rat at doses ≤250 mg/kg, and no test article-related 
adverse effects on cardiac function in conscious dogs at doses ≤25 mg/kg. The no observed adverse 
effect level (NOAEL) for IMR-687 in a GLP/OECD 13-week repeat-dose toxicity study in the rat 
was the maximum oral dose of 200 mg/kg/day, which resulted in an area under the concentration-
time curve (AUC) from time 0 to 24 hours post dose (AUC0-24) of 352,000 and 454,000 ng•h/mL 
in males and females, respectively. In a GLP/OECD 13-week study in the dog, the NOAEL for 
orally administered IMR-687 was 25 mg/kg/day, which resulted in an AUC0-24 of 83,200 and 
81,200 ng•h/mL in males and females, respectively. IMR-687 was negative in GLP/OECD 

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bacterial mutation, chromosome aberration, and Ames mutagenicity studies as well as in rat 
micronucleus assays. In addition, a 6-month toxicology study in the rat and a 9-month toxicology 
study in the dog are ongoing; draft results for the 6-month rat toxicology study and the 6-month 
in-life findings from the 9-month dog toxicology study will be available prior to the start of this 
study and a draft, unaudited report will be available prior to dosing any patient beyond 12 weeks. 
IMR-687 exhibited low plasma protein binding in mouse, rat, dog, monkey, and humans; no 
competitive inhibition for the 7 major human cytochrome P450 (CYP) isoforms up through 
concentrations of 100 μM; and no notable induction of CYP1A2 or CYP2B6 messenger 
ribonucleic acid (mRNA) expression in human hepatocytes. However, IMR-687 did show the 
potential for induction of CYP3A4 mRNA expression at high doses and was found to be a 
multidrug-resistant protein 1 (MDR1) substrate (human P-glycoprotein [P-gp]) in a study to 
evaluate MDR1-mediated efflux of IMR-687 in MDCK MDR1 cell monolayers. In addition, in a 
rat study to evaluate the potential for interactions between IMR-687 and HU that used high doses 
of both, the maximum plasma concentration (Cmax) and AUC0-24 of HU were 65% lower when 
given in combination with 250 mg/kg/day IMR-687 than when given in isolation, while IMR-687 
exposure was similar when administered either in isolation or with HU. There were no deaths or 
clinical signs in groups given IMR-687 and HU in combination or in isolation, and weight gains 
and food intake were similar across groups.  
Additional information on the nonclinical effects of IMR-687 is provided in the Investigator’s 
Brochure. 
4.1.3. 
Clinical Data 
4.1.3.1. 
Phase 1a Study of IMR-687 in Healthy Adult Volunteers (IMR-SCD-101) 
A first-in-human, randomised, double-blind, placebo-controlled study to evaluate the safety, 
tolerability, and pharmacokinetics (PK) of IMR-687 in up to 66 healthy male and female adults 
between the ages of 18 and 55 years, inclusive, has been conducted (IMR-SCD-101). The study 
was divided into 3 parts: a single ascending dose (SAD) study (Part A), a food effect (FE) study 
(Part B), and a multiple ascending dose (MAD) study (Part C). The last subject’s last visit has 
occurred for all 3 study parts and draft, unaudited, unblinded data are available for all cohorts 
except for the highest dose in Part C, which is still blinded. 
4.1.3.1.1. IMR-SCD-101: Part A (SAD) 
Part A sequentially evaluated single oral doses of 0.3, 1, 3, 4.5, and 6 mg/kg in 5 cohorts of 
subjects; in each cohort, 6 subjects were randomised to receive either IMR-687 (N=4) or placebo 
(N=2) in double-blind fashion. Study drug (IMR-687 or placebo) was administered following an 
overnight fast on Day 1 and subjects returned to the study unit on Day 5 for an end-of-study visit.  
All subjects completed Part A; there were no serious adverse events (SAEs) and all adverse events 
(AEs) were mild to moderate in severity, transient, self-limited, and easily monitorable. The most 
commonly occurring treatment-related AE was nausea, which was noted in 7 subjects who 
received IMR-687: 1 in the 1 mg/kg group and 3 each in the 4.5 and 6 mg/kg groups. At the highest 
dose level of 6 mg/kg, 2 of these subjects also experienced emesis, which was considered a 

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dose-limiting toxicity. Therefore, the maximum tolerated dose of IMR-687 in Part A was 
4.5 mg/kg (equivalent to a dose of 225 mg in a 50 kg patient, the minimum permitted weight for 
inclusion in this study).  
Assessments for vital signs (heart rate, blood pressure, temperature) and serial electrocardiograms 
(ECGs) did not demonstrate any clinically significant, dose-dependent findings. Review of 
selected safety labs, including white blood cell (WBC) count, absolute neutrophil count, 
haemoglobin/haematocrit, platelets, serum creatinine, and liver function tests (aspartate 
aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin, and alkaline 
phosphatase) did not reveal any clinically significant findings, either for individual subjects or in 
the assessments of group mean values for these parameters. 
IMR-687 geometric mean exposure (AUC0-inf, AUC0-last, and Cmax) increased in an approximately 
dose-proportional fashion and terminal 24-hour concentrations remained at or above the 
half-maximal concentration (IC50) for inhibition of PDE9 (10 nM or 5.8 ng/mL). Geometric mean 
half-life (t½) ranged from 3.55 to 5.72 hours across all dose levels, and median time to maximum 
concentration (tmax) ranged from 1.0 to 3.0 hours. 
4.1.3.1.2. IMR-SCD-101: Part B (Food Effect) 
In Part B, 12 healthy volunteers were administered two single oral doses of IMR-687 at 1 mg/kg. 
The FE part was open-label; all subjects received their first dose of IMR-687 in the fasted state 
(Period 1) and the second dose in the fed state (Period 1) after a 1-week washout between doses. 
All subjects completed both study periods in Part B; there were no serious adverse events (SAEs) 
and all adverse events (AEs) were mild in severity, transient, self-limited, and easily monitorable. 
Oral administration of IMR-687 to fasted subjects (Period 1) resulted in the following 
treatment-emergent adverse events (TEAEs) that were considered by the Investigator to be 
possibly related to study drug: nausea (n=1), dyspepsia (n=1), and headache (n=4). In Period 2, 
oral administration of IMR-687 to fed subjects did not result in any treatment-related TEAEs. 
Review of vital signs, serial ECGs, and laboratory parameters did not reveal any clinically 
significant findings. 
At a single oral dose of 1 mg/kg, the effect of food on the PK profile of IMR-687 was a delay in 
tmax (median delay of 3 hours), an approximately 26% decrease in Cmax, and a <10% decrease in 
AUC(0-inf). Thus, the high-fat meal had no notable impact on systemic exposure to IMR-687 despite 
a mild delay in the rate of absorption. 
4.1.3.1.3. IMR-SCD-101: Part C (MAD) 
Part C sequentially evaluated oral doses of 1, 3, and 4.5 mg/kg administered once daily for 7 days; 
in each dose cohort, 8 subjects were randomised to receive either IMR-687 (N=6) or placebo (N=2) 
in double-blind fashion. Based on the improved safety and tolerability profile of IMR-687 in the 
fed state in Part B, all subjects in the MAD part received IMR-687 or placebo immediately after a 
meal.   
At the 1 and 3 mg/kg dose levels, the most common AEs were associated with phlebotomy (thirst, 
sensation of warmth, and mild dizziness on Day 1 contemporaneous to phlebotomy [n=1, 

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1 mg/kg]; superficial thrombophlebitis [n=2, placebo]) or were headaches (n=1, 3 mg/kg; n=1, 
placebo).  
At the 4.5 mg/kg dose level (results are still blinded), TEAEs included hematoma at the 
phlebotomy site (n=1); nausea (n=1) that occurred 45 minutes after dosing on Day 7 and was 
transient and self-limiting; headache (n=1) on Day 1 that resolved the same day following 
treatment with acetaminophen; and mild nausea on Days 6 and 7 with a single bout of mild emesis 
on Day 7 (n=1). 
Review of vital signs, serial ECGs, and laboratory parameters did not reveal any clinically 
significant findings for subjects in the 1 or 3 mg/kg dose cohorts. Full results are pending for 
Cohort 3 (4.5 mg/kg); however, preliminary review of vital signs and ECG data did not 
demonstrate any clinically significant findings. 
On Days 1 and 7, increases in geometric mean Cmax were trending less than dose proportional, 
while increases in geometric mean AUC0-24 (or AUC0-t) and AUC0-∞ were closer to dose 
proportional. With a 4.5-fold increase in dose from 1 to 4.5 mg/kg, the geometric mean Cmax 
increased ~3.3-fold while the geometric mean AUC0-24 and geometric mean AUC0-∞ increased 4.3- 
and 4.2-fold, respectively, on Day 1. On Day 7, the geometric mean Cmax increased ~3.6-fold while 
the geometric mean AUC0-24 increased ~4.1-fold. Trough concentrations indicated steady state was 
achieved by or before Day 7 with once daily dosing. The geometric mean accumulation ratio for 
AUC(0-24) was ≤1.125 for all three dose levels, indicating no notable accumulation at steady state 
with once daily dosing. 
4.1.3.2. 
Phase 2 Study of IMR-687 in Adult Patients with Sickle Cell Anaemia 
(IMR-SCD-102) 
4.1.3.2.1. IMR-SCD-102: Interim Analysis Summary 
A pre-specified blinded interim analysis was performed after at least 18 subjects in Population A 
had ≥4 weeks of available data for soluble adhesion markers. In addition, 3-month RBC data were 
available for a subset of 13 of these Population A subjects. To maintain the study blind, summary 
tables were prepared by an independent unblinded statistician who is not affiliated with the 
ongoing conduct of the study. In addition, no unblinded data were presented on individual subjects, 
and all data except for safety were pooled by randomized assignment. 
As of the cut-off date (01 October 2018), safety measures (SAEs, AEs, vital signs) were analysed 
for 24 subjects enrolled in the study. Blinded safety evaluation found 58 AEs, with 4/58 events 
(7%) determined to be possibly related (2), probably related (1), or definitely related (1) to study 
drug. All these events were Grade 1 mild events that resolved without sequelae. No clinically 
relevant changes in vital signs were observed. Five SAEs were reported; all were categorized as 
sickle cell pain crises or VOCs. 
Nineteen subjects (9 male and 10 female), were evaluated after 5 weeks of treatment, with a focus 
on WBC and adhesion biomarkers. A PK assessment following the first dose of IMR-687 indicated 
that 50 mg PK concentrations were below the target exposure indicated by preclinical mouse 
concentration-time data and time above the IC90 (Table 5 and Figure 5). The 100 mg dose level 
demonstrated drug concentrations expected to be effective, but at the lower end of the predicted 

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therapeutic window. In line with these findings, in the 100 mg dose group, there was a trend to 
reduced soluble P-selectin (sP-sel), soluble E-selectin (sE-sel), soluble vascular cell adhesion 
molecule (sVCAM), and myeloperoxidase compared to placebo treatment. In addition, RBC 
parameters were assessed in 13 subjects after 13 weeks of treatment and the 100 mg dose showed 
a consistent increase in the percentage of F cells over time, an increase in total Hb, and a reduction 
in both absolute reticulocytes counts (ARCs) and % reticulocyte counts. There was no obvious 
decrease in sE-sel, sP-sel, sVCAM, ARC, or % reticulocytes, or increases in % F cells, HbF, or 
Hb with the 50 mg dose vs. placebo. 
Table 5 
Summary of PK Parameters in Fed Patients After a Single Dose of IMR-687 
(IMR-SCD-102 Part A Interim Analyses) 
 
50 mg 
100 mg 
Mean t½ (hr) 
4.83 
4.83 
Mean tmax (hr) 
NR 
NR 
Mean Cmax (ng/mL) 
533 
1310 
Mean AUC0-t (hr*ng/mL) 
2610 
6730 
Mean AUC0-24 (hr*ng/mL) 
2790 
7060 
Mean AUC0-∞ (hr*ng/mL) 
2900 
7340 
CL/F (L/hr) 
17/5 
14.1 
Vz/F (L) 
119 
97.7 
AUC = area under the time-concentration curve; CL/F = apparent total clearance; Cmax = maximum concentration; 
NR = not reported; PK = pharmacokinetic; t½ = half-life; tmax = time to Cmax; Vz/F = apparent volume of 
distribution 
Note: N=6 for both dose groups and all PK parameters. 

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Figure 5 
Individual Pharmacokinetic Concentrations After a Single Dose of IMR-687 
(IMR-SCD-102 Part A Interim Analysis) 
 
In summary, daily dosing of IMR-687 was safe and well tolerated in the 24 subjects enrolled in 
the study as of the 01 Oct 2018 data cut. Results of the interim analysis provide preliminary clinical 
evidence that IMR-687 may provide beneficial effects on both RBC and WBC biomarkers in SCD. 
Exposure data from the interim PK of the IMR-687 50 mg and IMR-687 100 mg dose groups and 
clinically relevant biomarkers suggest the planned 200 mg dose has the potential to achieve 
improved target coverage to mediate more profound changes in RBC and WBC biology. 
4.2. 
Rationale for Conducting the Study 
This is the first study in patients with SCA. The purpose of this study is to evaluate the safety, 
tolerability, PK, exploratory pharmacodynamics (PD), and clinical outcomes of IMR-687 in adult 
patients with SCA. Given that approximately 25% of patients with SCA are currently prescribed 
HU, it is possible that IMR-687, should it be approved, will be administered as a single agent or 
co-administered with HU. Therefore, the effects of IMR-687 will be evaluated in patients with 
SCA who are not receiving HU (Populations A and A1) as well as those who are currently 
receiving a stable dose of HU according to standard of care (Populations B and B1). 
4.3. 
Benefit/Risk Assessment 
The proposed doses in this study are 50, 100, and 200 mg daily, which are anticipated to be in the 
pharmacologically active range based on available nonclinical data (see Section 6.2 for dose 
selection rationale). The minimum weight for an eligible patient to enter this study is 50 kg; thus, 
the maximum possible per kilogram doses of IMR-687 are 1, 2, and 4 mg/kg. Based on the 
observed safety and tolerability of IMR-687 in the first-in-human study (Section 4.1.3), these dose 
levels should be well tolerated and may have a clinical beneficial PD effect in patients with SCA. 
The potential benefits and risks are summarized below. 
4.3.1. 
Potential Benefits 
This is the first study of IMR-687 in patients; therefore, the primary objective of this study is to 
determine the safety and tolerability of once daily oral doses of IMR-687 across a range of doses 

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anticipated to be pharmacologically active. However, potential benefits include the production of 
increased levels of HbF, which is associated with the decreased RBC sickling and improved 
bloodflow, and decreases in WBC adhesion molecules; individually and together these PD changes 
may lead to fewer painful SCA-associated crises and less need for blood transfusions. 
4.3.2. 
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. These potential risks are briefly summarized in 
the sections below. Further details are provided in the Investigator’s Brochure. 
4.3.2.1. 
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, 
particularly when administered in the fasted state. Nausea observed thus far was transient and 
self-limited. Emesis has occurred at 6 mg/kg when administered in the fasted state, and after 
multiple-dose administration at 4.5 mg/kg in the fed state (on Day 7). Administration of IMR-687 
with food mitigates nausea significantly and should be recommended. No correlate changes in 
liver function tests in any healthy volunteers administered IMR-687, or specifically in those 
subjects with nausea, with or without emesis, were observed. 
4.3.2.2. 
Central Nervous System 
Mild headaches (self-limiting or treatable with acetaminophen) were observed in the first-in-
human study in healthy normal volunteers, and appeared to occur with nausea.  
4.3.2.3. 
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. At doses of 
75 mg/kg in the safety pharmacology study, statistically significant heart rates were observed in 
dogs. In the 14-day dog toxicology study, the highest heart rates were noted in dogs at the highest 
dose level of 75 mg/kg, but did not reach statistical significance. 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 QTcF were noted in any cohort of healthy volunteers at 
any dose of IMR-687.  
Monitoring of vital signs is recommended for patients in IMR-687 studies. In the event of noted 
persistent and/or clinically significant tachycardia, other causes of tachycardia, particularly pain 
and dehydration in sickle cell patients, should also be considered. 

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5. 
OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS 
5.1. 
Primary Objective and Endpoint(s) 
The primary objective of this (second-in-human) study is: 
• To assess the safety and tolerability of IMR-687 in adult patients with SCA, defined as 
HbSS or sickle-β0 thalassemia, who are not receiving HU and in adult SCA patients 
who are receiving a stable dose of HU 
The safety and tolerability of IMR-687 will be assessed by the following endpoints: 
• Incidence and severity of AEs and SAEs 
• Observed values and changes from baseline in 12-lead ECG parameters, clinical laboratory 
tests (chemistry, haematology, coagulation, urinalysis), and vital signs 
• Physical examination findings 
• Use of concomitant medications and therapies 
5.2. 
Secondary Objectives and Endpoints 
The secondary objectives of this study are: 
• To characterise the PK profile of IMR-687 in adult patients with SCA who are/are not 
receiving a stable dose of HU 
• To characterise the PK profile of HU in adult patients with SCA before and after 
receiving IMR-687 to determine whether there is a clinically relevant PK interaction 
The PK profiles of IMR-687 and HU (administered alone and concomitantly with IMR-687) will 
be evaluated by the determination of PK parameters based on drug concentration levels in plasma 
obtained over time. 
5.3. 
Exploratory Objectives and Endpoints 
The exploratory objectives of this study are: 
• To assess the PD effects of IMR-687 in adult patients with SCA who are/are not 
receiving stable HU 
• To assess the potential efficacy of IMR-687 in adult patients with SCA who are/are not 
receiving stable HU 
The following endpoints will be evaluated to assess the PD activity of IMR-687 (additional 
exploratory PD biomarkers may also be tested): 
• Total haemoglobin (Hb) level 
• HbF value (%) 
• % F cells  
• Indices of red cell haemolysis (unconjugated bilirubin, reticulocyte count, lactate 
dehydrogenase [LDH], and haptoglobin levels) 

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• sE-sel, sP-sel, and sICAM-1 
• High-sensitivity C-reactive protein (hs-CRP) 
The following SCA-related clinical outcome measures will be evaluated to assess the potential 
efficacy of IMR-687: 
• Pain-related measures, including 
o Frequency, severity, and duration of pain  
o Impact of pain/fatigue on work/school and on activities of daily living (ADL) 
o Need for/use of pain medication 
o SCA-related events requiring professional medical or health care, including events 
requiring hospitalization or therapies, such as transfusions 
• The physical, social, and emotional impact of SCA as measured by the ASCQ-Me 
6. 
STUDY DESIGN 
6.1. 
Overall Design 
This is a randomised, double-blind, placebo-controlled study to evaluate the safety, tolerability, 
PK, and exploratory PD and clinical outcomes of the PDE9 inhibitor, IMR-687, administered once 
daily for 16 to 24 weeks in 2 populations of patients with SCA: those who are not receiving HU 
(Populations A and A1) and those who are currently receiving a stable dose of HU according to 
standard of care (Populations B and B1). Approximately 60 patients will be enrolled in 
Populations A and A1 combined and approximately 30 patients will be enrolled in Populations B 
and B1 combined. 
The overall study design is depicted in Figure 1, Figure 2, Figure 3, and Figure 4, for 
Populations A, A1, B, and B1, respectively. 
6.1.1. 
Population A 
Following a Screening period of up to 4 weeks, eligible patients in Population A (i.e., those 
enrolled prior to this amendment and not receiving HU) will receive either IMR-687 or placebo 
once daily for a total of 24 weeks. On Day 1, patients will be randomised 1:1:1 to receive oral 
IMR-687 50 mg, IMR-687 100 mg, or placebo; the first 6 patients (sentinel patients to initiate 
dosing in Part B) will be randomized as a separate block. For the first 12 weeks (Weeks 1-12), all 
patients will receive study medication once daily according to their randomised treatment 
assignment; if well tolerated for 12 weeks, each patient’s dose may be doubled (i.e., from 50 mg 
to 100 mg; from 100 mg to 200 mg; or placebo) for the next 12 weeks (Weeks 13-24). Note: 
Because placebo and all dose levels of IMR-687 are the same in appearance, dose escalation will 
not affect study medication blinding.  
Throughout the study, all available clinical safety data will be reviewed approximately every 
2 weeks by a Safety Review Committee (SRC; see Safety Review Committee). Dose escalation 

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will occur on an individual-patient basis on Day 85 patients enrolled in Population Aonly if 
approved by the SRC based on review of each patient’s individual clinical safety data.  
Safety, PK, PD, and efficacy assessments will be performed at the time points shown in Table 1. 
6.1.2. 
Population A1 
A pre-planned interim analysis of the data from the first 24 patients (Section 4.1.3.2.1) showed 
that daily dosing of IMR-687 was safe and well tolerated. In the 19 patients who had PK and PD 
biomarkers analysed, the 50 mg dose was considered to be subtherapeutic, and data indicated the 
planned 200 mg dose would likely achieve improved target coverage to mediate more profound 
changes in RBC and WBC biology. Subsequent patients (approximately 12 subjects) will not be 
randomized to the 50 mg dose level. 
Following a Screening period of up to 4 weeks, eligible patients in Population A1 (i.e., those 
enrolled after this amendment and not receiving HU) will receive either IMR-687 or placebo once 
daily for a total of 24 weeks. On Day 1, patients will be randomised 2:1 to receive oral IMR-687 
100 mg or placebo. For the first 4 weeks (Weeks 1-4), all patients will receive study medication 
once daily according to their randomised treatment assignment; if well tolerated for 4 weeks, each 
patient’s dose may be doubled (i.e., from 100 mg to 200 mg; or placebo) for the next 20 weeks 
(Weeks 5-24). Note: Because placebo and all dose levels of IMR-687 are the same in appearance, 
dose escalation will not affect study medication blinding.  
Throughout the study, all available clinical safety data will be reviewed approximately every 
2 weeks by a SSRC; see Safety Review Committee). Dose escalation will occur on an individual-
patient basis on Day 29 for patients enrolled on this amendment (version 005, 07 Jan 2019) only 
if approved by the SRC based on review of each patient’s individual clinical safety data.  
Safety, PK, PD, and efficacy assessments will be performed at the time points shown in Table 2. 
6.1.3. 
Population B 
Following a Screening period of up to 4 weeks, eligible patients in Population B (i.e., those 
enrolled prior to this amendment and receiving stable HU) will have blood samples drawn to 
characterise the PK profile of the patient’s prescribed dose of HU in the absence of IMR-687 (i.e., 
to characterise the patient’s baseline HU PK profile). 
Following completion of the Screening and lead-in periods, eligible patients in Population B will 
receive their standard-of-care, stable dose of HU in addition to either IMR-687 or placebo once 
daily for 16 weeks. Dosing in Population B will not begin until at least 4 weeks of safety data from 
at least 6 patients in Population A have been reviewed by the SRC and the SRC has determined 
that it is safe and appropriate to begin dosing in Population B. Following SRC approval to initiate 
dosing in Population B and once the lead-in period is complete, patients will be randomised 2:1 
on Day 1 to receive either IMR-687 50 mg or placebo. For the first 4 weeks (Weeks 1-4), patients 
will receive study medication once daily according to their randomised treatment assignment; for 
the following 12 weeks (Weeks 5-16), each patient’s dose may be doubled (i.e., from 50 mg to 
100 mg; or placebo). Note: Because placebo and all dose levels of IMR-687 are the same in 
appearance, dose escalation will not affect study medication blinding. 

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Throughout the study, all available clinical safety data (from Populations A, A1, B, and B1 will 
be reviewed approximately every 2 weeks by the SRC. Dose escalation in Population B will occur 
on an individual-patient basis on Day 29 only if approved by the SRC based on review of each 
patient’s individual clinical safety data.  
Safety, PK, PD, and efficacy assessments will be performed at the time points shown in Table 3. 
6.1.4. 
Population B1 
Following a Screening period of up to 4 weeks, eligible patients in Population B1 (i.e., those 
enrolled after this amendment and receiving stable HU) will enter a 4-week lead-in period and will 
have a single set of blood samples drawn to characterise the patient’s baseline HU PK profile. 
Once the baseline HU PK blood draws are complete, patients will be randomised 2:1 on Day 1 to 
receive oral IMR-687 50 mg or placebo for 24 weeks. For the first 4 weeks (Weeks 1-4), patients 
will receive study medication once daily according to their randomised treatment assignment; for 
the following 20 weeks (Weeks 5-24), each patient’s dose may be doubled (i.e., from 50 mg to 
100 mg; or placebo). Dose escalation will occur on Day 29 only if approved by the SRC based on 
review of each patient’s individual clinical safety data.  
Safety, PK, PD, and efficacy assessments will be performed at the time points shown in Table 4. 
6.2. 
Dose Selection Rationale 
The starting dose for this study of 50 and 100 mg correlates with an approximately 0.7 mg/kg and 
1.4 mg/kg dose for an average 70 kg adult, while the maximum planned dose of 200 mg correlates 
to an approximately 2.9 mg/kg dose for an average 70 kg adult. The minimum acceptable weight 
in this study is 50 kg. Therefore, the corresponding doses of 50, 100, and 200 mg are equivalent 
to maximum doses of approximately 1, 2, and 4 mg/kg.  
In nonclinical mouse models of sickle cell disease, IMR-687 at a dose of 30 mg/kg/day was 
effective at increasing the number of HbF+ RBCs, decreasing the percentage of sickled RBCs, and 
decreasing microvascular stasis after induced transient hypoxia/reperfusion. Based on the 
exposure of IMR-687 in these models, the target pharmacologically active range of IMR-687 in 
humans is expected to be between 0.3 to 3 mg/kg per day. 
Based on the observed safety and tolerability of IMR-687 in the first-in-human study, once daily 
doses of 50, 100, and 200 mg should be well tolerated, especially if taken with food, as 
administration with food appears to reduce the incidence of nausea. The most likely potential AEs 
of nausea and emesis are easily monitorable and are self-limiting if dosing is stopped. Furthermore, 
following once daily dosing for 7 days, minimal accumulation was observed and steady state was 
achieved by or before Day 7; therefore, the safety and tolerability profile observed in the MAD 
part of the first-in-human study can likely be extrapolated to longer-term dosing. Exposure (AUC) 
increased in a near dose-proportional manner (a 4.1-fold increase for a 4.5-fold change in dose 
[see Section 4.1.3.1.3]), and the mean exposure (AUC0-24) at 4.5 mg/kg on Day 7 was 
25.6 µg•h/mL, which is approximately 3.6-fold below the Day 14 exposure (AUC0-24) in the dog 
(most conservative species) at the NOAEL in the repeat-dose toxicology study. 

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6.3. 
Scientific Rationale for Study Design 
This is a phase 2a study intended to explore the potential use of IMR-687 to treat patients with 
SCA. This is the first study in a patient population (patients with SCA), and as such, is designed 
to examine the safety, tolerability, and PK, as well as the potential PD effects and clinical efficacy, 
of IMR-687 across a range of doses in adult patients with SCA. Given the possibility that IMR-687, 
if approved, could be administered as a single agent or co-administered with HU, the effects of 
IMR-687 will be evaluated in SCA patients who are not receiving HU (Populations A and A1) as 
well as in those who are currently receiving a stable dose of HU (Populations B and B1).  
Available nonclinical and healthy volunteer clinical data suggest that IMR-687 will be safe and 
well tolerated at once daily doses of 50, 100, and 200 mg and that these doses, if administered for 
at least 12 weeks, may demonstrate HbF induction and potential beneficial effects on markers of 
WBC adhesion (including sE-sel, sP-sel, and sICAM-1). Each test dose level (50, 100, and 200 mg 
in Population A and 100 mg in Population B) is planned to be administered for at least 12 weeks. 
In addition, given that the induction of HbF is directly and mechanistically related to relief from 
symptoms in SCA patients, the greatest likelihood to see a clinical effect is expected if IMR-687 
is administered for at least 24 weeks at a dose of at least 100 mg. Therefore, Population A is also 
designed to provide at least 12 weeks of data (and at most 24 weeks of data) at a dose of at least 
50 mg, as well as to assess the tolerability of the 200 mg dose level in sickle cell patients who have 
tolerated the 100 mg dose well. Population A1 is designed to provide at least 20 weeks of data at 
a dose of 200 mg. Population B1 is designed to provide at least 20 weeks data at a dose of 100 mg 
and to assess the tolerability and PD effects of IMR-687 in sickle cell patients.  
To minimise potential confounding factors and increase the interpretability of the findings, the 
study is randomised, double blind, and placebo controlled. As only approximately 25% of patients 
with SCA receive treatment with HU and concomitant use of HU is permitted in Populations B 
and B1, the use of a concurrent placebo control provides scientific rigor without affecting standard 
of care. 
Safety will be monitored intensively at regular site visits and, in addition to ongoing oversight of 
the study by the SRC, all patients will be seen in person once weekly for the first 4 weeks following 
initiation of treatment and dose escalation. Because there are no safety data on the administration 
of IMR-687 in patients with SCA, administration of IMR-687 will begin in Population A (patients 
not on HU).  
Results from Populations B and B1 are intended to provide information on IMR-687 when 
administered concomitantly with HU, both of which increase HbF levels through alternative 
biochemical pathways that increase intracellular cGMP. Furthermore, because there are no clinical 
data to support administration of IMR-687 concomitantly with HU, patients in Populations B and 
B1will initiate dosing at the low IMR-687 dose (50 mg) used in Population A and will escalate to 
the 100 mg dose only if the 50 mg dose has been safe and tolerated for 4 weeks. In addition, 
although available nonclinical data do not suggest that concomitant administration of HU with 
IMR-687 would increase IMR-687 exposure, dosing in Population B will not initiate until 4 weeks 
of safety data are available from Population A in 2 patients each at 50 mg (starting dose in 
Population B) and 100 mg (twice the starting dose), as well as 2 patients at placebo. 

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6.4. 
End of Study Definition 
6.4.1. 
Participant Completion 
The length of a patient’s participation in the study will be from the time informed consent is signed 
until the patient completes the end-of-study/follow-up visit and will be approximately 32 weeks 
for Populations A, A1, and B and approximately 36 weeks for Population B1. 
A patient is considered to have completed the study if he/she has completed the end-of-
study/follow-up visit as shown in schedules of assessments in Table 1 (Population A), Table 2 
(Population A1), Table 3 (Population B), and Table 4 (Population B1). 
6.4.2. 
Study Completion 
Study completion is defined as the final date on which data are collected (i.e., the last patient’s last 
visit or the last patient’s last scheduled assessment).  
7. 
STUDY POPULATION 
A total of 90 evaluable patients are expected to enrol in this study, approximately 60 patients in 
Populations A and A1 combined (patients not receiving HU) and approximately 30 patients in 
Populations B and B1 combined (patients on a stable dose of HU). 
7.1. 
Patient Inclusion Criteria 
Each patient must meet all of the following criteria to be enrolled in the study: 
1. Be a male or female ≥18 and ≤55 years of age. 
2. Have a confirmed diagnosis of SCA (HbSS or sickle-B0 thalassemia). Note: If not already 
documented in the patient’s record, the diagnosis of SCA must be confirmed via 
electrophoresis, high performance liquid chromatography (HPLC), and/or genotyping. 
3. Use of HU: 
a. For patients in the Populations A and A1: Have not received HU within 90 days prior 
to Screening and are not planning to take HU while on the study. 
b. For patients in Populations B and B1: Have received HU for at least 6 months, have 
been on a stable dose for at least 60 days prior to Screening, and are not planning to 
change the dose level, dose regimen, or discontinue HU within the next 6 months.  
4. Female patients must not be pregnant and be highly unlikely to become pregnant. Male 
patients must be unlikely to impregnate a partner. Male or female patients must meet at least 
one of the following criteria: 
c. A female patient who is not of reproductive potential is eligible without requiring the 
use of contraception. A female patient who is not of reproductive potential is defined 
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 

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local 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). 
d. A male patient who is not of reproductive potential is eligible without requiring the use 
of contraception. A male patient 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. 
e. A male or female patient 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 line with the preferred 
and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods), declaration of abstinence for the duration of 
the trial and withdrawal are not acceptable methods of contraception. Acceptable 
methods of highly effective birth control are combined or progestogen-only hormonal 
contraception that is associated with inhibition of ovulation, intrauterine device, and 
intrauterine hormone-releasing system.  
5. Be capable of giving informed consent and reading and signing the informed consent form 
after the nature of the study has been fully explained by the investigator or investigator 
designee. 
6. Be willing and able to complete all study assessments and procedures and to communicate 
effectively with the investigator and site staff. 
7.2. 
Patient Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from the study: 
1. Total Hb at Screening >12.5 g/dL or <6 g/dL. 
2. Reticulocyte count <100 x 109/L for Populations A and A1, or <80 x 109/L for Populations B 
and B1. 
3. Greater than 7 hospitalizations (for at least 24 hours) for VOC, including acute chest 
syndrome and priapism, within the prior year. 
4. (intentionally left blank) 
5. Blood transfusion or donation of blood or any blood product within 60 days of Day 1 or on 
chronic transfusion therapy regimen. 
6. Positive for human immunodeficiency virus (HIV), hepatitis C (HCV) antibodies (unless 
the patient has successfully completed drug therapy that results in cure/clearance of HCV), 
or hepatitis B surface antigen. 
7. For female patients of childbearing potential, a positive serum human chorionic 
gonadotropin (hCG) test (Screening) or a positive urine hCG test on Day 1. 

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8. Estimated glomerular filtration rate (eGFR) <50 mL/min as calculated by the equation from 
the Modification of Diet in Renal Disease Study using creatinine, age, sex, and ethnicity. 
9. ALT or AST >3x the upper limit of normal (ULN) 
10. Body mass index (BMI) <17.5 or >35 kg/m2; a total body weight <50 kg  
11. Use of PDE type 5 (PDE5) inhibitors (including but not limited to sildenafil, tadalafil, 
vardenafil) within 7 days prior to the first dose of study drug, or planning to use any time 
during study 
12. A history of drug or alcohol abuse as judged by the investigator within the past 1 year, or a 
positive alcohol (breathalyser) test (Screening or Day -1). 
13. A cancer that has not been in complete remission for at least 5 years. Patients with squamous 
cell or basal cell carcinoma of the skin, localised cervical cancer, or localised prostate cancer 
are eligible if, in the opinion of the investigator, the condition has been adequately 
diagnosed, and is determined to be clinically in remission, and the patient’s participation in 
the study would not represent a safety concern. 
14. 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. 
15. On ECG, a corrected QT interval (QTc), Fridericia’s formula (QTcF) >450 ms in men and 
>470 ms in women or the presence of clinically significant abnormalities as determined by 
the investigator. 
16. A history of major surgery within 4 weeks or minor surgery within 2 weeks of Day 1. 
17. Any flu-like syndrome or other respiratory infection within 2 weeks of Day 1 or vaccination 
with attenuated live virus within 4 weeks of Day 1. 
18. Participation in an investigational drug or device study within 30 days prior to Day 1. 
19. Use within 30 days prior to Day 1, or planning to use during the study, of any drugs or 
substances that are known to strongly inhibit or induce CYP enzymes, including but not 
limited to cimetidine, cyclosporine, erythromycin, omeprazole, rifampin, ritonavir, and St. 
John’s wort. If there is any question as to whether a substance is permitted, please review 
the product labelling (if applicable) and consult the Sponsor. 
20. Consumption of grapefruit, grapefruit juice, or grapefruit products within 24 hours prior to 
Day 1 or planning to consume grapefruit products during the study. 
21. Use within 30 days prior to Day 1, or planning to use during the study, of any CYP3A 
sensitive substrates (see Appendix A). If there is any question as to whether a substance is 
permitted, please review the product labelling (if applicable) and consult the Sponsor. 
22. Use within 30 days prior to Day 1, or planning to use during the study, of any drugs or 
substances known to be significant substrates or inhibitors of P-gp (see Appendix B). If 
there is any question as to whether a substance is permitted, please review the product 
labelling (if applicable) and consult the Sponsor.  

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23. Other prior or ongoing medical condition, physical findings, or laboratory abnormality that, 
in the investigator's opinion, could adversely affect the safety of the patient, make it unlikely 
that the course of treatment or follow-up would be completed, or impair the assessment of 
study results. 
24. In the opinion of the investigator, the patient is unable to meet the requirements of the study. 
7.3. 
Screen Failures 
Any patient who consents to participate in the study but is not randomised is considered a 
screen failure. Demographic data, eligibility criteria, reason not randomised (if other than 
failed 1 or more inclusion or exclusion criterion), and – if applicable – any SAEs will be 
recorded and reported for patients who are screen failures.  
8. 
STUDY INTERVENTION 
8.1. 
Name and Description 
8.1.1. 
Test Therapy (IMR-687) 
IMR-687 is the active investigational medicinal product (IMP) being tested in this clinical study. 
It is a novel organic compound that inhibits the cGMP-degrading enzyme, PDE9A. IMR-687 is in 
clinical development and is not authorised for marketing in any country. In earlier development 
studies, the active pharmaceutical ingredient (API) was alternately referred to as AF68722. The 
API is a white to off-white powder that is highly soluble in water. IMR-687 drug product will be 
supplied as 50, 100, or 200 mg white tablets for oral administration. The different doses of 
IMR-687 are visually identical in tablet form. Information on the IMP is provided in Table 6. 
Product characteristics, including Reference Safety Information, are provided in the Investigator’s 
Brochure. 

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Table 6: 
IMR-687 Active Investigational Medicinal Product 
Chemical Name: 
6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-
3-yl]-3-tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-
one 
Other Names or Designations: 
AF68722, 68722, and CK1598 
CAS RN: 
Not listed 
Molecular Formula: 
C21H26N6O2 
Molecular Weight: 
 
Dosage Form: 
 
Strength: 
 
Route of Administration 
 
Excipients: 
 
 
 
Manufacturer 
 
CAS RN = Chemical Abstracts Service Registry Number; EP = European Pharmacopoeia; NF = National Formulary 
8.1.2. 
Reference Therapy (Placebo) 
The reference IMP in this study is placebo. Placebo will consist of tablets containing matrix absent 
IMR-687 and will be identical in appearance to the IMR-687 tablets. 
8.2. 
Packaging and Labelling 
 
 
 
 
8.3. 
Preparation, Handling, Storage, and Accountability 
Upon receipt of the study medication, an inventory must be performed and a drug receipt log filled 
out 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. Any 
damaged or unusable study medication must be documented, and the site must notify the Sponsor. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI

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Only patients enrolled in the study may receive study medication, and only authorised site staff 
may supply or administer study medication to study patients. All study medication 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 
authorised site staff. 
The study site must maintain accurate records demonstrating dates and quantity of study 
medication received, to whom dispensed (patient-by-patient accounting), any amount returned, 
and accounts of any study medication that was accidentally or deliberately destroyed. At the end 
of the study, a final reconciliation must be made between the quantity of study medication 
supplied, dispensed, and subsequently destroyed or returned to the Sponsor. A written explanation 
must be provided for any discrepancies. 
Any unused study medication remaining at the end of the study will be returned to the Sponsor or 
destroyed after accountability has been performed by the Sponsor or Sponsor’s designee. 
8.4. 
Randomization and Blinding 
8.4.1. 
Randomization 
All patients who are screened (including screen failures) will be assigned a unique Screening 
identification number.  
On Day 1, eligible patients in Populations A, A1, B, and B1 will be assigned a unique number 
(randomization number) in sequential order. The randomization number codes the patient’s initial 
treatment assignment to IMR-687 50 mg, IMR-687 100 mg, or placebo for Population A, IMR-
687 100 mg or placebo for Population A1, or IMR-687 50 mg or placebo for Populations B and 
B1, according to the randomization schedule generated prior to the study. Randomization for 
Population A will be 1:1:1 for each of the 3 groups; randomization for Population A1 will be 2:1 
for IMR-687 100 mg and placebo, and randomization for Populations B and B1 will be 2:1 for 
IMR-687 50 mg and placebo. In Population A, the first 6 patients (sentinel patients to initiate 
dosing for Population B) will be randomized as a separate block. 
Randomization numbers will not be re-used once assigned. In the event that a patient is replaced, 
the replacement patient will receive the same treatment as the replaced patient and will be assigned 
a randomization number incremented by 
 (e.g., 
 would replace 
). 
8.4.2. 
Blinding 
To ensure that the patient and site are blinded with respect to each patient’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 
placebo, IMR-687 50 mg, IMR-687 100 mg, or IMR-687 200 mg. At each site visit, as needed, an 
unblinded study pharmacist will select a bottle containing the correct IMP and, if applicable, dose 
level and will provide the blinded study medication to the patient. 
Every attempt should be made to preserve the integrity of study drug blinding. Except for cases of 
emergency unblinding, as described in Section 8.4.3, the randomization code will remain unbroken 
PPD
PPD
PPD

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for patients and study personnel at the site until the database has been locked for each study 
population.  
8.4.3. 
Emergency Unblinding 
Unblinding is not always necessary to provide effective medical intervention and patient 
management in the event a patient experiences a VOC, an SAE, or an event that results in cessation 
of treatment (see Section 9.2). 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 patient will be provided to the investigator 
according to standard operating procedures at the contract research organisation (CRO). The 
Medical Monitor and Sponsor are available to the Investigator as needed for any considerations of 
unblinding a specific patient; however, the decision to unblind a specific patient relies solely on 
the clinical judgement of the Investigator and there is no requirement to discuss with the Medical 
Monitor and/or Sponsor prior to unblinding a specific patient by the Investigator.  
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 electronic 
case report form (eCRF) pages. 
8.5. 
Administration 
Patients will take IMR-687 or matched placebo tablets orally with food once per day for 24 weeks 
(Populations A, A1, and B1) or 16 weeks (Population B).  
8.6. 
Compliance/Adherence 
The investigator or designee must ensure that all patients 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; all study drug administration will be documented on the appropriate pages of the 
eCRF. 
8.7. 
Concomitant Medications/Therapies 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements) that the patient receives from the time of enrolment 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 
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. 

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8.7.1. 
Non-investigational Medicinal Products 
A non-investigational medicinal product (NIMP) is a product that is not under investigation, but 
will be used in the trial; a NIMP may include any background medication(s) administered to all 
participants. 
There are no NIMPs administered to Populations A and A1. 
HU is administered as a NIMP to patients in Populations B and B1. Patients in Populations B and 
B1 will take HU as prescribed by their treating physician according to their current, stable, 
standard-of-care dose.  
8.7.2. 
Prohibited Concomitant Medications/Therapies 
The following are not permitted at any time during the study. If any of the following are determined 
to be necessary for the well-being of the patient, the patient will be withdrawn from the study.: 
• PDE5 inhibitors (including but not limited to sildenafil, tadalafil, vardenafil). 
• Any drugs or substances, including grapefruit juice, that are known to strongly inhibit or 
induce CYP enzymes, including but not limited to cimetidine, cyclosporine, erythromycin, 
grapefruit or grapefruit juice, omeprazole, rifampin, ritonavir, and St. John’s wort. If there 
is any question as to whether a substance is permitted, please review the product labelling 
(if applicable) and consult the Sponsor. 
• Any drug or substance that is a CYP3A-sensitive substrate (other than opioids), including 
but not limited to alfentanil, avanafil, budesonide, buspirone, conivaptan, darifenacin, 
darunavir, dasatinib, dronedarone, ebastine, eletriptan, eplerenone, everolimus, felodipine, 
ibrutinib, indinavir, lomitapide, lurasidone, maraviroc, midazolam, naloxegol, nisoldipine, 
quetiapine, saquinavir, sirolimus, tacrolimus, ticagrelor, tipranavir, tolvaptan, triazolam. If 
there is any question as to whether a substance is permitted, please review the product 
labelling (if applicable) and consult the Sponsor. 
• Any drugs or substances that are significant substrates or inhibitors of P-gp, including but 
not limited to cyclosporine, lovastatin, propranolol, quinidine, and simvastatin. If there is 
any question as to whether a substance is permitted, please review the product labelling (if 
applicable) and consult the Sponsor. 
• Concomitant use of L-glutamine and erythropoietin (e.g., Procrit, Epogen). For 
erythropoietin, a washout period of at least 6 weeks is required before starting on study. 
• Any other investigational drug or device. 
Medications prohibited prior to study entry are described in the exclusion criteria in Section 7.2. 
8.8. 
Dose Modification 
If the SRC determines that it is safe to do so, each patient’s dose will be increased during the study. 
Patients in Population A will receive their randomised dose for the first 12 weeks of the study; 
beginning at Week 13, each patient’s dose may be doubled (i.e., from 50 mg to 100 mg; from 
100 mg to 200 mg; or placebo). Patients in Population A1 will receive their randomised dose for 

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the first 4 weeks of the study; beginning at Week 5, each patient’s dose may be doubled (i.e., from 
100 mg to 200 mg or placebo). Patients in Population B will receive their randomized dose for the 
first 4 weeks of the study; beginning on Week 5, each patient’s dose may be doubled (i.e., from 
50 mg to 100 mg or placebo). Patients in Population B1 will receive their randomised dose for the 
first 4 weeks of the study; beginning at Week 5, each patient’s dose may be doubled (i.e., from 
50 mg to 100 mg; or placebo). 
To maintain the blind, placebo and all dose levels of IMR-687 are identical in appearance.  
The SRC will decide whether or not to dose escalate on a patient-by-patient basis once it has 
reviewed all available safety data for a given patient. The SRC may decide to continue a patient 
on his or her initial randomized dose (i.e., not to dose escalate) or to double the patient’s blinded 
dose (i.e., dose escalate). Dose escalation will occur only at Week 13 for patients in Population A 
or at Week 5 for patients in Populations A1, B, and B1, and only once approved by the SRC. 
Dose reductions are not permitted during the study, including after a patient’s dose has been 
escalated. If, in his/her clinical judgement, the investigator believes that continued administration 
of study medication may pose an unacceptable safety risk to the patient, study drug should be 
discontinued (see also Section 9.2). 
9. 
STUDY, SITE, OR PARTICIPANT DISCONTINUATION 
9.1. 
Criteria for Study or Site Termination or Study Suspension 
The Sponsor may terminate this study or investigational site participation in this study at any time 
for any reason. Conditions that may warrant termination of the study or investigational site 
participation in this study include, but are not limited to: 
• Decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of IMR-687 
• Failure of the investigator to comply with the approved protocol, pertinent guidelines, 
and/or regulations 
• Submission of knowingly false information from the investigator to the Sponsor and/or 
regulatory authorities 
In addition, the Sponsor or the SRC may suspend the study (i.e., instruct cessation of IMP dosing 
in all patients) if, in their opinion, emerging data at that time indicate that the risk of continued 
dosing outweighs any possible benefit from study continuation. In the case of study suspension, 
dosing of further patient volunteers cannot restart without a positive opinion from the Medicines 
and Healthcare Products Regulatory Agency (MHRA) and Ethics’ Committee to recommence the 
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9.2. 
Treatment Discontinuation/Stopping Rules 
After consultation between the investigator and the sponsor CRO medical monitor, dosing of any 
individual patient may be stopped and the patient withdrawn from the study if any of the following 
arises: 
• The patient becomes pregnant 
• The patient misses ≥5 days of dosing within a 28-day period for any reason 
• For Population A and A1 patients – the patient has started, or will be started on HU during 
the period of the study for any reason (e.g., recurrent VOCs) 
• ALT or AST >5x ULN upon repeat testing 
• eGFR <30 mL/min upon repeat testing with suspicion of renal parenchymal damage 
• Any other clinical event or finding that in the clinical judgement of the investigator would 
pose an unacceptable safety risk to the patient to continue in the study 
Note: Patients who experience VOC(s) or other SCA-related events may remain in the study and 
continue to receive IMP, unless the investigator deems that continued treatment would pose an 
unacceptable safety risk to the patient. Patients who experience VOCs or other SCA-related events 
should not be unblinded (even if treatment is discontinued) unless the investigator believes that 
knowledge of the study drug assignment is essential to provide appropriate medical management 
of the patient (see Section 8.4.3). Patients who experience a VOC should receive all appropriate 
interventions as per local standard of care. These include hydration (oral and/or intravenous), rapid 
and adequate pain control (nonsteroidal anti-inflammatory drugs and/or opioids as appropriate), 
and rest (hospital admission may be necessary). Supplemental oxygen may also be of benefit. 
Assessment and treatment of a SCD patient with a new VOC depend solely on the clinical 
judgement of the Investigator, and should include management of potential sequelae of the VOC, 
such as renal failure or stroke.  
In patients who are not already on HU, dosing of HU is typically not initiated in the acute phase 
of a VOC. Consideration of starting HU in any given patient takes into account the patient’s prior 
response to SCD management, potential compliance/adherence for serial follow-up, and other 
potential clinical issues (e.g., likelihood for pregnancy in the future). The decision for starting HU 
in a previously naïve SCD patient is at the clinical discretion of the Investigator. Patients already 
on HU should remain on their stable outpatient dose, unless considered by the Investigator to 
require modulation of their dosing. Changes in dosing of HU is at the clinical discretion of the 
Investigator.  
In the event that treatment is prematurely discontinued, if possible, patients in Populations A, A1, 
or B1 should complete all assessments scheduled at the Week 25 study visit before being 
withdrawn from the study. Patients in Population B should complete all assessments scheduled at 
the Week 17 study visit before being withdrawn from the study.  
The investigator will document the reason(s) for treatment or study discontinuation on the eCRF. 
The Sponsor and the CRO medical monitor should be informed when a patient is withdrawn from 
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9.3. 
Participant Discontinuation/Withdrawal 
All patients who receive study drug should remain in the study whenever possible. However, 
patients are free to withdraw consent and/or discontinue participation in the study at any time, 
without providing a reason and without prejudice to further medical care. If the patient withdraws 
from the study, he/she must be provided with a point of contact to obtain further information about 
the study, if desired. Data and samples collected to the point of withdrawal may only be used after 
withdrawal if the patient consented to this. A patient who withdraws from the study may request 
destruction of any samples taken and not tested, and the investigator must document this in the site 
study records. 
A patient’s treatment and participation in the study may also be discontinued at any time at the 
discretion of the investigator, the CRO medical monitor, or the Sponsor. Justifiable reasons to 
discontinue a patient from treatment and the study may include, but are not limited to the 
following: 
• The patient was erroneously included in the study (i.e., did not meet eligibility criteria) 
• The patient experiences an SAE assessed as possibly or probably related to study drug 
• The patient is unable to comply with the requirements of the protocol 
• The patient participates in another investigational study 
• The patient withdraws consent 
• A patient for whom the blind is intentionally or accidentally broken  
In the event that a patient withdraws or is withdrawn from the study, if possible, the patient should 
complete all assessments scheduled at the Week 25 (Populations A, A1, and B1 [Table 1, Table 2, 
and Table 4, respectively]) or Week 17 (Population B, Table 3) study visit before being withdrawn 
from the study. 
A patient will be considered “discontinued due to an AE” if he or she withdraws from the study 
due to any AE, regardless of whether or not the AE is considered related to study drug. If the 
patient withdraws from the study due to an AE, the investigator should arrange for the patient to 
be followed appropriately until the AE has resolved or stabilised (in the opinion of the 
investigator). 
The investigator will document the reason(s) for treatment or study discontinuation on the eCRF. 
The Sponsor and the CRO medical monitor should be informed when a patient is withdrawn from 
the study. 
9.4. 
Lost to Follow-up 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  
If a patient fails to return to the clinic for a required study visit, the site must: 
• Attempt to contact the patient and reschedule the missed visit as soon as possible  

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• Counsel the patient on the importance of maintaining the assigned visit schedule  
• Ascertain whether or not the patient wishes to and/or should continue in the study. 
Before a patient is deemed lost to follow-up, the investigator or designee must make every effort 
to regain contact with the patient (where possible, 3 telephone calls and, if necessary, a certified 
letter to the patient’s last known mailing address or local equivalent methods). These contact 
attempts should be documented in the patient’s medical record. 
Should the patient continue to be unreachable, he/she will be considered to have withdrawn from 
the study.  
9.5. 
Patient Replacement 
To ensure an adequate number of patients to evaluate the safety and PK of IMR-687, any patient 
who is randomised but does not receive study drug may be replaced. In addition, any patient who 
discontinues prior to the Week 13 study visit (Populations A, A1, B, and B1) may be replaced 
subject to SRC agreement. Available data for all patients will be reported in data listings. 
9.6. 
Patient Telephonic Visits 
Patients enrolled in Populations A will have telephonic visits during Weeks 3, 4, 15, and 16. 
Patients enrolled in Populations A1 will have telephonic visits during Weeks 3, 15, and 16. 
Similarly, for patients enrolled in Populations B and B1, telephonic visits will occur during 
Weeks 3, 4, 6, 7, and 8. The telephonic visit should collect information on any AEs of significant 
clinical concern, as well as remind patients to continue to take study drug orally with food once a 
day, and to complete their daily app-based symptom questionnaire in a timely manner. 
If any AEs of significant clinical concern are identified during the telephonic visit, the patient will 
be requested to come into the site to be assessed by targeted physical exam and vital signs 
measurement. Physical exams and vital signs will not be measured at these time points if patients 
do not have AEs of concern. 
10. 
STUDY ASSESSMENTS AND PROCEDURES 
Study assessments and their timing are outlined in the Schedules of Assessments (Population A, 
Table 1; Population A1, Table 2; Population B, Table 3; and Population B1, Table 4).  
All eligibility (inclusion/exclusion) assessments must be completed at Screening (and, for 
Group B, prior to obtaining blood samples for the 24-hour baseline HU PK profile) and reviewed 
on Day 1 to confirm that potential patients meet all eligibility criteria. All eligibility criteria must 
be recorded on the eCRF, including reasons for screen failure or other exclusion from the study, if 
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10.1. 
Pharmacokinetic and Pharmacodynamic Assessments 
10.1.1. 
Blood Sample Collection 
Blood samples will be collected from all patients at the time points indicated in Table 1 
(Population A), Table 2 (Population A1), Table 3 (Population B), and Table 4 (Population B1) for 
the determination of IMR-687 and HU plasma concentrations and for determination of PD 
biomarker levels.  
On study days, when post-dose blood samples are drawn for IMR-687 or for HU PK, the exact 
date and time of IMR-687/placebo or HU, respectively, dose administration must be recorded on 
the eCRF. The exact date and time (actual) for each blood draw must also be recorded on the 
eCRF. 
The accepted window of time for blood draws for PK and PD parameters is shown in Table 7. The 
actual date and time of each sample will be recorded. The approximate total volume of blood to 
be withdrawn in shown in Appendix C. 
Table 7: 
Accepted Time Window for PK and PD Blood Draws 
Procedure 
Time Point (Relative Time) 
Window Allowance 
PK and PD 
Pre dose 
Within 30 minutes prior to dose 
PK 
Post-dose time points up through 
10 hours post dose  
± 5 minutes for each time point 
24 hours post dose  
± 1 hour at each time point 
PD = pharmacodynamics; PK = pharmacokinetics 
Refer to the Study Laboratory Manual for details on the collection, handling, and processing of 
blood samples. 
10.1.2. 
Analytical Methodology 
Plasma PK (IMR-687 and HU) concentrations and all PD biomarkers will be quantified using 
validated assays. Details of the method validation will be documented (for each assay) in a method 
validation report. 
10.2. 
Exploratory Clinical Outcome Assessments 
In this phase 2a study, the potential efficacy of IMR-687 will be evaluated by assessing measures 
related to pain and SCA-related events that require professional medical or health care attention. 
In addition, patient quality of life will also be evaluated. The same assessments will be performed 
in Population A, Population A1, Population B, and Population B1 at the time points indicated in 
Table 1, Table 2, Table 3, and Table 4, respectively. 
10.2.1. 
Pain-related Measures 
An app-based pain questionnaire (completed daily) will be used to evaluate the following 
pain-related measures: 
• Frequency, severity, and duration of pain 

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• Impact of pain/fatigue on work/school and on activities of daily living 
• Need for professional medical or health care  
• Need for pain medication 
In addition, the details of all opiate- and non-opiate-based pain medication use will be recorded on 
the eCRF, including the start date/time, dose, frequency, route of administration, and stop 
date/time; any change during the study must be recorded as a new record.  
If pain or any other SCA-related event results in the need for professional medical or health care, 
the details will also be recorded, including the event(s) that required care (e.g., VOCs), the need 
for hospitalization (start and stop dates/times for each hospitalization), and any therapies 
administered (e.g., transfusions). 
10.2.2. 
Quality of Life Measurement 
The ASCQ-Me will be administered to evaluate the potential effects of IMR-687 on the physical, 
social, and emotional impacts of SCA. 
10.3. 
Disease Confirmation and Pharmacogenomics 
If the study-prescribed genotype for a patient has not been previously confirmed, a 2-mL blood 
sample will be drawn at Screening for confirmation of diagnosis by electrophoresis, HPLC, and/or 
deoxyribonucleic acid (DNA) sequencing (as needed). An additional 3-mL sample may also be 
collected for possible pharmacogenomic analyses of genes that may affect treatment response 
(including but not limited to alpha globin and BCL11A). DNA sequencing will be performed only 
on samples collected from patients who have consented to genetic analysis. 
10.4. 
Safety Assessments 
Safety will be assessed by the incidence of AEs and SAEs, and evaluation of vital signs, physical 
examination findings, and ECG and clinical laboratory test results. 
10.4.1. 
Adverse Event and Serious Adverse Event Collection 
10.4.1.1. Time Period Adverse Event Collection 
Any AE, including any SAE, that occurs after the patient has signed informed consent but prior to 
assignment of a patient identification number will be recorded on the medical history page of the 
eCRF. AEs that occur following assignment of a patient identification number (randomization), 
including those that may occur prior to administration of study drug, will be recorded on the AE 
page(s) of the eCRF. AEs that occur following administration of study drug will be considered 
TEAEs. Adverse events (related and unrelated), including SAEs, will be recorded from the signing 
of informed consent through the end-of-study safety follow-up visit. 
All SAEs will be recorded and reported to the Sponsor or Sponsor’s designee within 24 hours, as 
indicated in Section 10.4.2.3. The investigator will also submit any updated SAE data to the 
Sponsor within 24 hours of it being available. 

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10.4.1.2. Follow-up 
After the initial AE/SAE report, the investigator is required to proactively follow each patient at 
subsequent visits and phone contacts. All SAEs will be followed until resolution, stabilization, the 
event is otherwise explained, or the patient is lost to follow-up (as defined in Section 9.4). 
10.4.2. 
Adverse Event Recording and Reporting 
10.4.2.1. Definitions 
10.4.2.1.1. Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a clinical study patient administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with this 
treatment. An AE can therefore be any unfavourable 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.  
10.4.2.1.2. Definition of a Serious Adverse Events 
An SAE is any AE that results in 1 or more of the following outcomes: 
• Death 
• Requires or prolongs hospitalization (In general, hospitalization signifies that the 
patient 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 
patient 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, diarrhoea, influenza, or accidental trauma 
[e.g., sprained ankle] that may interfere or prevent everyday life functions, but do not 
constitute a substantial disruption.) 
• Congenital anomaly or birth defect (that occurs in the offspring of a patient exposed 
to the investigational product.) 

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• Other medically important event (In general, this means an AE that, based on 
appropriate medical judgment, is considered to jeopardise the patient’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 10.4.2.3. 
10.4.2.1.3. 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 of severity of which is not consistent with the reference safety information 
(i.e., is unexpected). 
Reporting requirements for SUSARs are described in Section 10.4.2.4. 
10.4.2.2. Evaluation of Adverse Events / Serious Adverse Events 
10.4.2.2.1. Assessment of Severity 
AE severity (intensity) will be graded using the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0. The CTCAE is a descriptive terminology utilised 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 activities of daily living (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. 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 
(see Section 10.4.3.1). 

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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 10.4.2.1.2). 
10.4.2.2.2. Assessment of Causality 
The investigator will assess the potential relatedness of each AE to the investigational product. An 
investigator causality assessment (Unrelated, Unlikely, Possible, Probable, or Definite) 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. 
Not Related/Unrelated: Suggests that there is no causal association between the 
investigational product and the reported event. That is, another cause 
of the event is most plausible; and/or a clinically plausible temporal 
sequence is inconsistent with the onset of the event and the exposure 
to investigational product and/or causal relationship is considered 
biologically implausible. 
Unlikely Related: 
Suggests that the clinical picture is highly consistent with a cause 
other than the investigational product; however, the AE cannot be 
attributed with absolute certainty to another cause and a relationship 
between the investigational product and AE cannot be excluded with 
complete confidence. 
Possibly Related: 
Suggests that treatment with the investigational product may have 
caused or contributed to the AE (i.e., the event follows a reasonable 
temporal sequence from the time of drug administration and/or 
follows a known response pattern to the investigational product), but 
could also have been produced by other factors. 
Probably Related: 
Suggests a likely causal association of the AE with administration of 
the investigational product. This may be based on the known 
pharmacological action of the investigational product, known or 
previously reported adverse reactions to the investigational product 
or class of drugs, reasonable temporal association between 
administration of the investigational product and onset of the AE, or 
judgment based on the investigator’s clinical experience. 

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Definitely Related: 
Suggests that there is strong evidence of a causal relationship 
between exposure to the investigational product and the AE, such as 
other conditions (concurrent illness, concurrent medication reaction, 
or progression/expression of disease state) do not appear to explain 
the AE, the AE corresponds with the known pharmaceutical profile 
of the investigational product, the AE improves upon discontinuation 
of the investigational product and/or re-appears upon re-challenge. 
10.4.2.2.3. 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. 
10.4.2.3. Recording and Reporting Adverse Events and Serious Adverse Events 
All non-serious AEs 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 is initially notified by telephone, the phone call is to be immediately 
followed with by notification on study-specific SAE forms. The investigator must 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. 
SAE Reporting: 
Email:  
 
Fax:   
 
Initial SAE reports must be followed by detailed descriptions. These should include copies of 
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. 
SAEs occurring up to and including the patient’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 patient has been discharged from the study, and he/she considers the 
event to be reasonably related to the study medication 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 time frame detailed above 
PPD
PPD

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• Causality of the SAE(s) 
• Outcome of the SAE(s) 
• Medical records and laboratory/diagnostic information 
10.4.2.4. 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 Ethics Committee of all SAEs that occur at his 
or her site. Investigators will also be notified of all SUSARs that occur during the clinical study. 
Investigators will receive blinded information unless unblinded information is judged necessary 
for safety reasons. 
10.4.2.5. Exposure During Pregnancy 
Pregnancy data will be collected during this study for all patients. 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 patient must be followed until the outcome 
of the pregnancy is known (spontaneous miscarriage, elective termination, normal birth, or 
congenital abnormality) even though the patient will be withdrawn from the study per Section 9.2. 
If a patient within this study or a patient’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. 
10.4.3. 
Other Safety Parameters 
10.4.3.1. Clinical Laboratory Tests 
Samples for haematology, clinical chemistry (including liver function tests and lipid panel), 
coagulation panel, and urinalysis will be collected as outlined in the Schedules of Assessments in 
Table 1 (Population A), Table 2 (Population A1), Table 3 (Population B), and Table 4 
(Population B1). Laboratory tests may be repeated at any visit if there was an abnormal finding at 
the most recent previous evaluation or if additional information is clinically necessary to 
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See Table 8 for a list of parameters to be measured. The approximate total volume of blood to be 
drawn at each visit is shown in Appendix C. 
Table 8: 
Safety Laboratory Parameters to be Measured 
Chemistry: 
Sodium, potassium, calcium, chloride, bicarbonate, magnesium, phosphate, 
glucose, BUN, creatinine, CPK, total protein, ALP, LDH, albumin, bilirubin 
(total; direct; indirect), ALT, AST, and GGT 
Haematology: 
Absolute and differential WBC count, erythrocyte count, reticulocyte count, 
Hb (including HbF), haematocrit, platelet count, and RBC indices (mean 
corpuscular volume, mean corpuscular haemoglobin, and mean corpuscular 
haemoglobin concentration) 
Coagulation: 
Prothrombin time (PT) and activated partial thromboplastin time (aPTT) 
Urinalysis: 
Specific gravity, pH, protein, glucose, bilirubin, urobilinogen, ketones, and 
blood 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; 
AST = aspartate aminotransferase; BUN = blood urea nitrogen; CPK = creatinine phosphokinase; 
GGT = gamma-glutamyl transferase; Hb = haemoglobin; HbF = fetal haemoglobin; LDH = lactate dehydrogenase; 
PT = prothrombin time; RBC = red blood cell; WBC = white blood cell 
10.4.3.2. Vital Signs  
Vital signs should be measured in the sitting or semi-supine position, on the days and time points 
indicated in the Schedules of Assessments in Table 1 (Population A), Table 2 (Population A1) 
Table 3 (Population B), and Table 4 (Population B1). Additional vital sign measurements may be 
taken at the investigator’s discretion to evaluate symptoms or assess possible trends or patterns. 
Vital signs will include systolic and diastolic blood pressure (mmHg), heart rate (beats/minute), 
respiratory rate (breaths/minute), and temperature (°C). Any value outside of the current reference 
ranges will be flagged on the results (e.g., H [high] or L [low]). The investigator will score all 
abnormal assessment results as either clinically significant or not clinically significant based on 
his or her medical judgement. 
Any clinically significant change from baseline in vital signs will be documented as an AE on the 
AE eCRF. Screening/baseline events will be documented in the Medical History eCRF. Clinical 
significance is defined as any variation in vital signs that has medical relevance and may result in 
an alteration in medical care. The investigator will continue to monitor the patient until the finding 
is resolved or, in the judgment of the investigator, follow-up is no longer medically necessary. 
10.4.3.3. Electrocardiograms 
A standard 12-lead ECG will be performed in triplicate predose and postdose on the days and time 
points indicated in the Schedules of Assessments in Table 1 (Population A), Table 2 
(Population A1), Table 3 (Population B), and Table 4 (Population B1). Consecutive replicate 
ECGs will be obtained at approximately 1-minute intervals. ECGs may be obtained at additional 
times, if deemed clinically necessary. Collection of more replicates than expected at a particular 
time point is allowed if needed to ensure high-quality records.  

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ECGs will be interpreted by a qualified physician (the investigator or qualified designee) at the 
site as soon after the time of ECG collection as possible to evaluate the need for immediate patient 
management, should any clinically relevant findings be identified. 
After enrolment, if a clinically significant increase in the QT/QTc interval from baseline or another 
clinically significant quantitative or qualitative change from baseline is identified, the patient will 
be assessed by the investigator for symptoms (for example, palpitations, near syncope, syncope). 
The investigator or qualified designee is responsible for determining whether any change in patient 
management is needed and must document his/her review of the ECG printed at the time of 
evaluation from at least 1 of the replicate ECGs at each time point. The investigator will continue 
to monitor the patient until the finding is resolved or, in the judgment of the investigator, follow-up 
is no longer medically necessary. 
10.4.3.4. Physical Examinations 
A complete physical examination will be performed at the Screening and Day 1 visits as outlined 
in the Schedules of Assessments in Table 1 (Population A), Table 2 (Population A1), Table 3 
(Population B), and Table 4 (Population B1). These examinations will include height and weight 
plus the following assessments: general appearance; skin; head, ear, eye, nose, and throat; neck; 
lymph node; chest; heart; abdominal cavity; limb; CNS; and musculoskeletal. Clinically 
significant findings prior to Day 1 will be recorded on the Medical History eCRF. 
Subsequent physical examinations as indicated in the schedule of assessments will be 
symptom-based, and only changes from baseline will be recorded. Any clinically significant 
change from baseline will be documented as an AE on the AE eCRF. Clinical significance is 
defined as any variation in physical findings that has medical relevance and may result in an 
alteration in medical care. The investigator will continue to monitor the patient until the finding is 
resolved or, in the judgment of the investigator, follow-up is no longer medically necessary. 
11. 
STATISTICS 
11.1. 
General Considerations 
Data analysis will be performed for each population (A, A1, B, and B1) separately. Descriptive 
summary statistics will be provided for demographics, disposition, and IMR-687 exposure (and 
HU exposure for patients in Populations B and B1). The number and percentage of patients who 
discontinue from the study, along with reasons for discontinuations, will be tabulated and listed. 
Continuous data will be summarised using descriptive statistics (number of patients, mean, 
standard deviation [SD], median, minimum, maximum) and, where appropriate, coefficient of 
variation (%CV) and graphic representation. Categorical data will be summarised by sample size, 
number of events, and proportions. Data will be summarised by population (A and B) and dose 
cohort at each time point as appropriate. Graphs of actual values and changes over time may also 
be created as appropriate. 
Details of the statistical analyses/summaries described below will be provided in a statistical 
analysis plan prior to the database lock and study unblinding. 

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11.2. 
Analysis Datasets: 
Safety Analysis Set: is defined as all patients who have received any amount of study drug and 
from whom informed consent has been obtained, and will be used to summarise all safety and 
tolerability data. The Safety Analysis Set will be used for listings of all data, including safety, 
tolerability, and PK/PD concentrations and parameters. 
PK Concentration Set: is a subset of the safety analysis set and includes all patients who are 
enrolled in the study, have received one dose of IMR-687, and have any measurable IMR-687 
concentration-time data, without protocol deviations or events expected to affect PK. 
Pharmacokinetic IMR-687 (and HU for patients in Populations B and B1) concentration profiles 
will be summarised based on the PK concentration set. 
PK Evaluable Set: is a subset of the PK concentration set and includes all patients who have 
provided sufficient concentration data without protocol deviations or events that would be 
expected to affect the PK analysis. PK parameter data will be summarised based on the PK 
Evaluable Set. 
PD Evaluable Set: is a subset of the safety analysis set and includes all patients who have provided 
samples for PD analysis sufficient to obtain at least one valid PD observation, without protocol 
deviations or events that would be expected to affect the PD analysis. PD observation and 
parameter data will be summarised based on the PD Evaluable Set. 
11.3. 
Safety Analyses 
Descriptive statistics will be computed for safety parameters, as appropriate. The number and 
percentage of patients who discontinue from the study because of AEs will be tabulated; severity 
and frequency of AEs and SAEs will also be summarised. Absolute and, where appropriate, change 
from baseline in clinical laboratory values, vital signs, and ECG results will also be summarised. 
All safety data will be provided in listings. 
Further statistical evaluations will be applied for select endpoints, if warranted. 
11.4. 
Pharmacokinetic Analyses 
PK analysis parameters will be estimated using non-compartmental analysis methods. Patients will 
be analysed by actual dose received. 
Graphs of individual and mean IMR-687 (and HU for patients in Populations B and B1) plasma 
concentration over time will be generated by population and dose cohort as appropriate. The 
following PK parameters will be determined, as appropriate: Cmax, tmax, t½, AUC0-12, AUC0-24, 
AUClast, and AUC0-inf. Other PK parameters may be determined as appropriate. All AUC parameters 
will be calculated by the linear up/log down method. PK parameters will be summarised 
descriptively using the number of non-missing values (n), mean, median, SD, minimum, maximum, 
%CV, geometric mean, and geometric %CV. Dose proportionality will be assessed. 
To assess the potential drug interaction for HU with IMR-687 (test) and HU without IMR-687 
(reference) in Populations B and B1, log-transformed HU PK parameters (Cmax, AUC) will be 
analysed using analysis of variance (ANOVA), including terms for visit as a fixed effect and patient 

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as a random effect. Based on this analysis, point estimates and two-sided 90% confidence intervals 
(CI) for the ratios “IMR-687+HU/HU” will be calculated by back-transformation of the logarithmic 
data. Within-subject variability will be estimated.   
11.5. 
Analyses of Exploratory Endpoints 
Exploratory PD and clinical outcomes data for each time point will be listed by patient and 
summarised by population and dose cohort as appropriate. Correlations between PK and the 
exploratory endpoints may be assessed. Descriptive statistics will be computed as appropriate. 
11.6. 
Interim Analysis 
Two interim analyses are planned to review pooled data for specific biomarkers. The first analysis 
will be performed once at least 18 patients in Population A have at least 1 month of available data 
for sE-sel, sP-sel, and sICAM-1; the second analysis will be performed once at least 18 patients in 
Population A have at least 3 months of available data for HbF (%HbF and %F cells), sE-sel, and 
sP-sel. An additional planned interim analysis may be performed when approximately 12 patients 
have been dosed with 200 mg for 13 weeks. 
To maintain the study blind, summary tables will be prepared by a separate unblinded 
statistician/programmer who is not affiliated with the study team responsible for the ongoing 
conduct of the study. In addition, no unblinded data will be presented for individual patients. All 
data will be pooled by randomized assignment for each of the biomarkers. Additional details may 
be provided in a statistical analysis plan.  
Based on business reasons, the sponsor may decide to conduct the second and subsequent interim 
analyses as unblinded at the patient level. In this situation, a dedicated team at the sponsor will be 
unblinded and all personnel directly involved in the conduct of the study at both the sponsor and 
the vendors, including the CRO, will remain blinded to treatment allocation. All site personnel and 
patients will also remain blinded to treatment allocation. Details to define the process for 
unblinding and to ensure that no study related personnel will be unblinded to treatment allocation 
will be captured in a separate study-specific plan. 
11.7. 
Determination of Sample Size 
The sample sizes for Populations A, A1, B, and B1 were not based on formal statistical 
considerations. However, the number of subjects involved in this placebo-controlled study is 
considered sufficient to achieve the principal objectives of this exploratory study.  
Based on available data, it is expected that 12 to 24 patients treated at each dose of IMR-687 (50, 
100, and 200 mg) for at least 12 weeks compared with 12 placebo patients would be sufficient to 
assess the safety, tolerability, and PK of IMR-687 in Populations A and A1. In addition, based on 
the study design in Populations B and B1 (i.e., determination of a separate baseline HU PK profile 
prior to administration of IMP), it is expected that 12 active and 6 placebo subjects would be 
sufficient to assess the potential for a drug-drug interaction (e.g., a change in safety, HbF or other 
PD biomarkers, or HU [PK] exposure compared to HU administered alone) when HU and 
IMR-687 are administered concomitantly for at least 24 weeks. 

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11.8. 
Computer Systems 
Statistical analyses will be performed using SAS, and PK analyses will be performed using 
WinNonlin. 
12. 
DATA MANAGEMENT 
12.1. 
Data Collection Tools and Source Document Identification 
12.1.1. 
Source Data 
Source data are defined as “All information in original records and certified copies of original 
records or clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data are contained in source documents (original 
records or certified copies).” 
12.1.2. 
Source Documents 
Source documents are defined as “Original documents, data and records (e.g., hospital records, 
clinical and office charts, laboratory notes, memoranda, patients’ diaries of 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, patient files, and records kept at the pharmacy, at the 
laboratories, and at medico-technical departments involved in the clinical trial).” 
The investigator must maintain accurate documentation (source data) that supports the information 
entered in the CRF. 
12.1.3. 
Case Report Forms 
All patient data relating to the study will be recorded on an eCRF unless transmitted to the sponsor 
or designee electronically (e.g., laboratory data). Data entered in the eCRF that are transcribed 
from source documents must be consistent with the source documents or the discrepancies must 
be explained. The investigator is responsible for verifying that data entries are accurate and correct 
by signing the CRF. 
12.2. 
Audits and Inspections 
The investigator must permit audits, Research Ethics Committee (REC) / Institutional Review 
Board (IRB) review, and regulatory agency inspections and provide direct access to source data 
documents. 
The purpose of an audit or inspection by the Sponsor is to systematically and independently 
examine all study-related activities and documents to determine whether these activities were 
conducted, and data were recorded, analysed, and accurately reported according to the protocol, 
Good Clinical Practice (GCP) guidelines of the International Council on Harmonisation (ICH), 
and any applicable regulatory requirements.  

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The investigator should contact the Sponsor immediately if contacted by a regulatory agency about 
an inspection. 
12.3. 
Archiving 
Records and documents, including signed informed consent forms (ICFs), pertaining to the 
conduct of this study must be retained by the investigator for a period of 2 years after the last 
marketing application approval, or, if not approved, 2 years following the discontinuance of the 
test article for investigation unless local regulations or institutional policies require a longer 
retention period. No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or party without written 
notification to the sponsor. 
12.4. 
Data Monitoring 
The sponsor or designee is responsible for the data management of this study, including quality 
checking of the data. The investigator must permit study-related monitoring and provide direct 
access to source data documents. Study monitors will perform ongoing source data verification to 
confirm that data entered into the CRF by authorised site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of patients are being protected; and 
that the study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. The monitor will be 
available between site visits if the investigator(s) or other staff needs information or advice. 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1. 
Compliance 
This study will be conducted in accordance with the protocol. Prospective, planned deviations or 
waivers to the protocol are not permitted, and patients who do not meet all eligibility criteria may 
not be enrolled. In the event of accidental protocol deviations, the deviation(s) must be documented 
and reported to the principal investigator and the Sponsor. 
This study will also be conducted in accordance with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organisations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
• Applicable ICH GCP Guidelines 
• Applicable laws and regulations, including the Medicines for Human Use (Clinical Trials) 
Regulations 2004 and any relevant amendments 
The protocol, protocol amendments, informed consent form, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an REC/IRB by the investigator 
and reviewed and approved by the REC/IRB; the investigator must submit written approval to the 

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Sponsor before he or she can enrol any patient into the study. In addition, no patients will be 
enrolled in the UK until Clinical Trial Authorisation is obtained from the MHRA. 
Substantial amendments to the protocol will require REC/IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate hazard 
to study patients.  
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the REC/IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
local health authorities and the REC/IRB, including (if applicable) a final report within 
1 year of the end of the study 
• Notifying the REC/IRB of SAEs or other significant safety findings as required by 
REC/IRB procedures 
• Notifying the REC/IRB of the end of the studyz 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of US Code of Federal Regulations Title 21, ICH guidelines, the REC/IRB, European 
regulation 536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
13.2. 
Serious Breaches to GCP or the Protocol 
A “serious breach” is a breach which is likely to effect to a significant degree either the safety or 
physical or mental integrity of the patients of the trial; or the scientific value of the trial. 
The site will immediately notify the sponsor of any case where the above definition applies during 
the conduct of the study. The sponsor will notify the licensing authority in writing of any serious 
breach of the conditions and principles of GCP in connection with this trial; or the protocol. 
13.3. 
Written Informed Consent 
The investigator or qualified designee will ensure that the patient is given full and adequate oral 
and written information about the nature, purpose, possible risk, and benefit of the study. Patients 
must be informed that their participation is voluntary and that they are free to discontinue from the 
study at any time. The patient should be given the opportunity to ask questions and allowed time 
to consider the information provided. 
The patient’s signed and dated informed consent must be obtained before conducting any study 
procedures. The medical record must include a statement that written informed consent was 
obtained before the patient was enrolled in the study and the date the written consent was obtained. 
The authorised person obtaining the informed consent must also sign the ICF. 
The site must maintain the original, signed ICF. A copy of the signed and dated ICF must be given 
to the patient. 

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13.4. 
Data Protection and Patient Confidentiality 
All investigators and trial site staff must comply with all applicable local laws and regulations 
regarding the collection, storage, processing and disclosure of personal information.  
Patients will be assigned a unique identifier by the sponsor. Any patient records or datasets that 
are transferred to the sponsor will contain the identifier only; patient names or any information 
which would make the patient identifiable will not be transferred.  
The patient must be informed that his/her personal study-related data will be used by the sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to the 
patient.  
The patient must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorised personnel appointed by the sponsor, by appropriate 
REC/IRB members, and by inspectors from regulatory authorities. 
13.5. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. 

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14. 
LIST OF REFERENCES 
Akinsheye I, Alsultan A, Solovieff N, Ngo D, Baldwin CT, Sebastiani P, et al. Fetal haemoglobin 
in sickle cell anaemia. Blood. 2011 Jul 7;118(1):19-27. doi: 10.1182/blood-2011-03-325258. Epub 
2011 Apr 13. Review. PMID: 21490337. 
Almeida CB, Scheiermann C, Jang JE, Prophete C, Costa FF, Conran N, Frenette PS. Hydroxyurea 
and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle 
cell disease in mice. Blood. 2012 Oct 4;120(14): 2879-2888. Doi: 10.1182/blood-2012-02-409524. 
Epub 2012 Jul 25. 
Alsultan A, Ngo D, Bae H, Sebastiani P, Baldwin CT, Melista E, et al. Genetic studies of foetal 
haemoglobin in the Arab-Indian haplotype sickle cell-β(0) thalassemia. Am J Hematol. 
2013 Jun;88(6):531-2. doi: 10.1002/ajh.23434. Epub 2013 May 2. 
Barbosa CG, Aleluia AC, Pacheco AP, Paz SS, Zanette AM, Lyra IM, et al. Genetic modulation 
of HbF in Brazilians with HbSC disease and sickle cell anaemia. Am J Hematol. 
2013 Oct;88(10):923-4. doi: 10.1002/ajh.23538. Epub 2013 Sep 3. PMID: 2382843. 
Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, et al. Effect of HU on the frequency of 
painful crises in sickle cell anaemia. Investigators of the Multicenter Study of Hydroxyurea in 
Sickle Cell Anemia. N Engl J Med. 1995;332(20):1317-22. 
Cokic VP, Smith RD, Beleslin-Cokic BB, Njoroge JM, Miller JL, Gladwin MT, et al. Hydroxyurea 
induces foetal haemoglobin by the nitric oxide-dependent activation of soluble guanylyl cyclase. 
J Clin Invest. 2003;111(2):231-9. 
Erard F, Dean A, Schechter AN. Inhibitors of cell division reversibly modify haemoglobin 
concentration in human erythroleukemia K562 cells. Blood. 1981 Dec;58(6):1236-9. 
Heeney MM, Ware RE. Hydroxyurea for children with sickle cell disease. Pediatr Clin North Am. 
2008 Apr;55(2):483-501, x. doi: 10.1016/j.pcl.2008.02.003. Review. PMID: 18381097 
Hutson PH, Finger EN, Magliaro BC, Smith SM, Converso A, Sanderson PE, et al. The selective 
phosphodiesterase 9 (PDE9) inhibitor PF-04447943 (6-[(3S,4S)-4-methyl-1- (pyrimidin-
2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-
4Hpyrazolo[3,4 d]pyrimidin-4-one) enhances synaptic plasticity and cognitive function in rodents. 
Neuropharmacology. 2011 Sep;61(4):665-76. doi: 10.1016/j.neuropharm.2011.05.009. Epub 2011 
May 19. 
Lanzkron S, Carroll CP, Haywood C Jr. Mortality rates and age at death from sickle cell disease: 
U.S., 1979-2005. Public Health Rep. 2013 Mar-Apr;128(2):110-6. PMID: 23450875. 
Paulukonis ST, Eckman JR, Snyder AB, Hagar W, Feuchtbaum LB, Zhou M, Grant AM, Hulihan 
MM. Defining sickle cell disease mortality using a population-based surveillance system, 2004 
through 2008. Public Health Rep. 2016 Mar-Apr;131(2):367-375. PMID: 26957672. 
Piel FB, Patil AP, Howes RE, Nyangiri OA, Gething PW, Dewi M, Temperley WH, Williams TN, 
Weatherall DJ, Hay SI. Global epidemiology of sickle haemoglobin in neonates: a contemporary 
geostatistical model-based map and population estimates. Lancet. 2013 Jan 12;381(9861):142-
151. doi: 10.1016/S0140-6736(12)61229-X. Epub: 2012 Oct 25. 

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Platt OS, Orkin SH, Dover G, Beardsley GP, Miller B, Nathan DG. Hydroxyurea enhances foetal 
haemoglobin production in sickle cell anaemia. J Clin Invest. 1984 Aug;74(2):652-6. 
Platt OS, Thorington BD, Brambilla DJ, Milner PF, Rosse WF, Vichinsky E, et al. Pain in sickle 
cell 
disease 
— 
rates 
and 
risk 
factors. 
N 
Engl 
J 
Med. 
1991;325:11-16. 
DOI: 10.1056/NEJM199107043250103. 
Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, et al. Mortality in sickle 
cell disease. Life expectancy and risk factors for early death. N Engl J Med. 
1994;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. doi: 10.1002/ajh.23457. Epub 2013 May 30. 
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. doi: 10.1016/j.neuropharm.2008.07.005. Epub 2008 Jul 12. 
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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15. 
APPENDICES 
Appendix A: Sample List of Prohibited CYP3A-Sensitive Substrates 
Note: This list is not intended to be exhaustive. If there is any question as to whether 
or not a substance is permitted, please review the product labelling (if applicable) 
and consult the Sponsor. 
Appendix B: Sample List of Prohibited P-gp Substrates and Inhibitors 
Note: This list is not intended to be exhaustive. If there is any question as to whether 
or not a substance is permitted, please review the product labelling (if applicable) 
and consult the Sponsor. 
Appendix C: Approximate Volume of Blood to be Drawn at Each Study Visit 

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Appendix A: Sample List of Prohibited CYP3A Sensitive Substrates 
Drug (oral) 
Therapeutic Class 
Max AUC ratio 
Inhibitor 
Inhibitor Dose (oral) 
Accession or NDA # 
Published 
ABT-384 
Diabetes Treatments 
17.8 
ketoconazole 
400 mg QD (10 days) 
23431112 
2013 May 
alfentanil 
Opioids 
36.5 
indinavir/ ritonavir1 
800 mg/100 mg BID (1 day) 
19225389 
2009 Mar 
alisporivir 
Antivirals 
7.9 
ketoconazole 
400 mg QD (23 days) 
25008118 
2014 Oct 15 
almorexant 
Hypnotics - Sedatives 
10.7 
ketoconazole 
400 mg QD 14 days 
24604243 
2014 May 
alpha-dihydroergocryptine 
Dopaminergic Agonists 
13.3 
erythromycin 
500 mg TID (4 days) 
11503008 
2001 Aug 
aplaviroc 
CCR5 Receptor Antagonists 
7.7 
lopinavir/ ritonavir1 
400/100 mg BID (21 days) 
16934050 
2006 Sep 
aprepitant 
Neurokinin-1 Receptor Antagonists 
5.0 
ketoconazole 
400 mg QD (5-10 days) 
Emend® Prescribing Info 
2007 Nov 
atazanavir 
Protease Inhibitors 
25.9 
ritonavir1 
100 mg QD (2 days) 
22288567 
2012 Aug 
atorvastatin 
Statins a 
9.4 
tipranavir/ ritonavir1 
500 mg/200 mg BID (8 days) 
19667285 
2009 Oct 
avanafil 
Erectile Dysfunction Treatments 
12.8 
ketoconazole 
400 mg QD (5 days) 
NDA # 202276 
2012 
BIRL 355 
NNRTIs 
30.6 
ritonavir1 
100 mg x 2 
18824608 
2008 Dec 
bosutinib 
Kinase Inhibitors 
8.1 
ketoconazole 
400 mg QD (4.5 days) 
21148045 
2011 Dec 
brecanavir 
Protease Inhibitors 
19.1 
ritonavir1 
100 mg single dose 
16723584 
2006 Jun 
brotizolam 
Benzodiazepines 
5.1 
itraconazole 
200 mg QD (4 days) 
15521894 
2004 Nov 
budesonide 
Corticosteroids 
6.8 
ketoconazole 
200 mg QD (4 days) 
10945311 
2000 Jul 
buspirone | CYP3A in vivo Probe 
Anxiolytics 
19.2 
itraconazole 
100 mg BID (4 days) 
9333111 
1997 Sep 
capravirine 
Antivirals 
9.3 
ritonavir1 
100 mg QD (14 days) 
15205383 
2004 Jul 
casopitant 
Neurokinin-1 Receptor Antagonists 
12.1 
ketoconazole 
400 mg QD (7 days) 
20124517 
2010 Aug 
cobimetinib 
Kinase Inhibitors 
6.6 
itraconazole 
200 mg QD (14 days) 
NDA # 206192 
2015 
conivaptan 
Vasopressin Antagonists 
10.8 
ketoconazole 
200 mg BID (3 days) 
NDA # 021697 
2005 
danoprevir 
Antivirals 
6.0 
ritonavir1 
100 mg BID (10 days) 
22624502 
2012 Jul 
darifenacin 
Anticholinergics 
5.3-11.6 
ketoconazole 
400 mg QD (8 days) 
Enablex® Prescribing Info 
2004 Dec 
darunavir 
Protease Inhibitors 
10.7 
ritonavir1 
100 mg BID (9 days) 
19131522 
2009 Apr 
dasatinib 
Kinase Inhibitors 
5.0 
ketoconazole 
200 mg BID (6 days) 
NDA # 021986 
2006 
dronedarone 
Antiarrhythmics 
24.8 
ketoconazole 
200 mg QD (8 days) 
NDA # 022425 
2009 
ebastine 
H1 Receptor Antagonists 
42.5 
ketoconazole 
400 mg QD (8 days) 
15752381 
2005 Mar 
eletriptan | CYP3A in vivo Probe 
Triptans 
5.9 
ketoconazole 
not available 
Relpax® Prescribing Info 
2004 May 
eliglustat (in subjects CYP2D6 PMs) 
Glucosylceramide Synthase Inhibitors 
6.2 (in CYP2D6 PMs) ketoconazole 
400 mg QD - PBPK Modeling 
NDA # 205494 
2014 
elvitegravir 
HIV-Integrase Strand Transfer Inhibitors 
19.9 
ritonavir1 
100 mg BID (10 days) 
NDA # 203100 
2012 
eplerenone 
Diuretics 
5.4 
ketoconazole 
200 mg BID (6 days) 
15204695 
2004 Mar 
everolimus 
Immunosuppressants 
14.7 
ketoconazole 
200 mg BID (8 days) 
15831774 
2005 May 
felodipine | CYP3A in vivo Probe 
Calcium Channel Blockers 
6.3 
itraconazole 
200 mg QD (4 days) 
9129558 
1997 Apr 
ibrutinib 
Kinase Inhibitors 
23.9 
ketoconazole 
400 mg QD (6 days) 
NDA # 205552 
2013 
indinavir 
Protease Inhibitors 
5.5 
ritonavir1 
400 mg BID (15 days) 
9797204 
1998 Nov 
isavuconazole 
Antifungals 
5.2 
ketoconazole 
200 mg BID (24 days) 
NDA # 207500 
2015 
ivacaftor 
Miscellaneous Agents 
8.5 
ketoconazole 
400 mg QD (10 days) 
NDA # 203188 
2012 
L-771,688 
Alpha/Beta Adrenergic Antagonists 
60 
ketoconazole 
400 mg QD (10 days) 
15901753 
2005 Jun 
levomethadyl (LAAM) 
Drug Addiction Treatments 
5.5 
ketoconazole 
400 mg single dose 
15289792 
2004 Aug 

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lomitapide 
Other Antilipemics 
27.3 
ketoconazole 
200 mg BID (9 days) 
NDA # 203858 
2012 
lopinavir 
Protease Inhibitors 
up to 30 
ritonavir1 
RIT adm. as booster 
Kaletra® Prescribing Info 
2004 Oct 
Drug (oral) 
Therapeutic Class 
Max AUC ratio 
Inhibitor 
Inhibitor Dose (oral) 
Accession or NDA # 
Published 
lovastatin | CYP3A in vivo Probe 
Statins a 
36.4 
itraconazole 
200 mg QD (4 days) 
8689812 
1996 Jul 
lumefantrine 
Antimalarials 
5.7 
lopinavir/ ritonavir1 
400/100 mg BID (> 1 month) 
22316571 
2012 May 
lurasidone 
Antipsychotics 
9.3 
ketoconazole 
400 mg QD (7 days) 
NDA # 200603 
2010 
maraviroc 
CCR5 Receptor Antagonists 
10 
saquinavir / ritonavir1 
400/100 mg BID (7 days) 
18333864 
2008 April 
midazolam | CYP3A in vivo Probe 
Benzodiazepines 
26.4 
ritonavir1 
100 mg x 3 
20002087 
2009 Dec 
midostaurin 
Kinase Inhibitors 
10.4 
ketoconazole 
400 mg QD (10 days) 
24085261 
2013 Dec 
naloxegol 
Gastrointestinal Agents 
12.4 
ketoconazole 
400 mg QD (5 days) 
204760 
2014 
neratinib 
Kinase Inhibitors 
5.2 
ketoconazole 
400 mg QD (4.5 days) 
21395644 
2011 Apr 
nisoldipine 
Calcium Channel Blockers 
25.3 
ketoconazole 
200 mg QD (5 days) 
10206086 
1999 Mar 
paritaprevir4 
Antivirals 
6.1 
lopinavir/ ritonavir1 
400/100 mg BID (14 days) 
NDA # 206619 
2014 
perospirone 
Antipsychotics 
6.8 
itraconazole 
200 mg QD (5 days) 
16418697 
2006 Feb 
quetiapine 
Antipsychotics 
6.2 
ketoconazole 
200 mg QD (4 days) 
16390352 
2006 Jan 
ridaforolimus 
Kinase Inhibitors 
8.5 
ketoconazole 
400 mg QD (14 days) 
22290273 
2012 May 
saquinavir 
Protease Inhibitors 
236.6 
ritonavir1 
100 mg single dose 
23381882 
2013 Jun 
sildenafil | CYP3A in vivo Probe 
Erectile Dysfunction Treatments 
9.9 
ritonavir1 
300-500 mg BID (7 days) 
10930961 
2000 Aug 
simeprevir 
Protease Inhibitors 
6.5 
erythromycin 
500 mg TID (7 days) 
NDA # 205123 
2013 
simvastatin | CYP3A in vivo Probe 
Statins a 
16.1 
grapefruit juice DS 
200 mL TID (2 days) 
9834039 
1998 Nov 
sirolimus 
Immunosuppressants 
10.9 
ketoconazole 
200 mg QD (10 days) 
Rapamune® Prescribing Info 
tacrolimus 
Immunosuppressants 
78.0 
telaprevir2 
750 mg TID (13 days) 
21618566 
2011 Jul 
terfenadine 
H1 Receptor Antagonists 
5.6 
nefazodone 
200-300 mg BID (8 days) 
11240972 
2001 Mar 
ticagrelor 
Anticoagulants and Antiplatelets 
7.3 
ketoconazole 
200 mg BID (10 days) 
NDA # 022433 
2011 
tilidine3 
Treatments of Pain and Inflammation 
20.3 
voriconazole 
400 mg single dose 
19916995 
2009 Nov 
tipranavir 
Protease Inhibitors 
13.4 
ritonavir1 
200 mg BID (21 days) 
15682350 
2004 Nov-Dec 
tolvaptan 
Vasopressin Antagonists 
5.4 
ketoconazole 
200 mg QD (3 days) 
NDA # 022275 
2009 
triazolam | CYP3A in vivo Probe 
Benzodiazepines 
40.7 
ritonavir1 
200 mg BID (1 day) 
16513448 
2006 Mar 
ulipristal 
Hormones 
5.9 
ketoconazole 
400 mg QD (7 days) 
Ella® Prescribing Info 
2014 Jul 
vardenafil 
Erectile Dysfunction Treatments 
49.1 
ritonavir1 
300-600 mg BID (8 days) 
NDA # 021400 
2003 
vicriviroc 
CCR5 Receptor Antagonists 
5.4 
ritonavir1 
100 mg QD (14 days) 
21348539 
2011 Apr 
voclosporin 
Immunosuppressants 
18.1 
ketoconazole 
400 mg QD (10 days) 
24330024 
2014 Jun 
Notes:  
• The present list includes CYP3A substrates with AUC ratios of at least 5 fold. 
• Some known substrates of the enzyme may not be listed because they do not have changes in exposure reaching that level, or may not have DDI studies with AUC/CL changes available. 
• Example of substrate with no changes in AUC available: fluticasone—multiple case reports of Cushing’s Syndrome with ritonavir 
• CYP3A Inhibition may not be the sole mechanism for the observed interactions. Many substrates of CYP3A are also substrates of P-glycoprotein (P-gp) 
1 Ritonavir also inhibits multiple transporters, including P-gp 
2 Telaprevir also inhibits multiple transporters, including P-gp 
3 Tilidine is a substrate of CYP3A and CYP2C19 and inhibition of both enzymes by voriconazole may contribute to the change in AUC 
4 Paritaprevir is also a substrate of multiple transporters, including P-gp DS= double strength 
a Statins, particularly atorvastatin, may be administered concomitantly at the discretion of the Investigator, because any decrease in their exposure is not likely to pose significant risk over the short term course of this study 

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Appendix B: Sample List of Prohibited P-gp Substrates and Inhibitors 
Inhibitora 
Therapeutic Class 
Inhibitor Dose (oral) 
Substrateb 
Max AUC ratio 
Accession or NDA # 
Published 
alogliptin 
Dipeptidyl Peptidase-4 Inhibitors 
100 mg QD (7 days) 
fexofenadine 
1.26 
NDA # 022271 
2013 
amiodarone 
Antiarrhythmics 
400 mg/day (5 days)  
digoxin (IV)  
-26.5% (CL)  
3964797  
1985 Jan  
800 mg/day (7 days) 
digoxin 
1.68 
2487521 
1989 Mar 
AZD5672 
CCR5 Receptor Antagonists 
150 mg QD (13 days) 
digoxin 
1.33 
21075975 
2011 Feb 
azithromycin 
Antibiotics 
250 mg QD (5 days) 
fexofenadine 
1.72 
11318079 
2001 Mar 
canagliflozin 
Sodium-dependent Glucose Cotransporter 2 Inhibitors 
300 mg QD (7 days) 
digoxin 
1.20 
NDA # 204042 
2013 
captopril 
ACE Inhibitors 
12.5 mg TID (7 days) 
digoxin 
1.39 
11471775 
2001 Jul 
carvedilol 
α/β Adrenergic Antagonists 
6.25 mg BID (7 days) 
digoxin 
1.57 
16767433 
2006 Jul 
clarithromycin 
Antibiotics 
500 mg BID (7 days)  
digoxin  
1.68  
18214850  
2008 Jul 
500 mg BID (4 days) 
dabigatranc 
1.49 
23210726 
2013 Jul 
clopidogrel 
Anticoagulants and Antiplatelets 
300 mg single dose 
dabigatran 
1.35 
22782539 
2013 Mar 
conivaptan 
Diuretics 
40 mg BID (10 days) 
digoxin 
1.43 
NDA # 021697 
2005 
cremophor EL 
Transporter Modulators 
1440 mg SD 
fexofenadine 
1.28 
25882073 
2015 Jun 
cremophor RH40 
Transporter Modulators 
600 mg TID (9 days) 
digoxin 
1.21 
12732840 
2003 May 
curcumin 
Food Products 
1000 mg QD (14 days) 
talinolol 
1.54 
22725663 
2012 Dec 
diltiazem 
Calcium Channel Blockers 
60 mg TID (10 days) 
digoxin 
1.44 
12070557 
2002 Jun 
dronedarone 
Antiarrhythmics 
400 mg BID (10 days) 
digoxin 
2.33 
NDA # 022425 
2009 
eliglustat 
Glucosylceramide Synthase Inhibitors 
100 mg (PMs) and 150 mg (others) (7 days) 
digoxin 
1.49 
NDA # 205494 
2014 
erythromycin 
Antibiotics 
500 mg TID (7days) 
fexofenadine 
2.09 
NDA # 021963 
1996 
2 g single dose 
talinolol 
1.52 
10783825 
2000 Apr 
felodipine 
Calcium Channel Blockers 
2.5 mg single dose 
digoxin 
1.49 
3443063 
1987 
fostamatinib 
Anti-inflammatory Drugs 
0.25 mg QD (15 days) 
digoxin 
1.37 
26514315 
2015 Dec 
fluvoxamine 
Selective Serotonin Reuptake Inhibitors 
50 mg QD (7 days) 
fexofenadine 
1.78 
22367658 
2012 Apr 
ginkgo 
Herbal Medications 
120 mg TID (14 days) 
talinolol 
1.25 
19280523 
2009 Mar 
indinavir 
Protease Inhibitors 
80 mg TID (21 days) 
fexofenadine 
3.31 
22273859 
2012 Feb 
indinavir/ritonavir 
Protease Inhibitors 
800 mg/100 mg BID (1 day) 
fexofenadine 
4.84 
19225389 
2009 Mar 
itraconazole 
Antifungals 
200 mg QD (5 days) 
digoxin 
1.68 
9421099 
1997 Dec 
100 mg BID (5 days) 
fexofenadine 
3.01 
16084853 
2006 May 
isavuconazole 
Antifungals 
Not Provided 
digoxin (not provided) 
1.25 
NDA # 207500 
2015 
ivacaftor 
Other 
150 mg (9 days) 
digoxin 
1.32 
25103957 
2015 Jan 
ketoconazole 
Antifungals 
400 mg QD (7 days) 
fexofenadine 
2.74 
Allegra® Product Label 
1996 
lapatinib 
Kinase Inhibitors 
1500 mg QD (8 days) 
digoxin 
1.63 
Embase # 20160047065 
2015 Nov 
Not Provided 
digoxin (IV) 
2.80 
Tykerb® Product Label 
2007 
lopinavir/ritonavir 
Protease Inhibitors 
400 mg/100 mg BID (14 days)  
digoxin  
1.81  
18183034  
2008 Jul 
400 mg/100 mg single dose 
fexofenadine 
4.14 
16809801 
2006 July 
mibefradil 
Calcium Channel Blockers 
150 mg QD (7 days) 
digoxin 
1.31 
7669484 
1995 May 
milk thistle 
Herbal Medications 
140 mg TID (14 days) 
talinolol 
1.30 
19555315 
2009 Sep 
mirabegron 
Beta3-Adrenoreceptor Agonist 
100 mg QD (14 days) 
digoxin 
1.16 
NDA # 202611 
2012 
nelfinavir 
Protease Inhibitors 
1250 mg BID (14 days) 
digoxin 
1.35 
22190694 
2012 Mar 
nifedipine 
Calcium Channel Blockers 
10 mg TID (7 days) 
digoxin 
1.23 
3943268 
1986 Jan 
nitrendipine 
Calcium Channel Blockers 
20 mg QD (7 days) 
digoxin 
1.16 
3816917 
1986 
paritaprevir/ritonavir/ombitasvir Antivirals 
150/100/25 mg QD (19 days) 
digoxin 
1.35 
26459906 
2015 Jan 

IMR-SCD-102 
 
 
Protocol Amendment US version 008 dated 28 June 2019 
Protocol Amendment UK version 011 dated 28 June 2019 
 
 
 
Proprietary and Confidential                                                         Page 77 of 78 
paroxetine 
Selective Serotonin Reuptake Inhibitors 
20 mg QD (7 days) 
fexofenadine 
1.38 
22367658 
2012 Apr 
Inhibitora 
Therapeutic Class 
Inhibitor Dose (oral) 
Substrateb 
Max AUC ratio 
Accession or NDA # 
Published 
propafenone 
Antiarrhythmics 
300 mg TID (3 days)  
digoxin (IV)  
1.29  
2708548  
1989 Jan  
600 mg QD (7 days) 
digoxin 
-31% (CL) 
2911842 
1989 
250-500 mg/kg QD (7 days) 
digoxin 
-67% (CL)d 
2299507 
1990 Feb 
quercetin 
Food Product 
500 mg TID (7days) 
fexofenadine 
1.56 
19221726 
2009 Jun 
quinidine 
Antiarrhythmics 
200 mg QID (6 days) 
digoxin (IV) 
-64% (CL) 
7309901 
1981 Oct 
600 mg BID (8 days) 
digoxin 
2.66 
3997300 
1985 Mar 
25 mg single dose 
fexofenadine 
2.14 
24722393 
2014 Sep 

IMR-SCD-102 
 
 
Protocol Amendment US version 008 dated 28 June 2019 
Protocol Amendment UK version 011 dated 28 June 2019 
 
 
 
Proprietary and Confidential                                                         Page 78 of 78 
 
Appendix C: Approximate Volume of Blood to be Drawn at Each Study Visit 
Time 
Point 
All 
Pops 
mL 
IMR-687 PK 
HU PK 
 
PD Parameters 
 
Safety 
Param
eters 
Total Sample 
Pop 
A 
mL 
Pop 
A1 
mL 
Pop 
B 
mL 
Pop 
B1 
mL 
Pop 
B 
mL 
Pop 
B1 
mL 
Pop 
A 
mL 
Pop 
A1 
mL 
Pop 
B 
mL 
Pop 
B1 
mL 
ALL 
POP 
mL 
Pop 
A 
mL 
Pop 
A1 
mL 
Pop 
B 
mL 
Pop 
B1 
mL 
Screening 
5 
— 
 
— 
— 
— 
 
— 
— 
— 
— 
18 
23 
23 
23 
23 
Lead-in 
(Pops B 
and B1 
only) 
— 
— 
 
— 
— 
16 x 
2  a 
16 x 
1 
— 
— 
— 
— 
— 
— 
— 
32 
16 
Day 1 
— 
18 
18 
18 
18 
— 
— 
12 
12 
12 
12 
18 
48 
48 
48 
48 
Week 2 
— 
— 
 
— 
— 
— 
— 
— 
— 
— 
— 
18 
18 
18 
18 
18 
Week 5 
— 
 
18 
18 
18 
16 
16 
12 
12 
12 
12 
18 
30 
48 
64 
64 
Week 9 
— 
— 
— 
— 
— 
— 
— 
12 
12 
  12 
12 
18 
30 
30 
30 
30 
Week 13 
— 
18 
— 
— 
— 
— 
— 
12 
12 
12 
12 
18 
48 
30 
30 
30 
Week 17 
— 
— 
— 
18 
— 
16 
— 
12 
12 
12 
12 
18 
30 
30 
64 
30 
Week 21 
— 
— 
— 
— 
— 
— 
— 
12 
12 
— 
12 
18 
30 
30 
18 
30 
Week 25 
(Pop 
A/A1/B1 
only) 
— 
18 
18 
— 
18 
— 
16 
12 
12 
— 
12 
18 
48 
48 
— 
64 
Week 29 
(Pop A/A1 
only) 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
18 
18 
18 
— 
18 
 
Study Total mL  
323 
323 
327 
371 
a One full HU PK profile will be obtained at baseline. 
Abbreviations: — = not applicable/not done; HU = hydroxyurea; PD = pharmacodynamics; PK = pharmacokinetics; Pop = population.