Clinical trial NCT04254978
Conditions: Essential Thrombocythemia
Sponsor: Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc., (Rahway, New Jersey USA)
Start date: 2020-09-08; Completion date: 2023-03-23
Enrollment: 73 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 2b open label study of an orally administered LSD1 inhibitor, Bomedemstat (MK-3543, formerly called IMG-7289), in patients with essential thrombocythemia.

This study investigates the following:

* The safety and tolerability of Bomedemstat
* The pharmacodynamic effect of Bomedemstat

Detailed description:
This is a Phase 2 multi-center, open-label study evaluating the safety, efficacy and pharmacodynamics of Bomedemstat administered orally once daily in patients with essential thrombocythemia (ET). Patients will be dosed with Bomedemstat for 169 consecutive days in the Initial Treatment Period (ITP). Qualifying patients may continue to receive Bomedemstat in the Additional Treatment Period (ATP).

Safety will be evaluated by clinical assessments of safety parameters i.e., safety laboratory testing, adverse event reporting, physical examination and vital sign assessments. Pharmacodynamics will be evaluated by hematology assessment, patient reported symptom burden, change in spleen size by palpation and other measures.

To ensure safety, a Safety Advisory Board will perform periodic reviews of safety parameters and pharmacodynamic markers.

Arms: arm 1: Bomedemstat administered daily for 169 consecutive days
Interventions: intervention 1: Bomedemstat
Intervention descriptions: intervention 1: Oral administration

Protocol documents:
Prot_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase 2 Multi-Center, Open Label Study to
Assess the Safety, Efficacy and
Pharmacodynamics of IMG-7289 in Patients
With Essential Thrombocythemia
NCT04254978 
September 9, 2020 


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INVESTIGATOR SIGNATURE PAGE 
Protocol Title: 
A Phase 2 Multi-Center, Open Label Study to Assess the 
Safety, Efficacy and Pharmacodynamics of IMG-7289 in 
Patients with Essential Thrombocythemia 
Protocol No.: 
IMG-7289-CTP-201 
Version and Date Final: 
Original Protocol: 11 November 2019 
Amendment 1:  03 December 2019 
Amendment 2:  09 September 2020 
Sponsor: 
Imago BioSciences, Inc.  
2729 Debbie Court 
San Carlos, CA 94070 - USA 
Imago BioSciences, Ltd. 
The Bryn 
Redwick, 
Magor, Caldicot 
NP26 3DE, UK 
Imago BioSciences B.V. 
Olympisch Stadion, 24 
Amsterdam, 1076 DE 
The Netherlands 
Declaration of Investigator 
I confirm that I have read and understood this protocol and agree to conduct the study as 
outlined in the protocol and other information supplied to me. I agree to conduct the study 
in compliance with: all local legal and regulatory requirements, good clinical practice as 
described in the International Council on Harmonization document “Guidance for Industry – 
E6 Good Clinical Practice: Consolidated Guidance”; and the Declaration of Helsinki. 
 
 
Investigator Signature 
Date 
 
 
Investigator Name (Print) 
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2 
PROTOCOL SYNOPSIS 
Protocol Title:  A Phase 2 Multi-Center, Open Label Study to Assess the Safety, Efficacy and 
Pharmacodynamics of IMG-7289 in Patients with Essential Thrombocythemia 
Protocol No:  IMG-7289-CTP-201 
Sites:  Approximately 25 sites in Australia, Italy, Germany, New Zealand, UK and US with 
additional sites and countries as needed. 
Study Objectives:   
Hypothesis: IMG-7289 is a safe and tolerable orally available agent when administered to 
patients with essential thrombocythemia; inhibition of LSD1 by IMG-7289 will reduce both the 
number of megakaryocytes and their capacity to secrete growth factors and inflammatory 
cytokines to the clinical benefit of patients with ET.     
Primary Objectives:  To evaluate in ET patients the effect of IMG-7289 on: 
• 
Safety and tolerability 
• 
Reduction of platelet counts to ≤ 400 k/μL (400 x 109/L) in the absence of new 
thromboembolic events 
Investigational Drug: The active drug substance is identified as IMG-7289(bomedemstat).  
IMG-7289 is an irreversible inhibitor of LSD1. The chemical name is: N-[(2S)-5-{[(1R, 2S)-2-(4-
fluorophenyl) cyclopropyl]amino}-1-(4- methylpiperazin-1-yl)-1-oxopentan-2-yl]-4-(1H-1,2,3-
triazol-1-yl)benzamide, bis-tosylate salt. 
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IMG-7289 will be supplied as capsules in multiple strengths. These strengths, based on IMG-7289 
free base, i.e., the active substance, may include: 5 mg, 10 mg, 25 mg and 50 mg. Capsule 
strengths provided may change throughout the duration of the study. Such details will be 
included via updates to the Pharmacy Manual. 
Study Population: Approximately 60 patients eighteen years of age or older in a population of 
ET patients requiring platelet control that have failed at least one standard therapy (failure is the 
equivalent of inadequate response or intolerance). 
Methodology:  This is a Phase 2 multi-center, open-label study evaluating the safety, efficacy and 
pharmacodynamics of IMG-7289 administered orally once daily in patients with essential 
thrombocythemia (ET). 
Preclinical testing of LSD1 inhibition in mouse models of myeloproliferative neoplasm induced 
apoptosis in mutant stem/progenitor cells, reduced inflammatory cytokines, reduced spleen 
length and weight, decreased bone marrow fibrosis if present, and reduced extramedullary 
hematopoiesis. Additionally, LSD1 inhibition with IMG-7289 was shown in a Jak2V617F mouse 
model of ET/polycythemia vera (PV) to selectively decrease the number of malignant 
megakaryocytes as well as reduce elevated platelets, red cells and granulocytes (Jutzi et al., 
2018). To date, IMG-7289 has been investigated in patients with acute myeloid leukemia, 
myelodysplastic syndrome and myelofibrosis patients, with notable changes in the myelofibrosis 
population including dose-dependent decreases in IL-8, platelets, and neutrophils. 
The therapeutic goal for the treatment of ET is to inhibit the activity of LSD1 in hematopoietic 
cells for only a fraction of the 24-hour dosing cycle, sufficient to reduce the production of 
platelets whose over-production characterizes this condition. Considerations leading to the 
choice of a safe starting dose include chronic toxicology studies in conjunction with the clinical 
experience of the eighty-five patients who have received IMG-7289 to date.  Using all available 
information in conjunction with the therapeutic goal for the treatment of ET, the starting dose of 
IMG-7289 of 0.6 mg/kg QD has been selected.  Refer to Section 3.6 for additional detail on the 
rationale for the starting dose and dose regimen. 
To ensure patient safety, a Safety Advisory Board (SAB) will perform reviews at least quarterly of 
safety parameters and pharmacodynamic markers to draw conclusions around the safety and 
pharmacodynamic effect of IMG-7289. The SAB will also review patient dose titrations and may 
recommend adjustments. 
Study Conduct:  This study consists of two treatment periods: the Initial Treatment Period (ITP), 
followed by the Additional Treatment Period (ATP). In the ITP, patients will be treated daily for 
169 days. The ATP offers treatment to qualifying patients for an additional 169 days. 
During the ITP, patients will initially return for study assessments every other week (bi-weekly) 
for the first 12 weeks (ITP Days 15, 29, 43, 57, 71 and 85) and then monthly for 12 weeks (ITP 
Days 113, 141 and 169). It is anticipated that by Week 12 (Day 85) the great majority of patients 
will have achieved a stable dose. For safety purposes, bi-weekly visits may continue at the PI’s 
discretion post Day 85 if necessary. On Day 169, bone marrow sampling is also required. 
Additionally, at the Day 169 visit a ‘qualification’ assessment will be made to determine whether 
the patient is deriving clinical benefit (defined as not meeting “progressive disease” criteria as 
per Appendix 16.5) and safely tolerating IMG-7289. For the patients who qualify for entry into 
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the ATP, transition should occur without interruption in dosing. Patients not deriving clinical 
benefit will discontinue IMG-7289 and undergo End of Treatment (EoT), pre-End of Study (pre-
EoS) and End of Study (EoS) visits. 
In the ATP, treatment may continue for an additional 169 days in those patients deriving clinical 
benefit, as determined by the Principal Investigator. Qualifying patients will return for study 
assessments monthly (ATP Days 1, 29, 57, 85, 113, 141 and 169). It is anticipated that patients 
continuing in the ATP will have already achieved a stable dose, with every other week visits no 
longer necessary. For safety purposes, every other week visits may continue at the PI’s 
discretion, if necessary. On Day 169 of every other ATP (i.e., ATP 2, ATP 4, etc.), the equivalent of 
yearly, bone marrow sampling is also required. At the Day 169 visit, a ‘qualification’ assessment 
will be made to determine whether the patient is continuing to derive clinical benefit. Such 
patients thereby qualify for re-entry into the ATP, which is iterative; patients may continue to 
receive IMG-7289 for as long as they continue to qualify. 
Patients will be followed closely throughout the study for both Adverse Events (AEs) and signs of 
toxicity by frequent monitoring of clinical signs and symptoms as well as safety labs. 
Pharmacodynamic effects will be closely monitored by frequent hematology assessments of 
peripheral blood, and requisite bone marrow aspirates and biopsies. Throughout dosing, 
transfusions may be administered if needed in accordance with standard institutional guidelines. 
IMG-7289 Dosing:  Through the use of dose titration, the dose of IMG-7289 will be adjusted for 
each patient to that dose that provides sufficient exposure to safely inhibit thrombopoiesis for a 
fraction of the dosing cycle (designated as the Dpi). 
Initial Treatment Period (ITP): 
All patients will be treated daily, for up to 169 days of dosing. Treatment will begin on Day 1 at 
the starting dose (Ds) of 0.6 mg/kg QD.  Details on the selection and rationale for the starting 
dose and dosing schedule can be found in Sections 3.6.1 and 3.6.2.  Dose-titration, both upward 
and downward, is contingent on the hematology assessment and comparison of hematology 
values from the prior study visit.  Up-titrations may begin on ITP Day 28 and occur no more 
frequently than every 4 weeks from the previous up- or down-titration.  Down-titrations can be 
made at any time in the best interest of the patient.  Up-titrations will be made in increments of 
0.2 mg/kg/d, and down-titrations in decrements of 0.1 or 0.15 mg/kg/d. 
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Study Duration:  Screening procedures may commence up to 28 days prior to the start of 
treatment.   Patients may initially receive up to 24 weeks of dosing while on-study. Patients will 
be followed for 14 days post last dose. Therefore, the anticipated duration of participation in the 
study is expected to be approximately 30 weeks from first patient visit to last patient visit. 
Additional treatment may be given, contingent on an assessment of patient benefit. 
Study Assessments:  The assessments outlined below are also summarized in Study 
Assessments Section 9 and in the Schedule of Assessments Sections 16.1. 
The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF; Appendix 16.6) will be 
completed during  Screening (as close to Day -7 as possible), pre-dose Day 1, weekly from Day 7 
through the EoS Visit, and upon suspicion of relapse.  Multiple questionnaires will need to be 
provided to the patient at each visit for completion during each ‘off week’.  
ECOG Performance Status (Appendix 16.4) will be performed at Screening, and on Days 85 and 
169 of the ITP, on Day 169 of the ATP for as long as the patient continues to qualify, at EoT, 
EoS/ET, and upon suspicion of relapse.  
Patient Global Impression of Change (PGIC; Appendix 16.7) will be performed at Days 85 and 169 
of the ITP, on Day 169 of the ATP for as long as the patient continues to qualify, at EoT, EoS/ET, 
and upon suspicion of relapse. 
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Adverse events (AEs) will be assessed at every visit post first dose through the EoS visit.  
Note for UK: Non-serious events occurring pre-first IMG-7289 dose will be recorded as Medical 
History; those occurring post first IMG-7289 dose through the EoS visit will be recorded as AEs.  
Serious AEs (SAEs) will be recorded from time of consent through the EoS/ET visit or until the 
Investigator and Imago determine follow-up is no longer necessary. 
Physical Examinations (PE): a Full Physical Exam, including vital signs, and height will be 
performed at Screening. Limited Physical Exams (LPE), including vital signs, will be performed 
on Day 1 and at every study visit throughout the study (noted exception: if patient’s dose has not 
stabilized and more frequent visits than detailed in the visit schedule are deemed necessary, 
LPEs are not required at these additional visits).  
 
 
 
 
 
Serum pregnancy testing will be performed for women of child-bearing potential (WOCBP) at 
Screening, pre- dose Day 1, monthly (i.e., Days 29, 57, 85, 113, 141 and 169) throughout the study, 
upon suspicion of relapse, at the EoT, pre-EoS, and EoS/ET visits, and if pregnancy is suspected 
while the patient remains on-study. 
Bone marrow aspirate* and biopsy will be performed**: 
• 
At Screening (no more than 28 days prior to the first IMG-7289 dose). 
• 
At Day 169 visit (±7 days). 
• 
Approximately every 12 months thereafter, at Day 169 (±7 days) of every other 
Additional Treatment Period (i.e., ATP 2, ATP 4, etc.), the equivalent of yearly, for as 
long as the patient continues to qualify. 
• 
At EoT, EoS/ET, and upon suspicion of relapse, unless performed within the prior 5 
weeks. 
*Aspirate from the first pull whenever possible, but no later than the second, is required (except in case of dry tap). 
**The total number of bone marrow evaluations required during the Initial Treatment Period is 2 in ~30 weeks. 
Additional marrow evaluation is required only if the patient qualifies for the Additional Treatment Period, is 
suspected to have relapsed after demonstrating response, or upon evidence of progressive disease. 
Clinical laboratory measures: The following laboratory measures will be performed at Screening, 
pre-dose Day 1, then as described below for individual panels, upon suspicion of relapse, and at 
the EoT, pre-EoS, and EoS/ET visits: 
• 
Hematology with automated differential – at every visit throughout the  study 
• 
Chemistry – monthly (i.e., Days 29, 57, 85, 113, 141 and 169) throughout the study 
• 
Coagulation – Days 85 and 169 throughout the study 
• 
Urinalysis – Days 85 and 169 throughout the study 
• 
Note:  In Italy, HIV, HAV, HBsAg, HBsAb, HBcAb and HCV testing must also be performed 
at Screening and EoT/ET. 
 
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Mutant (variant) allele burden:  The following laboratory samples will be collected at the time-
points noted: 
• 
Germline samples for genomic analysis - Screening 
• 
Peripheral blood for genomic analysis 
o Screening, Day 169, and at Day 169 of every ATP (i.e., ATP 1, ATP 2, etc.) for as 
long as the patient continues to qualify  
o At EoT, EoS/ET and upon suspicion of relapse*  
• 
Bone marrow for genomic analysis 
o Screening, Day 169, and at Day 169 of every other ATP (i.e., ATP 2, ATP 4, etc.), 
the equivalent of yearly, for as long as the patient continues to qualify  
o At EoT, EoS/ET and upon suspicion of relapse* 
*Required at EoT, EoS/ET and upon suspicion of relapse unless performed within the prior 5 weeks. 
Future Correlative Studies:  Blood will be collected in conjunction with each genomic blood 
sampling time-point, as detailed above, for the purposes of potential correlative studies 
Titration Assessment:  At every visit following Day 1 patients will be assessed for dose titrations 
using the titration and re-challenge rules in Table 1.  
• 
Up-titrations are permitted no more frequently than every 4 weeks from the previous  
up- or down-titration.   
• 
Down-titrations are permitted at any time in the patient’s best interest. 
Cytokines: Sample collection time-points are below. 
• 
Pre-dose Day 1, Days 15, 29, 57, 85 and 169, and at Day 169 of the ATP for as long as 
the patient continues to qualify 
• 
At EoT, and at ET (ET required only if the patient discontinues during the ITP) 
Qualification Assessments: 
• 
Initial Treatment Period Day 169: Assess whether the patient is eligible for the ATP. If it is 
determined that the patient is deriving clinical benefit and safely tolerating IMG-7289, 
then the patient qualifies for and may enter the ATP upon completion of the Day 169 visit.  
• 
Additional Treatment Period Day 169: Assess whether the patient continues to be 
eligible for the ATP. Refer to ITP Day 169 above, as the process is the same. 
Eligibility Criteria: Patients must meet all applicable Inclusion and none of the Exclusion 
Criteria.  
Inclusion Criteria: 
1. Age ≥ 18 years. 
2. Diagnosis of Essential Thrombocythemia per World Health Organization (WHO) 
diagnostic criteria for myeloproliferative neoplasms (Arber et al., 2016).  
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3. Patients who have failed at least one standard therapy (failure is the equivalent of 
inadequate response or intolerance).  European Leukemia Net (ELN) criteria for 
intolerance / resistance to hydroxyurea (Appendix 16.8) may be used in association 
with Investigator discretion.  Ruxolitinib refractoriness or intolerance will be left to 
the discretion of the Investigator. 
4. Requires treatment in order to lower platelet counts based on patient age over 60 or 
history of thrombosis. 
5. Platelet count > 450 k/μL (450 x 109/L) pre-dose Day 1. 
6. Peripheral blast count < 1% pre-dose Day 1. 
7. ANC ≥ 0.5 x 109/L pre-dose Day 1. 
8. Fibrosis Score < grade 2, as per a slightly modified version (Arber et al., 2016) of the 
European Consensus Criteria for Grading Myelofibrosis (Thiele et al., 2005). 
9. Life expectancy > 36 weeks. 
10. Able to swallow capsules. 
11. Amenable to bone marrow evaluations and peripheral blood sampling during the study. 
12. Must have discontinued ET therapy at least 1 week (4 weeks for interferon) prior to study 
drug initiation. 
13. Women of childbearing potential (WOCBP) and fertile men (see Section 6.1) must agree 
to use an approved method of contraception from Screening until 14 days* after last 
IMG-7289 dose. Methods of contraception include: estrogen and progestogen combined 
hormonal contraception which inhibits ovulation; progestogen-only hormonal 
contraception associated with inhibition of ovulation; intrauterine device (IUD); bilateral 
tubal occlusion; vasectomized partner in a monogamous sexual relationship (vasectomy 
or tubal ligation at least six months prior to dosing); and, complete sexual abstinence 
(defined in Section 6.1). Males with a pregnant partner must agree to use a condom to 
avoid exposure to the developing child. Patients practicing abstinence must agree to use 
an approved method of contraception should they become sexually active during the 
study. 
*The risk of embryofetal toxicity is fully mitigated by 28 days which is >10 half-lives of the drug at the doses 
used in this study. 
Exclusion Criteria 
1. Hemoglobin < 10 g/dL prior to dosing on Day 1. 
2. Transfusion dependency, defined as requiring 2 or more units of pack red blood cells 
per month for more than 3 months, or a hemoglobin level of ≤8g/dL in the preceding 
8 weeks before the start of dosing.  
3. Eastern Cooperative Oncology Group (ECOG) questionnaire score of 3 or greater at 
Screening. 
4. History of splenectomy. 
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5. Has undergone major surgery ≤4 weeks prior to starting study drug or has not recovered 
from side effects of such surgery. 
6. Unresolved treatment related toxicities from prior therapies (unless resolved to  
≤ Grade 1). 
7. Uncontrolled active infection. 
8. Known positive for HIV if not well-controlled (i.e., undetectable viral load) or infectious 
hepatitis, type A, B or C. 
Note for Italy: Active infection with hepatitis A virus, B virus (positive hepatitis B surface antigen; 
note: positive hepatitis B surface antibody and positive hepatitis B core antibody are not exclusionary 
provided disease is not active, which should be clearly documented in the patient’s medical history) or 
C virus (patients with positive hepatitis C antibody result would require confirmation of active disease 
with a positive hepatitis C polymerase chain reaction (PCR) test), seropositivity for human 
immunodeficiency virus (HIV). 
9. Current use of monoamine oxidase A and B inhibitors (MAOIs). 
10. Evidence at the time of screening of increased risk of bleeding, including any of the 
following: 
• 
Activated partial thromboplastin time (aPTT) > 1.3 x the upper limit of normal 
• 
International normalized ratio (INR) >1.3 x the local upper limit of normal 
• 
History of severe thrombocytopenia or platelet dysfunction unrelated to a 
myeloproliferative disorder or its treatment  
• 
Known bleeding disorder (e.g., dysfibrinogenaemia, factor IX deficiency, 
hemophilia, Von Willebrand’s disorder, Disseminated Intravascular Coagulation 
[DIC], fibrinogen deficiency, or other clotting factor deficiency) 
11. Evidence at the time of Screening of significant renal or hepatic insufficiency (unless due 
to hemolysis, or leukemic infiltration) as defined by any of the following local lab 
parameters: 
• 
Calculated glomerular filtration rate (GFR; using the Cockcroft-Gault equation) 
<40 mL/min or serum creatinine > 1.5 x the local upper limit of normal  
• 
Aspartate transaminase (AST) or alanine aminotransferase (ALT) ≥2 x the local 
upper limit of normal 
12. Current use of a prohibited medication (e.g., romiplostim) or expected to require any of 
these medications during treatment with the investigational drug. 
13. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to IMG-7289 or LSD1 inhibitors (i.e., monoamine oxidase inhibitors; 
MAOIs) that contraindicates their participation. 
14. History of any illness/impairment of gastrointestinal (GI) function that might interfere 
with drug absorption (e.g., chronic diarrhea), confound the study results or pose an 
additional risk to the patient by participation in the study; patients with gastric bypass 
surgery. 
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15. Use of an investigational agent within less than 14 days, or the equivalent of at least  
7 half-lives of that agent, whichever is the longer, prior to the study Day 1. 
16. Females who are pregnant or breastfeeding or plan to become pregnant or breastfeed 
during the study. 
17. A concurrent second active and non-stable malignancy (patients with a concurrent second 
active but stable malignancy, such as non-melanoma skin cancers, are eligible). 
GUIDELINES:  These guidelines are for use by the Investigator, study staff and patient to 
safeguard patient safety while maintaining data integrity. 
1. In general, supportive care (transfusions, administration of anti-fungals, etc.) should be 
maintained in accordance with institutional policy.  
2. Patients taking medications with the potential to induce or inhibit CYP3A4 or CYP2D6 should 
be monitored closely for potential effects of co-administration; particular attention should be 
given to anti-infectives in the azole class. 
3. Cessation of IMG-7289 is invariably associated with a rebound in thrombopoiesis and platelet 
counts may easily exceed the baseline value. When IMG-7289 is discontinued, the platelet count 
should be monitored closely and an alternative cytoreductive therapy to lower platelets should 
commence within 24-48 hours. 
Management of Study Toxicities:  Adverse event intensity will be evaluated using the National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5, 
published 27 November 2017. Please refer to Section 8.2 for additional detail on management of 
study toxicities, including reduction of the starting dose based on dose limiting toxicity (DLT). 
Definitions: 
Hematologic Toxicity: Hematologic values outside of the normal reference range are inherent 
features of MPNs and are expected effects of many therapeutic attempts to manage these 
diseases. The effects of IMG-7289 on normal myeloid hematopoiesis observed in non-clinical and 
clinical studies are expected; these are pharmacodynamic effects of LSD1 inhibition by IMG-7289, 
thus are not regarded as adverse. These events, with the exceptions below, will not be considered 
DLTs. 
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Dose limiting toxicity (DLT): Any one of the following AEs that occurs through Day 7 of the Initial 
Treatment Period and is considered by the Investigator to be possibly, probably or definitely 
related to IMG-7289: 
• 
Any Grade 2 or above thrombocytopenia associated with clinically significant 
bleeding*  
• 
Any Grade 3 or above thrombocytopenia; 
• 
Any Grade 4 or 5 non-hematologic adverse event; 
• 
Any Grade 3 or above non-hematologic adverse event with failure to recover to Grade 
2 within 7 days of drug cessation, with the following exceptions: 
o nausea, vomiting or diarrhea that responds to standard medical care 
o aesthenia lasting less than 14 days 
• 
Any Grade 3 electrolyte abnormality unrelated to the underlying malignancy (for 
example, hyperkalemia is related to thrombocytosis and would therefore not qualify 
as DLT) and persisting greater than 24 hours. 
*Clinically significant bleeding is defined as an event that is life-threatening, cannot be controlled and/or 
results in hemodynamic instability. 
Patients who experience a DLT may have their dose adjusted downward if the Medical Monitor 
and Principal Investigator (PI) deem it safe for the patient to continue on IMG-7289.  Any patient 
that experiences DLT that results in discontinuation of IMG-7289 therapy may begin alternative 
cytoreductive therapy to lower platelets within 24-48 hours. 
Please contact the Imago medical monitor to discuss IMG-7289 dose modifications for the 
management of clinically significant changes in platelets, neutrophil counts, or other hematologic 
parameters. 
Stopping Rules: 
IMG-7289 will be discontinued in the event of the following: 
• 
Post DLT, the Medical Monitor and Principal Investigator deem it unsafe for the patient to 
continue on IMG-7289. 
• 
Post dose reduction due to DLT, the patient fails to demonstrate significant improvement 
within 21 days. 
• 
Post temporary interruption of IMG-7289 due to platelet counts below 50 k/μL (50 x 109/L), 
the patient's platelet counts don’t return to >150 k/μL (150 x 109/L) within 21 days. 
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3 
INTRODUCTION 
3.1 
Background on the Disease to be Treated 
The BCR-ABL1-negative myeloproliferative neoplasms (MPNs) are a family of related neoplastic 
disorders of bone marrow.  The three main chronic BCR-ABL1-negative MPNs are polycythemia vera 
(PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF).  The cardinal clinical 
features of these disorders are increased red cell mass in PV, increased platelet count in ET, and bone 
marrow fibrosis in PMF.  The MPNs are clonal disorders arising most frequently from acquired 
(somatic) mutations in a multipotent hematopoietic stem/progenitor cell, resulting in abnormalities 
in red cell, granulocyte and platelet production often in association with marrow fibrosis and 
extramedullary hematopoiesis and, in some cases evolution to acute myeloid leukemia (AML). 
ET is an indolent hematologic cancer characterized by reduced quality of life, thrombocytosis, 
elevated cytokines, an increased rate of thrombosis and bleeding and the potential to develop 
myelofibrosis and acute myeloid leukemia (Vannucchi et al., 2017). Transformation to post-ET 
myelofibrosis and post-ET acute leukemia occurs at a rate of 4–11% and 2.1–5.3% at 15 years, 
respectively (Cerquozzi and Tefferi, 2015).  Risk factors for poor survival include age over 60, 
leukocytosis, and a prior history of thrombosis (Barbui et al., 2012).  Indications for pharmacologic 
treatment in ET include extreme thrombocytosis, elderly age, JAK2V617F mutational status, and history 
of thrombosis or presence of cardiovascular risk factors (Rumi et al., 2017).  There are no specific 
treatments for ET.  Treatments principally manage symptoms but do not alter the natural history of 
the disease (Spivak 2017).  Standard first-line pharmacologic treatment to reduce thrombocytosis is 
hydroxyurea (HU) which has a low incidence of acute toxicity but is regarded by some as mutagenic.  
However, approximately 20-25% of ET patients will be resistant or intolerant of HU per ELN criteria 
and treatment with HU has been demonstrated to worsen symptom burden (Sever et al., 2014; Geyer 
et al., 2015). Low-dose pegylated interferon-α2a early in the course of the disease reduces 
splenomegaly and can produce molecular remissions but is associated with cytopenias and 
neurotoxocities and is not approved for this indication in many countries (Kiladjian et al., 2008).   
Thus, there remains unmet need for therapeutic interventions that reduce thrombocytosis and 
improve symptom burden in patients with ET. 
3.2 
Background on the Drug Target 
LSD1, also known as KDM1A, is an enzyme that removes mono- and dimethyl groups from histone 
(H) H3 at critical lysines (K), K4 and K9 (Shi et al., 2004).  Methylation of histone H3K4 and H3K9 is 
a post-translational modification associated with changes in the confirmation of chromatin 
(Bannister and Kouzarides, 2011; Beisel and Paro, 2011).  Chromatin is collective term for the 
association of nuclear macromolecules consisting of DNA, protein scaffolding, enzymes enhancing 
transcription and synthesis of RNA (Kornberg, 1974).  The DNA and its protein scaffold of histones 
form an ordered complex called the nucleosome.   Each nucleosome is composed of two copies of 
each of the four histone proteins, H2A, H2B, H3 and H4, forming an octamer around which DNA is 
wrapped.  The rates of gene transcription are heavily influenced by the accessibility of transcription 
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factors and the RNA polymerase complexes to template DNA at promoters (Bannister and 
Kouzarides, 2011; Beisel and Paro, 2011). 
Epigenetics refers to the regulation of gene expression resulting from chemical modifications of 
histones, the DNA bases such as cytosine or RNA, changes that do not alter the actual DNA sequence 
(Bird, 2002).  Enzymes that modify these substrates by the addition or removal of these chemical 
changes are called epigenetic regulators.  Histone and nucleic acid modifications provide binding 
sites for proteins and components of the transcriptional machinery that affect transcriptional gene 
silencing or activation (Kouzarides, 2007).  Histone modifications include acetylation (Ac), 
methylation (Me), phosphorylation (Ph) and ubiquitination (Ub).  By virtue of altering the local state 
of chromatin, LSD1 is an epigenetic regulator of gene expression.  The primary therapeutic effects of 
LSD1 inhibition in the treatment of essential thrombocythemia come from the down regulation of 
megakaryopoiesis and thrombopoiesis, functions that require LSD1 activity.  
LSD1 is localized to specific sites in the genome through the agencies of proteins that bind DNA 
directly, generally transcription factors (TFs) (Whyte et al., 2012; Whyte et al., 2013).  Many TFs, both 
activators such as V-Myb Avian Myeloblastosis Viral Oncogene Homolog (MYB) and steroid hormone 
receptors, as well as repressors such as growth factor independence 1 transcription repressor (GFI1) 
and RE-1 silencing transcription factor (REST), recruit LSD1 to specific genomic locations (Metzger 
et al., 2005; Saleque et al., 2007; Lin et al., 2010).  LSD1 is part of a larger protein complex, containing, 
e.g., Co-RE-1 silencing transcription factor (CoREST) or nucleosome remodeling and histone 
deacetylase (NuRD), which dictates the cell- and site-specific chromatin remodeling (Lee et al., 2005; 
Foster et al., 2010).  These complexes may also include DNA methytransferase 1 (DNMT1) and 
histone deacetylases 1, 2 and 3 (HDAC1, 2, and 3) activities all of which contribute to maintaining or 
modifying the epigenetic state at that specific genomic site (Shi et al., 2005; Orkin and Hochedlinger, 
2011).  Thus, an important property of LSD1 beyond its own enzymatic activity is its function as a 
scaffold for other proteins and epigenetic enzymes that are co-recruited to genomic sites.  Likewise, 
LSD1 bound to specific sites precludes the binding of other factors that may influence transcription.  
LSD1 is unique among the many histone demethylases in that it coordinates flavin adenine 
dinucleotide (FAD) to oxidatively remove one or two methyl groups, in the process producing H2O2 
and formaldehyde.   As such, FAD is an essential co-factor for LSD1 activity (Shi et al., 2004).  The 
other 34 histone lysine demethylases, collectively termed the Jumonji demethylases, employ an iron-
dependent mechanism to remove methyl groups from histone lysines (Klose et al., 2006).  
LSD1 is an essential gene; loss of LSD1 activity leads to early embryonic lethality (Wang et al., 2009; 
Foster et al., 2010).  The protein is also needed for regulating the balance between self-renewal and 
proliferation (Wang et al., 2007).  A conditional in vivo LSD1 knockdown (KD) using a doxycycline-
inducible short hairpin LSD1 (shLSD1) established LSD1 as a central regulator of hematopoietic stem 
cells (HSCs) and progenitor cells (Sprussel et al., 2012). An inducible LSD1 KD resulted in profound 
but reversible thrombocytopenia, neutropenia and anemia; monocyte numbers were increased as 
monopoiesis does not require LSD1 activity.  LSD1 KD for 27 days led to an increase in circulating 
multipotent progenitors (MPPs) and HSCs with a concomitant down-regulation of chemokine (C-X-C 
motif) receptor 4 (CXCR4) without affecting the size of the quiescent long-term HSC pool (Sprussel et 
al., 2012).   
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LSD1 plays a key role in regulating the progression from pluripotency to terminal differentiation and 
balancing self-renewal and proliferation (Adamo et al., 2011; Wang et al., 2007; Whyte et al., 2012).   
LSD1 is recruited to “high confidence” promoters and super-enhancers of genes essential for normal 
development by the “master” transcription factors octamer-binding transcription factor 4 (OCT4), 
SRY (sex determining region Y)-box 2 (SOX2), Nanog and the co-activator Mediator.  Though not 
essential for maintenance of the embryonic stem cell (ESC) state, as part of the NuRD complex, LSD1 
“decommissions” enhancers of genes maintaining the pluripotency program allowing ESC to 
differentiate.  LSD1 is essential for the complete shutdown of the ESC gene expression program as 
cells transition to more differentiated cell states (Whyte et al., 2012).  The role LSD1 plays in ESCs is 
phenomenologically similar to the essential role LSD1 plays during myeloid hematopoiesis, in which 
enhancers active in HSCs generating a stem-cell gene expression signature are also 
“decommissioned”, allowing commitment of progenitors to specific myeloid lineages (Lara-Astiaso et 
al., 2014).  Enhancers essential for terminal myeloid differentiation in lineage-specific progenitor 
cells, the so-called de novo enhancers, must be poised for activation by the placement of H3K4me1 
marks.  As progenitors commit to differentiation, LSD1 is down-regulated dramatically allowing de 
novo enhancers and promoters to be stably activated with progressive methyl or acetyl additions on 
H3K4 and H3K27, respectively (Lara-Astiaso et al., 2014).    
3.3 
Background on LSD1 in Myeloid Neoplasia and Essential Thrombocythemia 
Over-expression of LSD1 messenger RNA (mRNA) and excess LSD1 protein have been observed in 
many tumor types, including poorly-differentiated neuroblastoma, squamous cell carcinoma, 
Ewing’s sarcoma, AML, neuroendocrine carcinomas and epithelial tumors such as breast, prostate, 
bladder, small cell lung and colon cancers (Metzger et al., 2005; Kahl et al., 2006; Schulte et al., 2009; 
Lim et al., 2010).  In MPNs, LSD1 was over-expressed mainly in megakaryocytes and erythroid 
precursors and to a lesser degree in early myeloid cells (Niebel et al., 2014). Treatment of various 
tumor types in culture with LSD1 inhibitors (LSDi) has been reported to inhibit tumor growth, reduce 
their potential for migration and invasion, reduce clonogenic potential and eliminate cancer stem 
cells, induce markers of differentiation appropriate to the cell lineage, and induce apoptosis 
(Somervaille and Cleary, 2006; Somervaille et al., 2009; Harris et al., 2012; Zhang et al., 2013).  In 
various models of mouse leukemia, treatment with LSD1 inhibitors induced monocytic markers of 
differentiation, reduced clonogenic potential of leukemia initiating cells (LICs), and induced cell 
death (Harris et al., 2012).   
LSD1 activity is present in a high proportion of malignant myeloid blasts cells (Lin et al., 2011;  
Rhodes et al., 2007; Wouters et al., 2009).  LSD1 gene expression is among the highest in 
immunophenotypically stem/progenitor populations of myeloid neoplastic cells (Goardon et al., 
2011; Somervaille et al., 2009; Harris et al., 2012).   
LSD1 may play a direct role in regulating pathogenic signaling from the activated JAK-STAT pathway.  
The JAK-STAT signaling pathway is activated by the canonical MPN mutations in MPL, JAK2 and CALR 
via the phosphorylation of STAT3 and STAT5, transcription factors that activate specific sets of genes 
with pleiotropic effects (Chen and Mullally, 2014).  STAT3 activity as a transcription factor is 
modulated by methylation on lysine (K140) and is one of many reported non-histone substrates for 
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LSD1 (Yang et al., 2010).   
Proof-of-concept studies of the therapeutic activity of LSD1 inhibition were performed in well 
established, pre-clinical mouse models of MPNs (Jak2V617F, MplW515L).  Compared to mice treated with 
vehicle, LSD1 inhibition (LSDi) in MplW515L mice markedly suppressed myeloproliferation reducing 
granulocyte and platelet counts, thus establishing therapeutic efficacy. Spleen weights in treated 
animals showed a dose-proportional decrease.  Histopathological analysis of bone marrow and 
spleen confirmed a marked reduction in myeloproliferation, as well as a reversal of extramedullary 
hematopoiesis (EMH).  Most notably, there was near-complete resolution of reticulin fibrosis in the 
bone marrow in the LSDi treatment arm.  LSD1 inhibition had a significant impact on serum 
inflammatory cytokine concentrations as exemplified by a very marked reduction in the plasma 
concentration of the Chemokine (C-X-C Motif) Ligand 5 (Cxcl5 or IL-8 in humans), a key participant 
in the pathologic inflammatory state of MPN.   
LSD1 inhibition also reduced the mutant cell burden.  In mice treated with vehicle, 74.6% of 
circulating cells were green fluorescent protein cell-positive (GFP+), while only 43.2% of circulating 
cells were GFP+ in LSDi-treated mice.  Flow cytometry analysis of spleen and bone marrow revealed 
reduced numbers of CD11b+/Gr1+ myeloid cells and CD41+ megakaryocytes.  The numbers of mutant 
GFP+ myeloid cells and megakaryocytes in these tissues were also significantly reduced by LSDi 
treatment.  The decrease in platelet counts and mutant clone burden, and the resolution of fibrosis 
after 28 days of LSD1 inhibition supports targeting LSD1 in patients with MPN. 
3.5 
Potential Clinical Risks and Benefits when Treating with an LSD1 Inhibitor 
The treatment effects with an LSD1 inhibitor (LSDi) are distinct from treatment with standard 
cytotoxic agents or with Janus Kinase (JAK) inhibitors.   LSD1 inhibition has specific effects on each 
myeloid lineages.  LSD1 activity is needed for the differentiation of progenitors to red cells, platelets 
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and granulocytes; LSD1 activity is not needed for monopoiesis.  Hence, LSD1 inhibition changes the 
cellular composition in the marrow and the morphology of these cells.  Likewise, distribution of blood 
cells based on lineage is also affected with an increase in the production of monocytes and a 
decreasing in the other myeloid cell types; the production of platelets appears to be more sensitive 
to LSD1 inhibition and red cell production the least.  There is no evidence to suggest that inhibition 
of LSD1 has any effect on the proper function of platelets or neutrophils.  In the treatment of ET, the 
intent is not to inhibit LSD1 completely; the treatment thesis is to titrate drug exposure to that which 
lowers platelets into the desired range.  The sensitivity to a given exposure of IMG-7289 in ET 
patients, however, may be variable and understanding that dose-response is one of the objectives of 
this study. 
The morphologic and clinical pathology changes may not be familiar to clinicians and 
hematopathologists.   As such, there is potential for confusion in the interpretation of peripheral 
hematologic parameters and the morphology of bone marrow cells.  Outlined below are some of the 
anticipated clinical scenarios that might be observed in ET patients treated with IMG-7289 based on 
non-clinical and clinical studies conducted by Imago BioSciences and published reports of the effects 
of inhibiting LSD1: 
1. With complete pharmacologic inhibition of LSD1, the red cell, platelet and neutrophil counts can 
be expected to decrease as a function of the lifespan of each cell type, that is, with zero order 
kinetics; hence, a linear decrease over time.  Human platelets circulate for an average of seven to 
ten days; if LSD1 were to be inhibited completely, the platelet count would be predicted to fall 
below 10 x 109/L (10 k/µL) within a week.  The time to observe these drug-induced effects on 
blood cell production may be less for a patient starting out with a lower granulocyte or red cell 
mass or platelet count.  In this study, the goal is to safely reduce platelet production.  
Notwithstanding, as thrombopoiesis appears most sensitive to LSD1 inhibition, severe 
thrombocytopenia represents the greatest clinical risk. 
2. The effects of LSD1 inhibition on normal hematopoiesis are fully reversible.  IMG-7289 is an 
irreversible inhibitor of LSD1 but as drug is cleared and the amount of active LSD1 enzyme 
increases, megakaryocyte maturation and platelet production return to normal.  These changes 
are manifest as early as 24-48 hours.  (N.B. Platelet counts, as well as granulocyte counts, can 
exceed baseline values after several days-to-weeks of no drug exposure, owing, in part, to the rise 
in the plasma concentration of growth factors such as GM-CSF and thrombopoietin that 
accompanies LSD1 inhibition.)     
3. Cessation of IMG-7289 is invariably associated with a rebound in thrombopoiesis, hence platelet 
counts may easily exceed the baseline value.  When IMG-7289 is discontinued, the platelet count 
should be monitored closely and an alternative cytoreductive therapy to lower platelets should 
commence within 24-48 hours after the cessation of IMG-7289.   
4. As a consequence of inhibition of LSD1 in both rat and dog, megakaryocytes appear dysplastic 
and form syncytia in proportion to the degree of LSD1 inhibition.  Platelet volumes also increase 
dramatically as LSD1 inhibition reaches a maximum and platelet counts fall.  These effects are 
reversible after cessation of drug exposure. 
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4 
HYPOTHESIS AND OBJECTIVES 
This trial will study the effects of IMG-7289, an irreversible inhibitor of the enzyme LSD1 as a 
treatment of essential thrombocythemia (ET). ET is an indolent hematologic cancer characterized 
by reduced quality of life, thrombocytosis, elevated cytokines, and increased rates of thrombosis 
and bleeding that can evolve to myelofibrosis and/or acute myeloid leukemia. LSD1 is an enzyme 
that regulates the maturation of megakaryocytes from progenitor cells, as well as the function of 
mature megakaryocytes. In ET, acquired mutations in hematopoietic stem cells cause JAK/STAT 
activation which results in an over-abundance of activated megakaryocytes that in turn produce an 
excess of platelets, growth factors and inflammatory cytokines. 
4.1 
Hypothesis 
IMG-7289 is a safe and tolerable orally available agent when administered to patients with ET; 
inhibition of LSD1 by IMG-7289 will reduce both the number of megakaryocytes and their capacity 
to secrete growth factors and inflammatory cytokines to the clinical benefit of patients with ET. 
4.2 
Objectives 
The following primary and exploratory objectives will be evaluated in patients with essential 
thrombocythemia (ET) treated with IMG-7289: 
4.2.1 Primary 
• 
Safety and tolerability 
• 
Reduction of platelet counts to ≤ 400 k/μL (400 x 109/L) in the absence of new thromboembolic 
events 
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5 
INVESTIGATIONAL PLAN 
5.1 
Overview 
This is a Phase 2 multi-center, open-label study evaluating the safety, efficacy and 
pharmacodynamics of IMG-7289 administered orally once daily in patients with essential 
thrombocythemia (ET).    
The therapeutic goal for the treatment of ET is to inhibit the activity of LSD1 in hematopoietic cells 
for only a fraction of the 24-hour dosing cycle, sufficient to reduce the production of platelets, 
whose over-production characterizes this condition. Considerations leading to the choice of a safe 
starting dose include chronic toxicology studies in conjunction with the clinical experience of the 
patients who have received IMG-7289 to date.  Using all of the information available in conjunction 
with the therapeutic goal for the treatment of ET, an IMG-7289 starting dose of 0.6 mg/kg QD has 
been selected.  Refer to Section 3.6 for additional detail on the rationale for the starting dose and 
dose regimen. 
To ensure patient safety, a Safety Advisory Board (SAB) will perform reviews at least quarterly of 
safety parameters and pharmacodynamic markers to draw conclusions around the safety and 
pharmacodynamic effect of IMG-7289.  The SAB will also review patient dose titrations and may 
recommend adjustments. 
This study consists of two treatment periods:  The Initial Treatment Period (ITP), followed by the 
Additional Treatment Period (ATP).  In the ITP, patients will be treated daily for 169 days.  In the 
ATP, which is iterative, treatment may continue for an additional 169 days in those patients deriving 
clinical benefit (defined as not meeting “progressive disease” criteria as per Appendix 16.5) and 
safely tolerating IMG-7289; this definition applies throughout the document and will not be repeated 
with each reference to clinical benefit), as determined by the Principal Investigator.   
All patients will undergo follow-up period visits, including an End-of-Treatment (EoT) visit on the 
day of last dose or as soon as possible thereafter, a pre-End-of-Study (EoS) visit approximately 7 days 
post last dose, and an End-of-Study (EoS) visit approximately 14 days post last dose.  Patients that do 
not enter the ATP, or discontinue early, will undergo follow-up beginning with an EoT visit. 
Patients will be followed closely throughout the study for both Adverse Events (AEs) and signs of 
toxicity by frequent monitoring of clinical signs and symptoms as well as safety labs.  Efficacy and 
pharmacodynamic effects will be closely monitored by frequent hematology assessments of 
peripheral blood, and requisite bone marrow aspirates and biopsies.  Throughout dosing, 
transfusions may be administered if needed in accordance with standard institutional guidelines. 
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5.1.1 Initial Treatment Period 
Through the use of dose titration, the dose of IMG-7289 will be adjusted in each patient to that dose 
that provides sufficient exposure to safely inhibit thrombopoiesis for a fraction of the dosing cycle 
(designated as the Dpi).  Treatment will begin on Day 1 at the IMG-7289 Ds of 0.6 mg/kg QD for all 
patients, with dose-titration contingent on the comparison of hematology values from the prior visit.  
Up-titrations may begin on ITP Day 28 and occur no more frequently than every 4 weeks from the 
previous up- or down-titration.  Down-titrations can be made at any time in the best interest of the 
patient.  
 
 
 
 
 
 
 
   
 
  
During the ITP, patients will initially return for study assessments every other week (bi-weekly) for 
the first 12 weeks (ITP Days 15, 29, 43, 57, 71 and 85) and then monthly for 12 weeks (ITP Days 113, 
141 and 169). It is anticipated that by Week 12 (Day 85) the majority of patients will have achieved a 
stable dose. For safety purposes, bi-weekly visits may continue at the PI’s discretion post Day 85 if 
necessary. On Day 169 bone marrow sampling is also required. Additionally, at the Day 169 visit a 
‘qualification’ assessment will be made to determine whether the patient is deriving clinical benefit 
and safely tolerating IMG-7289. For the patients who qualify for entry into the ATP, transition should 
occur without interruption in dosing. Patients not deriving clinical benefit will discontinue IMG-7289 
and undergo End of Treatment (EoT), pre-End of Study (pre-EoS) and End of Study (EoS) visits. 
5.1.2 Additional Treatment Period (ATP) for Qualifying Patients Only 
In the ATP, treatment may continue for an additional 169 days in those patients deriving clinical 
benefit, as determined by the Principal Investigator.   For the purposes of clarity and efficiency, rather 
than continuing to present chronological days/ weeks, visits are presented as ‘ATP Day 1’, followed 
by, ‘ATP Days 29, 57, 85’, etc.  Qualifying patients will ‘re-start’ IMG-7289 on ATP Day 1, with dose 
titration continuing as per the Titration Rules table (Section 7.2.3); there should be no interruption 
in dosing (Day 169 = Day 1 of the next ATP).  Additional dose-titration may occur in consultation with 
the Medical Monitor.  
Qualifying patients will return for study assessments monthly (ATP Days 1, 29, 57, 85, 113, 141 and 
169). It is anticipated that patients continuing in the ATP will have already achieved a stable dose, 
with every other week visits no longer necessary. For safety purposes, every other week visits may 
continue at the PI’s discretion, if necessary. On Day 169 of every other ATP (i.e., ATP 2, 4, etc.), the 
equivalent of yearly, patients will undergo bone marrow sampling. At the Day 169 visit, a 
‘qualification’ assessment will be made to determine whether the patient is continuing to derive 
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clinical benefit. Such patients thereby qualify for re-entry into the ATP, which is iterative; patients 
may continue to receive IMG-7289 for as long as they continue to qualify.  Patients not deriving 
clinical benefit will discontinue IMG-7289 and undergo EoT, pre-EoS and EoS visits.  
6 
STUDY POPULATION 
6.1 
Study Entry Criteria 
For purposes of eligibility, the following definitions apply: 
• 
A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche 
and until becoming post-menopausal unless permanently sterile. Permanent sterilisation 
methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.  
• 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a post-menopausal state in women not using hormonal 
contraception or hormonal replacement therapy. However, in the absence of 12 months of 
amenorrhoea, a single FSH measurement is insufficient.  
• 
A man is considered fertile after puberty unless permanently sterile by bilateral 
orchidectomy. 
• 
Abstinence is defined as refraining from heterosexual intercourse.  True abstinence, when this is 
in line with the preferred and usual lifestyle of the subject is permitted. Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the 
duration of exposure to IP, and withdrawal are not acceptable methods of contraception. 
6.1.1 Inclusion Criteria 
Patients must meet all of the applicable criteria to be eligible for enrollment in this study: 
1. Age ≥ 18 years. 
2. Diagnosis of Essential Thrombocythemia per World Health Organization (WHO) diagnostic 
criteria for myeloproliferative neoplasms (Arber et al., 2016). 
3. Patients who have failed at least one standard therapy (failure is the equivalent of inadequate 
response or intolerance).  European Leukemia Net (ELN) criteria for intolerance / resistance 
to hydroxyurea (Appendix 16.8) may be used in association with Investigator discretion.  
Ruxolitinib refractoriness or intolerance will be left to the discretion of the Investigator. 
4. Requires treatment in order to lower platelet counts based on patient age over 60 or history of 
thrombosis. 
5. Platelet count > 450 k/μL (450 x 109/L) pre-dose Day 1. 
6. Peripheral blast count < 1% pre-dose Day 1. 
7. ANC ≥ 0.5 x 109/L pre-dose Day 1. 
8. Fibrosis Score < grade 2, as per a slightly modified version (Arber et al., 2016) of the European 
Consensus Criteria for Grading Myelofibrosis (Thiele et al., 2005). 
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9. Life expectancy > 36 weeks. 
10. Able to swallow capsules. 
11. Amenable to bone marrow evaluations and peripheral blood sampling during the study. 
12. Must have discontinued ET therapy at least 1 week (4 weeks for interferon) prior to study drug 
initiation. 
13. Women of childbearing potential (WOCBP) and fertile men (see Section 6.1.) must agree to use 
an approved method of contraception from Screening until 14 days* after last IMG-7289 dose. 
Methods of contraception include: estrogen and progestogen combined hormonal 
contraception which inhibits ovulation; progestogen-only hormonal contraception associated 
with inhibition of ovulation; intrauterine device (IUD); bilateral tubal occlusion; vasectomized 
partner in a monogamous sexual relationship (vasectomy or tubal ligation at least six months 
prior to dosing); and, complete sexual abstinence (defined in Section 6.1). Males with a 
pregnant partner must agree to use a condom to avoid exposure to the developing child. 
Patients practicing abstinence must agree to use an approved method of contraception should 
they become sexually active during the study. 
*The risk of embryofetal toxicity is fully mitigated by 28 days which is >10 half-lives of the drug at the doses 
used in this study. 
6.1.2 Exclusion Criteria 
Patients will be excluded from the study if they meet any of the following criteria: 
1. Hemoglobin < 10 g/dL prior to dosing on Day 1. 
2. Transfusion dependency, defined as requiring 2 or more units of pack red blood cells per 
month for more than 3 months, or a hemoglobin level of ≤8g/dL in the preceding 8 weeks 
before the start of dosing.  
3. Eastern Cooperative Oncology Group (ECOG) questionnaire score of 3 or greater at Screening. 
4. History of splenectomy. 
5. Has undergone major surgery ≤4 weeks prior to starting study drug or has not recovered from 
side effects of such surgery. 
6. Unresolved treatment related toxicities from prior therapies (unless resolved to ≤ Grade 1). 
7. Uncontrolled active infection. 
8. Known positive for HIV if not well-controlled (i.e., undetectable viral load) or infectious 
hepatitis, type A, B or C. 
Note for Italy: Active infection with hepatitis A virus, B virus (positive hepatitis B surface antigen; 
note: positive hepatitis B surface antibody and positive hepatitis B core antibody are not 
exclusionary provided disease is not active, which should be clearly documented in the patient’s 
medical history) or C virus (patients with positive hepatitis C antibody result would require 
confirmation of active disease with a positive hepatitis C polymerase chain reaction (PCR) test), 
seropositivity for human immunodeficiency virus (HIV). 
9. Current use of monoamine oxidase A and B inhibitors (MAOIs). 
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10. Evidence at the time of screening of increased risk of bleeding, including any of the following: 
• 
Activated partial thromboplastin time (aPTT) > 1.3 x the upper limit of normal 
• 
International normalized ratio (INR) >1.3 x the local upper limit of normal 
• 
History of severe thrombocytopenia or platelet dysfunction unrelated to a 
myeloproliferative disorder or its treatment 
• 
Known bleeding disorder (e.g., dysfibrinogenaemia, factor IX deficiency, hemophilia, 
Von Willebrand’s disorder, Disseminated Intravascular Coagulation [DIC], fibrinogen 
deficiency, or other clotting factor deficiency). 
11. Evidence at the time of Screening of significant renal or hepatic insufficiency (unless due to 
hemolysis, or leukemic infiltration) as defined by any of the following local lab parameters: 
• 
Calculated glomerular filtration rate (GFR; using the Cockcroft-Gault equation) 
<40 mL/min or serum creatinine > 1.5 x the local upper limit of normal  
• 
Aspartate transaminase (AST) or alanine aminotransferase (ALT) ≥2 x the local upper 
limit of normal 
12. Current use of a prohibited medication (e.g., romiplostim) or expected to require any of these 
medications during treatment with the investigational drug. 
13. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically 
related to IMG-7289 or LSD1 inhibitors (i.e., monoamine oxidase inhibitors; MAOIs) that 
contraindicates their participation. 
14. History of any illness/impairment of gastrointestinal (GI) function that might interfere with drug 
absorption (e.g., chronic diarrhea), confound the study results or pose an additional risk to the 
patient by participation in the study; patients with gastric bypass surgery. 
15. Use of an investigational agent within less than 14 days, or the equivalent of at least  
7 half-lives of that agent, whichever is the longer, prior to the study Day 1. 
16. Females who are pregnant or breastfeeding or plan to become pregnant or breastfeed during the 
study. 
17. A concurrent second active and non-stable malignancy (patients with a concurrent second active 
but stable malignancy, such as non-melanoma skin cancers, are eligible). 
6.2 
Patient Enrollment 
A sufficient number of patients who fulfil the inclusion/exclusion criteria documented in Section 6.1 
will be screened to ensure approximately 60 patients are enrolled and treated in this study.    
6.3 
Patient Withdrawal 
In accordance with the Declaration of Helsinki, Good Clinical Practice (GCP), and International 
Council on Harmonization (ICH) Guidelines and applicable regulations governing human subject 
protection, a subject has the right to withdraw from the study at any time for any reason.  Subjects 
may also be removed from the study by the Sponsor or Investigator.   
 
  Patients will be requested to 
return for follow-up beginning with an End of Treatment visit as per Section 9.6.1. 
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The Sponsor or Investigator may remove patients from the study for various reasons, including:  
• 
Taking another investigational medicinal agent during their involvement in the study;  
• 
Use of a prohibited medication; 
• 
Major violation of, or deviation from, study protocol procedures which, in the judgment of the 
Medical Monitor, could adversely affect the patient or the integrity of the study including missing 
an extended duration of IMG-7289 doses or other evidence of major non-compliance;  
• 
Withdrawal from the study is, in the Investigator’s judgment, in the patient’s best interest; 
• 
Experiencing a Dose Limiting Toxicity (DLT), as per Section 8.2.2. 
6.5 
Guidelines 
Patient safety is paramount. The guidelines provided below are intended to provide some 
consistency across sites by providing guidance to be used by the Investigator, the study staff and the 
patient to safeguard patient safety while maintaining data integrity.  The guidelines are not intended 
to supersede best clinical judgment by the Investigator.  Please contact the Medical Monitor with 
questions or with planned/known divergences from these guidelines. 
1. In general, supportive care (transfusions, administration of anti-fungals, etc.) should be 
maintained in accordance with institutional policy. 
2. Patients taking medications with the potential to induce or inhibit CYP3A4 or CYP2D6 should be 
monitored closely for potential effects of co-administration; particular attention should be given 
to anti-infectives in the azole class. 
3. Cessation of IMG-7289 is invariably associated with a rebound in thrombopoiesis and platelet 
counts may easily exceed the baseline value. When IMG-7289 is discontinued, the platelet count 
should be monitored closely and an alternative cytoreductive therapy to lower platelets should 
commence within 24-48 hours. 
6.6 
Prohibited Medications 
Please consult the Medical Monitor with any questions pertaining to prohibited medications. 
1. All cytotoxic agents, including standard-of-care therapies for ET 
2. All hematopoietic growth factors: romiplostim, eltrombopag, granulocyte and granulocyte-
macrophage colony stimulating factor (G-CSF and GM-CSF) and erythropoietin (EPO) 
3. Monoamine oxidase A and B inhibitors  
4. Anticoagulant and nonsteroidal anti-inflammatory drug (NSAID; including aspirin) use are only 
prohibited in patients when their platelet count is < 50 k/μL (50 x 109/L) 
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7.2 
Dispensing, Administration, Dosage and Missed Doses 
7.2.1 Dispensing 
All material supplied is for use only in this clinical study and should not be used for any other purpose.  
Only patients enrolled in the study may receive study drug, in accordance with all applicable 
regulatory requirements. Only authorized site staff may dispense study drug. 
The Investigator is responsible for IMG-7289 accountability, reconciliation and record maintenance 
(Section 14.5).  
 
 
   
 
7.2.2 Administration 
Appropriately trained personnel of the study site will provide instruction pertaining to IMG-7289 
administration and supervise the administration of IMG-7289 on any day that it is taken in the clinic.  
With the exception of ITP Day 1, it is not required that IMG-7289 be taken in the clinic; this will be 
determined based on the patient’s regular daily dosing time.  When applicable, the date and time of 
each administration in the clinic will be recorded in the source notes. 
 
:  Initial Treatment Period 
In the ITP, all patients will be treated daily for 169 days.  Dosing will begin on Day 1 at the starting 
dose (Ds) of 0.6 mg/kg/d IMG-7289, free base, for all patients.  Details on the selection of and rationale 
for the starting dose and dosing schedule can be found in Section 3.6. 
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Through the use of dose titration, the dose of IMG-7289 will be adjusted for each patient to that dose 
that provides sufficient exposure to safely inhibit thrombopoiesis for a fraction of the dosing cycle 
(designated as the Dpi).  Dose-titration, both upward and downward, is contingent on the hematology 
assessment and comparison of hematology values from the prior visit.  Up-titrations may begin on 
ITP Day 28 and occur no more frequently than every 4 weeks from the previous up- or down-
titration.  Down-titrations can be made at any time in the best interest of the patient.   
 
 
   
 
 
 
 
   
 
  
 
 
Please consult the medical monitor regarding dose modifications of IMG-7289 should an adverse 
event (AE) requiring a dose reduction occur, and also for the management of clinically significant 
changes in platelets, neutrophil counts, or other hematologic parameters. 
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8.2 
Management of Study Toxicities 
Adverse event intensity will be evaluated using the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 5, published 27 November 2017. 
Dose-limiting toxicity and stopping rules are defined in Sections 8.2.2 and 8.2.3 below.  Expected  
IMG-7289 toxicities based on non-clinical and clinical studies are reported in the latest available 
edition of the Investigator’s Brochure.   
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8.2.2 Dose Limiting Toxicity (DLT) 
DLT is defined as any one of the following AEs that occurs through Day 8 of the ITP and is considered 
by the Investigator to be possibly, probably or definitely related to IMG-7289: 
• 
Any Grade 2 or above thrombocytopenia associated with clinically significant bleeding*  
• 
Any Grade 3 or above thrombocytopenia; 
• 
Any Grade 4 or 5 non-hematologic adverse event;  
• 
Any Grade 3 or above non-hematologic adverse event with failure to recover to Grade 2 within 7 
days of drug cessation, with the following exceptions: 
o nausea, vomiting or diarrhea that responds to standard medical care 
o aesthenia lasting less than 14 days 
• 
Any Grade 3 electrolyte abnormality unrelated to the underlying malignancy (for example, 
hyperkalemia is related to thrombocytosis and would therefore not qualify as DLT) and 
persisting greater than 24 hours.   
*Clinically significant bleeding is defined as an event that is life-threatening, cannot be controlled and/or 
results in hemodynamic instability. 
Patients who experience DLT will have their dose adjusted downward if the Medical Monitor and 
Principal Investigator deem it safe for the patient to continue on IMG-7289.  Any patient that 
experiences DLT that results in discontinuation of IMG-7289 therapy may begin alternative therapy 
within 24-48 hours of discontinuation if their physician deems this safe and appropriate regarding 
the resolution of the DLT. 
Please consult the Medical Monitor for IMG-7289 dose modifications for the management of clinically 
significant changes in platelets, neutrophil counts, or other hematologic parameters. 
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 Term 
Protocol Meaning 
Collect MPN-SAF 
 
MPN-SAF is to be completed by the patient in their native 
language and in the format provided.  The MPN-SAF will be 
completed during Screening (as close to Day -7 as possible), pre-
Dose Day 1 and weekly from Day 7 through the EoS Visit.  Ideally, 
the MPN-SAF will be completed at the same time and day each 
week for consistency.  On visit days, the MPN-SAF should be 
completed prior to the study visit, and if the patient arrives 
without a completed MPN-SAF, then it will be completed during 
the visit and collected prior to the patient departing.  Importantly, 
multiple MPN-SAF forms will need to be provided to the patient 
for completion between visits, during each ‘off week’.  Date of 
completion should be documented on each MPN-SAF completed.  
Full Local Lab Assessment 
Assessment consisting of the following test panels performed 
locally (see Section 10.1.1 for specific analytes required): 
• 
Hematology with automated differential 
• 
Biochemistry 
• 
Serum pregnancy test for women of child-bearing potential 
(WOCBP); results to be reviewed prior to dosing, if applicable 
Bone Marrow Sampling 
Dosing Instructions 
• 
Instruct patients to refer to their Dosing Card every day for 
details on IMG-7289 dosing and what to do if a dose is missed  
• 
Take their IMG-7289 in accordance with Section 7.2.2 
• 
Handle any missed IMG-7289 doses as per Section 7.2.5 
• 
Bring all medication to every clinic visit, including empty 
bottles 
Administer  
IMG-7289 
Administer IMG-7289 with a glass of water, instruct patient to 
continue to fast for at least 30 minutes, and, if dosed in clinic, 
record the exact time of dosing. 
Adverse Events and Concomitant 
Medications 
Use non-directive questions (i.e., “How are you feeling”) to query 
patient re: any AEs that may have occurred.  Also, inquire about 
medication changes since the last visit. 
 Note:  If at any time additional clinical evaluation outside of the visit schedule is deemed necessary 
by the Investigator, then unscheduled visits should occur as appropriate. 
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9.1 
Informed Consent  
Patients must provide written informed consent before undergoing any study-related procedures.  
The Principal Investigator (PI), or designee, will explain to the patient the aims of the study, the risks 
and benefits involved and that their participation is voluntary.  Each patient will acknowledge receipt 
of this information and that they wish to participate in the study by giving written informed consent 
for their involvement in the study in the presence of the PI, or designee, who will also sign and date 
the Participant Information Sheet/Consent Form (PISCF). Time, date, name of the person taking 
consent and any questions raised by the patient must be documented in the source data. 
9.2 
Screening Period, Including Enrollment 
The Screening period is comprised of a Screening visit at which all assessments may be performed 
on the same day or multiple days, as needed, throughout the 28 day screening period.  If the patient 
screen fails, document the reason(s) in the source data and on the Screening & Enrollment log. 
Note for UK: AEs will be assessed at every visit.  Non-serious events occurring pre-first IMG-7289 
dose will be recorded as Medical History; those occurring post first IMG-7289 dose through the EoS 
visit will be recorded as AEs.  Serious AEs (SAEs) will be recorded from time of consent through the 
EoS or until the Investigator and Imago determine that follow-up is no longer necessary. 
9.2.1 Screening (Days -28 to Day -1) 
• 
Review of all Inclusion and Exclusion Criteria 
• 
Complete medical/medication history including: 
o 2016 WHO criteria for ET (Appendix 16.2).  
o Disease history (i.e., past bleeding episodes and thromboembolic events)  
o History of all treatments for their current disease (including clinical course with 
hydroxyurea and/or other ET therapy) or any previous oncologic conditions; including 
chemical, surgical and/or radiotherapeutic  
o All concomitant medication, in addition to any used in the 15 days prior to Screening 
• 
Calculate ECOG Performance Status (Appendix 16.4) 
• 
MPN-SAF, to be completed as close to Day -7 as possible.  Additionally, provide patient with copy 
of the MPN-SAF for completion prior to dosing on Day 1.  (Appendix 16.6) 
• 
Full PE, including Vital Signs – review of all body systems as indicated by signs/symptoms  
• 
Height (without shoes) 
• 
Full Local Laboratory Assessment 
• 
Coagulation 
• 
Urinalysis  
• 
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9.2.2 Enrollment 
For eligibility purposes, the following should be reviewed and/or confirmed: 
• 
History of recent surgical procedures  
• 
Recent use of investigational drugs 
• 
Laboratory results, including historical laboratory values, will be assessed by the Principal 
Investigator (PI) before enrollment.  Any deviation in laboratory values that are confirmed on  
re-examination to be clinically significant by the PI and that would jeopardize the safety of the 
patient or impact on the validity of the study results will result in exclusion of that patient. 
Once Screening procedures have been performed and it is confirmed that the patient can be enrolled, 
patients will be enrolled in accordance with procedures detailed in the Study Reference Manual.   
If the patient screen fails during this time, document the reason(s) in the patient’s source data and 
on the Screening & Enrollment log. 
9.2.3 Last Day of Screening Period (Day -1)  
On Day -1, contact the patient and remind them to: 
• 
Report to the clinic the following day at the agreed time 
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9.4 
Additional Treatment Period (ATP) 
Those patients deriving clinical benefit and safely tolerating IMG-7289; this definition applies 
throughout the document and will not be repeated with each reference to clinical benefit) that enter 
the Additional Treatment Period will ‘re-start’ IMG-7289.  For the purposes of clarity and efficiency, 
rather than continuing to present chronological days/weeks, visits are presented as ‘ATP Day 1’, 
followed by, ‘ATP Days 29, 57, 85,’ etc.   
The visits and procedures contained herein may repeat as long as the patient continues to qualify for 
additional treatment.  Continued treatment in the ATP should occur without interruption in dosing; 
Day 1 assessments may be performed on the same day as Day 169 of the prior treatment period. 
Procedures are presented below for each visit by assessments performed pre-dose, at dosing, and 
post-dose (as applicable). 
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Screening assessments and each study visit up to and including the EoS visit.  Not included, however, 
   
    
 
 
 
 
 
 the particular 
analyte will only be analysed if the test is available at the particular institution.   
10.1.1 Local Laboratory Measures 
Biochemistry: Serum creatinine, uric acid, urea* or blood urea nitrogen (BUN)*, albumin, total 
bilirubin, gamma glutamyltransferase (GGT), alkaline phosphatase (ALP), alanine aminotransferase 
(ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), C-reactive protein (CRP) and 
serum ferritin.     
Hematology: Hemoglobin, red blood cell count (RBC) (including nucleated RBC), hematocrit, 
platelets, white cell count and automated assessment of neutrophils, lymphocytes, monocytes, 
reticulocytes and blasts.   
Coagulation: Prothrombin time (PT)*, activated partial thromboplastin time (aPTT) and 
International normalized ratio (INR). 
Serum Pregnancy Test: For WOCBP, a serum pregnancy test will be utilized according to institution 
standard procedure.   The result must be confirmed prior to next scheduled dose of IMG-7289.   
Urinalysis: Leucocyte esterase, nitrites, urobilinogen, protein, pH, blood, specific gravity, ketones, 
bilirubin and glucose. 
Additional Tests for Italy:  HIV test, HAV, HBsAg, HBsAb, HBcAb, HCV 
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10.1.2 Central Laboratory Measures 
11 SAFETY 
The Investigator is responsible for monitoring the safety of patients enrolled in this study.   
Once an Investigator determines a patient is a treatment failure (see Section 6.8) or if the patient is 
withdrawn from treatment early due to a Dose Limiting Toxicity, the patient should discontinue 
study treatment and undergo follow-up period visits beginning with EoT (see Section 9.6.1).   
11.1 Pregnancy  
It is not known whether IMG-7289 can affect reproductive capacity, and the direct effects of IMG-
7289 and the indirect effects of prior IMG-7289 exposure on fetal development are also unknown. 
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Every effort should be made to prevent pregnancy throughout the entire duration of participation in 
this study.  All patients of reproductive potential involved in the study are required to use effective 
methods of contraception during the study and for 14 days after the last IMG-7289 dose.  Female 
patients will be instructed to notify the Investigator immediately if they become pregnant; male 
patients will be instructed to notify the Investigator immediately if they discover that their sexual 
partner is pregnant.  Pregnancy data during the study will be reported in an expedited manner using 
the Pregnancy Report Form and following the SAE reporting process (see Section 11.2.4).  It will be 
necessary to collect detailed information on the course of any pregnancy occurring in a patient on 
study, including pregnancies in the partners of male patients, assuming consent to do so is provided.  
If the outcome and/or a complication of the pregnancy meets serious criteria (i.e., miscarriage or 
congenital anomaly/birth defect), then it should be reported as an SAE using the SAE Report Form. 
Pregnant patients will discontinue study medication for the duration of the pregnancy.  The 
pregnancy will be followed by the Investigator and the outcome of the pregnancy will be reported to 
the Pharmacovigilance group as per the Study Reference Manual (SRM).   
All patients will be encouraged to discuss contraception and pregnancy concerns with their physician 
in advance of becoming pregnant.  Full disclosure of a patient’s participation in this study to their 
general practitioner is strongly recommended. 
11.2 Adverse Events  
The Investigator is responsible for monitoring the safety of patients who have enrolled in the study 
and for accurately documenting and reporting information as described in this section. Patients will 
be instructed to report to the Investigator any AE that they experience.  Investigators will ask about 
the occurrence of AEs at each visit.  Investigators are required to document all AEs occurring during 
the clinical study, commencing with the first dose of IMG-7289 through to the End of Study Visit 
(scheduled at 14 days post last IMG-7289 dose).  Adverse event recording will continue for patients 
who discontinue study treatment early but remain in follow-up, until their End of Treatment, Pre-
End of Study and End of Study Visits have been completed. 
Note: Any medical event which occurs from the time of Informed Consent but prior to dosing with 
IMG-7289 must still be documented in the patient’s medical notes and will be recorded on the 
appropriate medical history eCRF pages.  In the UK only, serious AEs (SAEs) will be recorded from 
time of consent. 
Adverse events will be recorded on designated eCRF pages. Each AE is to be characterised (i.e., 
verbatim term) and information provided regarding its seriousness, start and stop dates, intensity, 
outcome, and causal relationship with the study drug.  
An AE is any undesirable physical, psychological or behavioral effect experienced by a patient during 
participation in an investigational study, in conjunction with the use of the drug or biologic, whether 
or not product-related.  This includes any untoward signs or symptoms experienced by the patient 
from the time of first dose with IMG-7289 until completion of the study. 
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Adverse events may include, but are not limited to: 
• 
Subjective or objective symptoms spontaneously offered by the patient and/or 
observed by the Investigator or medical staff 
• 
Findings at physical examinations 
• 
Laboratory abnormalities of clinical significance 
It is important Investigators record accurate AE terms in the eCRFs.  Wherever possible, a specific 
disease or syndrome rather than individual associated signs, symptoms or laboratory parameter will 
be identified by the Investigator and recorded in the eCRF.  However, if an observed or reported sign, 
symptom or laboratory parameter is not considered a component of a specific disease or syndrome 
by the Investigator, or is atypical, it should be recorded as a separate AE in the eCRF. 
Disease signs, symptoms, and/or laboratory abnormalities already existing prior to the use of the 
investigational product are not considered AEs after treatment unless they reoccur after the patient 
has recovered from the preexisting condition or in the opinion of the Investigator they represent a 
clinically significant exacerbation in intensity or frequency.   
Clinical significance is defined as any variation in signs, symptoms, or testing that has medical 
relevance and may result in an alteration in medical care.  The Investigator will continue to monitor 
the patient until the assessment returns to Baseline or until the Investigator determines that follow-
up is no longer medically necessary. 
11.2.1 Adverse Event Intensity 
Adverse event intensity will be evaluated using the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 5, published 27 November 2017. For AEs 
not included in the NCI CTCAE, the Investigator will be required to assess the intensity of the adverse 
drug/biologic experience using the following categories and associated guidelines:   
Grade Guideline 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL* 
3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL** 
4 
Life-threatening consequences; urgent intervention indicated 
5 
Death related to AE 
Note 1: A semi-colon indicates ‘or’ within the description of the grade. 
Note 2: Activities of Daily Living (ADL)  
*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. 
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11.2.2 Adverse Event Relatedness 
The Investigator will make a judgment regarding whether or not, in his/her opinion, the AE was 
related to study drug.  The Investigator will also evaluate any changes in laboratory values, make a 
determination as to whether the change is clinically significant, and whether or not the change(s) 
were related to study drug.  However, even if the Investigator feels there is no relationship to the 
study drug, the AE or clinically significant laboratory abnormality MUST be recorded in the eCRF.  
Below are guidelines for relationship assessment: 
• 
Unrelated: There was no relationship of the adverse event to the use of the drug or 
biologic. This may include, but is not limited, to the adverse experience being an expected 
outcome of a previously existing or concurrent disease, concomitant medication or 
procedure the subject experienced during their treatment period.  
• 
Remote/Unlikely: Adverse events which are judged probably not related to the drug or 
biologic.  
• 
Possible: There was no clear relationship of the adverse event to the use of the drug or 
biologic; however, one cannot definitively conclude that there was no relationship. 
• 
Probable: While a clear relationship to the drug or biologic cannot be established, the 
event is associated with an expected adverse event (per the current Investigator 
Brochure or SAB findings) or there is no other medical condition or intervention which 
would explain the occurrence of such an experience.  
• 
Definite: The relationship of the use of the drug or biologic to the experience is considered 
definitively established. 
If a causal relationship is considered probable, possible, or definite by the Investigator or Sponsor 
(dependent on the regional reporting requirements), the AE is considered to be “related” for 
purposes of regulatory reporting. If a causal relationship is considered remote/unlikely or unrelated, 
the AE is considered “unrelated” for purposes of regulatory reporting.   
11.2.3 Serious Adverse Events 
Serious adverse events will be reportable from the time of first dose (time of consent for UK patients) 
through the End of Study Visit (scheduled for approximately 14 days post last IMG-7289 dose) or 
until the Investigator and Imago BioSciences determine that follow-up is no longer necessary.  
Serious adverse events that are suspected to be drug related will be reported even if they occur when 
the patient is no longer on the study.   
An SAE is any AE that results in any of the following outcomes: 
Death 
Life-threatening experience. Any adverse event that places the patient, in the view of the reporter, 
at immediate risk of death from the adverse event as it occurred, i.e., does not include an adverse 
event that had it occurred in a more severe form, might have caused death. 
Required or prolonged inpatient hospitalization¥. The adverse event resulted in an initial 
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inpatient hospitalization or prolonged an existing hospitalization of the patient. If a patient is 
hospitalized as part of the clinical use of the product, a period of normal hospitalization will be 
outlined in the protocol or by the judgment of the Investigator. Hospitalizations longer than this 
period will be prolonged hospitalizations. 
Persistent or significant disability/incapacity. An adverse event that resulted in a substantial 
disruption of a person’s ability to conduct normal life functions. 
Congenital Anomaly. The exposure of the patient to the drug or biologic during pregnancy that is 
judged to have resulted in the congenital anomaly/birth defect. 
Important medical events. Adverse events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse event when, based upon appropriate 
medical judgment, may jeopardise the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. Important medical events or interventions 
may be considered an SAE based upon medical judgment of the Investigator.   
11.2.4 Reporting Serious Adverse Events  
SAEs will be reported promptly, using the SAE Report Form, once the Investigator determines that 
the event meets the protocol definition of an SAE.  The Investigator or designee will report the SAE 
within 24 hours of his/her becoming aware of these events regardless of relationship of the 
SAE to the use of study drug, in accordance with the instructions in the Study Reference Manual. 
The Investigator will always provide an assessment of relatedness at the time of the initial report as 
described in Section 11.2.2.  The SAE Report will always be completed as thoroughly as possible with 
all available details of the event within the designated time frames. Copies of relevant patient records, 
autopsy reports, and other documents may be requested.   
If the Investigator does not have all information regarding an SAE, he/she will not wait to receive 
additional information before reporting the SAE. The SAE Report will be updated when additional 
information is received within 24 hours of receipt of such information. 
Important:  For fatal and life-threatening events, the Sponsor’s Medical Monitor should be contacted 
immediately.  A death occurring during the study or information related to such occurrence that 
comes to the attention of the Investigator during the study must be reported immediately to the 
Sponsor.  A detailed SAE reporting procedure and contact information will be included in the Study 
Reference Manual (SRM) and provided to the site before any patients are consented. 
Additionally, the Institutional Review Board (IRB), Independent Ethics Committee (IEC) and Human 
Research Ethics Committee (HREC), as applicable, must be notified in writing of any SAEs that require 
expedited reporting to Regulatory Authorities.  Depending upon regional requirements, it is the 
responsibility of either the Investigator or Imago BioSciences to notify the IRB/IEC/HREC.  All SAEs 
meeting expedited reporting requirements will be reported to appropriate regulatory agencies by 
Imago BioSciences or their designee as soon as possible and within the timeframes specified in the 
various regions in which the study is to be conducted.  
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12 ANALYSIS AND STATISTICAL CONSIDERATIONS 
12.1 General Considerations 
Detailed methodology for summary and statistical analyses of the data collected in this trial will be 
documented in a Statistical Analysis Plan (SAP).  This document may modify the plans outlined in the 
protocol; however, any major modifications of the primary endpoints definition and/or its analysis 
will also be reflected in a protocol amendment.  Additional statistical analyses other than those 
described in this section may be performed if deemed appropriate and included in the SAP. 
12.2 Power 
This study is designed to make an assessment of the safety, tolerability, and efficacy of IMG-7289 for 
the treatment of essential thrombocythemia.  This is a single-arm trial with a primary endpoint that 
is a proportion variable (The proportion of subjects who achieve success defined as a reduction of 
platelet counts to ≤400k/μL (400 x 109/L) in the absence of new thromboembolic events). The test 
of significance is a one-sided test at the alpha=0.025 level of significance (equivalent to a two-sided 
test at the alpha=0.05 level of significance).  
 
 
 
  
 
 
  
 
 
 
 
 
 
  
with a sample size of 21 subjects, there is an 80% probability that the study will be successful (where 
“success” is defined as rejecting the null hypothesis that the true rate is as low as 5%).  If the sample 
size is increased to 30 subjects, the probability of study success is 90%.  The primary objective of this 
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12.3 Treatment Assignment and Blinding 
This is an open-label study.  The Investigators, other hospital personnel, patients and Sponsor will 
know the identity of the treatment.   
Effort will be made, as appropriate, to maintain continuity of study staff who administer/evaluate 
various assessments at each site 
 
 
12.4 Study Endpoints 
12.4.1 Primary Endpoints 
• 
The safety and tolerability of IMG-7289 will be assessed by the analysis of adverse events (AEs), 
as well as changes in physical examinations, vital signs and laboratory values as detailed below.  
o Monitoring of Adverse Events (AEs) including determination of thromboembolic events, 
dose limiting toxicities (DLTs), serious adverse events (SAEs), and AEs.  AEs will be 
assessed 
 
 
, using the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.   
o Changes in physical examinations, vital signs and laboratory values will also be evaluated 
• 
The reduction of platelet counts will be evaluated and assessed based on local laboratory 
measurements of platelet counts from Day 1 to each visit where platelets are measured.  
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Demographics will be tabulated and summarized. Medical and surgical history data at Screening will 
be listed, as will Physical Examination data 
 at Screening, and at 
subsequent visits.  All characteristics at baseline 
 
 
will be tabulated and summarized. 
All patients receiving at least one dose of IMG-7289 will be included in the safety analysis.   
Laboratory values outside the laboratory normal ranges will be summarized and assessed
 
   
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Treatment-emergent adverse events will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) and summarized 
 
 
  
Concomitant medications will be listed by patient and coded using the WHO drug dictionary.  Medical 
history will be listed by patient. 
Descriptive statistics 
 
 will be calculated for quantitative safety data 
as well as for the differences to baseline, when appropriate.  
 
 
 
 
12.6 Pharmacodynamic Data  
The primary efficacy objective for this study is to evaluate the reduction of platelet counts to  
≤ 400 k/μL (400 x 109/L) in the absence of new thromboembolic events.  The primary efficacy 
endpoint is the proportion of patients who achieve a reduction of platelet counts to ≤ 400 k/μL  
(400 x 109/L) in the absence of new thromboembolic events, which will be analyzed using an exact 
one-sample binomial test. 
 
The proportions and corresponding 95% confidence intervals (CIs), 
, will be summarized and presented for each post baseline study visit. 
 
 Two-sided p-values will 
be calculated for Day 169 visit to test the null hypothesis, assuming the test statistic follows an exact 
binomial distribution.  
 
 
The durability of platelet count reduction is an exploratory efficacy objective.  
 
  The proportion 
of subjects who achieved a durable response will be summarized by treatment period. 
 
 
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13 STUDY ADMINISTRATION 
The names, titles, and addresses of the Investigators and study personnel are available from Imago 
BioSciences. 
13.1 Ethical Considerations 
This research will be carried out in accordance with the protocol, US Code of Federal Regulations, 
GCP, 21 CFR Parts 50, 56, and 312, the ethical principles set forth in the Declaration of Helsinki, and 
the ICH harmonized tripartite guideline regarding GCP (E6 Consolidated Guidance, April 1996). 
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13.3 Institutional Review Board (IRB), Independent Ethics Committee (IEC) and Human 
Research Ethics Committee (HREC) 
This protocol, the PISCF, relevant supporting information and all types of patient recruitment or 
advertisement information must be submitted to IRB/IEC/HREC for review and must be approved 
before the study is initiated.  Any amendments to the protocol must also be approved, where 
necessary, by the IRB/IEC/HREC prior to implementing changes in the study. 
The Investigator is responsible for keeping the IRB/IEC/HREC apprised of the progress of the study 
and of any changes made to the protocol as deemed appropriate, but in any case, at least once a year.  
The Investigator must also keep the IRB/IEC/HREC informed of any AEs, according to the 
IRB/IEC/HREC policy. 
13.4 Study or Site Termination 
The End-of-Trial date is considered to be the date of Database Lock.  
If Sponsor, an Investigator, or regulatory authorities discover conditions during the study that 
indicate that the study or related activities at a particular site should be terminated, this action may 
be taken after appropriate consultation between Sponsor and the Investigator.  Conditions that may 
warrant study or site termination include but are not limited to: 
1. The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients 
2. Patient recruitment is unsatisfactory 
3. Data recording is inaccurate or incomplete 
4. Investigator(s) do not adhere to the protocol or applicable regulatory guidelines in 
conducting the study 
5. GCP is not being maintained or adequately followed 
6. Administrative reasons 
7. Reasons unrelated to the study. 
Study or site termination and follow-up will be performed in compliance with the conditions set forth 
in 21 Code of Federal Regulations (CFR) Section 312 and/or other national and local regulations, as 
applicable, and in compliance with the principles set forth in International Council on Harmonisation 
(ICH) Good Clinical Practices (GCPs), including ICH E6, and ethical principles established by the 
Declaration of Helsinki. 
13.5 Study Monitoring Requirements 
Monitoring and auditing procedures developed by Imago BioSciences will be followed in order to 
comply with ICH Good Clinical Practice (GCP) guidelines.  On-site checking of the eCRFs for 
completeness and clarity, cross checking with source documents, and clarification of administrative 
matters will be performed, when possible.  Additionally, off-site or ‘remote’ monitoring visits may be 
conducted as needed.  Remote monitoring may consist of centralized monitoring or remote data 
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review. Centralized monitoring is the remote, cross-functional review and evaluation of 
accumulating in-house data conducted by data managers, central monitor associates, medical 
directors, the clinical team, and biostatisticians. The review of data within and across sites 
proactively identifies missing or inconsistent data, data trends, systematic or significant errors and 
enables site performance characteristics to be analyzed. Remote data review is intended to 
encompass as many activities performed in a routine on-site monitoring visit as is functionally 
possible, and as permitted by site policy and procedure.  The remote review of data may be actioned 
via multiple pathways, often contingent on site’s capabilities.  Remote data review, specifically, has 
become critically important in the COVID-19 environment as a measure of safeguarding patient 
safety, while also minimizing risks to trial data integrity and facilitating GCP compliance.  Note: 
Remove data review will only be implemented in Germany in times of increased safety measures such 
as the COVID-19 pandemic and only in special cases.  Please see Section 16.9 for additional 
information pertaining to remote data review.  
Monitoring visits will consist of site qualification visits, periodic visits during the study period, and 
site close-out visits.   
The Investigator will permit authorised representatives of Imago BioSciences and the respective 
national or local authorities to inspect facilities and records relevant to this study. 
Imago BioSciences or its designee will monitor the study.  Monitoring will be done by visits from 
representatives of Imago BioSciences (monitors) who will review the eCRFs and source documents.  
The monitors will ensure that the investigation is conducted according to protocol design and 
regulatory requirements by frequent communications (letter, email, telephone, and fax). The 
monitor/representative of Imago will perform an Investigator Site File review to confirm all 
documents required to reconstruct the conduct of the clinical trial are present.  The ISF supports the 
validity of the research, as well as the conduct and integrity of the data collected, and needs to be 
maintained by the Investigator (or designee) and inspection ready at all times.  
All unused study materials are to be returned to Imago BioSciences or its designee after the clinical 
period of the trial has been completed, or be disposed of at the site according to institutional policies 
but not prior to the approval of the Sponsor and with appropriate documentation.   
13.6 Quality Assurance 
The study will be initiated and conducted under the sponsorship of Imago BioSciences.  IMG-7289 
and clinical supplies will be supplied by Imago BioSciences.  Representatives of Imago BioSciences 
will monitor the study to verify study data, medical records, worksheets, and eCRFs are in accordance 
with current International Council on Harmonisation (ICH) GCPs and the respective local and 
national government regulations and guidelines. 
The Investigator will contact the Sponsor immediately if contacted by a regulatory agency about an 
inspection at his or her center. The purpose of Sponsor audit or inspection is to systematically and 
independently examine all study-related activities and documents to determine whether these 
activities were conducted, and data were recorded, analyzed, and accurately reported according to 
the protocol, ICH/GCP guidelines, and any applicable regulatory requirements. 
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13.7 Confidentiality 
The information obtained during the conduct of this clinical study is confidential, and disclosure to 
third parties other than those noted below is prohibited. 
The patient’s identifying information will not leave the clinical site at which they are recruited.  The 
patient will be identified on all study documentation using a code number and their initials (where it 
is lawful to collect such information). 
Information obtained during the conduct of this study will be collected, processed, and transmitted 
to or for the benefit of Imago BioSciences in accordance with the applicable regulations and 
principles of confidentiality for each participating country.  Information contained therein will be 
maintained in accordance with applicable law protecting patient privacy, including the provisions of 
46 CFR Part 164 promulgated under the Health Insurance Portability and Accountability Act (HIPAA) 
and may be inspected by the clinical researcher, the researcher’s staff, Sponsor and its 
representatives, partners, advisors, affiliates, successors, and clinical research contractors and 
subcontractors to check, process, evaluate, and use the information collected during the study.  The 
patient PISCF (or a separate data protection consent form if required locally) will be used to obtain 
participant consent to authorise transfer and processing of data consistent with applicable law.  
Processing, evaluation, or use of the information will be performed by a health professional for 
medical purposes and/or by those operating under a duty of confidentiality that is equivalent to that 
of a health professional.  Information obtained from the study will likely be used by Imago 
BioSciences or its affiliates or successors in connection with the development of study drug, including 
possible filing of applications with governmental authorities for marketing approval, and for other 
pharmaceutical and medical research purposes.  The study Investigator is obliged to provide Sponsor 
with complete test results and all data developed in this study.  This information may be disclosed to 
other physicians who are conducting similar studies and to the applicable regulatory authorities as 
deemed necessary by Imago BioSciences.  Patient-specific information may be provided to other 
appropriate medical personnel only with the patient’s permission, as necessary and in accordance 
with other applicable privacy laws and regulations protecting patient health information.   
To ensure compliance with the ICH GCP guidelines, data generated by this study must be available 
for inspection upon request by representatives of the appropriate national and local authorities, 
Imago BioSciences, and the IRB/IEC/HREC for each study site. 
The raw dataset will be available to Imago BioSciences on completion of the study.  Imago BioSciences 
will actively pursue publication of the results of the study in cooperation with the Lead Investigators 
subject to the terms and conditions of the clinical trial agreement between Imago BioSciences and 
Investigators.  The Lead/Coordinating Investigator will have the right to submit for publication any 
results arising from the study subject to the terms and conditions of the Clinical Trial and 
Confidentiality Disclosure Agreements.  The Lead/Coordinating Investigator, with the agreement of 
Imago BioSciences, will coordinate the principal publication of the data arising from the study.  
Patient names and other personal data relating to an identified or identifiable patient (such as 
photographs, audio, videotapes, or other factors specific to physical, physiological, mental, economic, 
cultural, or social identity), may not be disclosed in any publication without prior written 
authorisation, in compliance with patient privacy law, from Imago BioSciences and the patient. 
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14 INVESTIGATOR REQUIREMENTS 
14.1 Protocol Adherence 
Each Investigator must adhere to the protocol as detailed in this document and agrees that any 
changes to the protocol must be approved by Imago BioSciences’s authorised representative in 
writing prior to seeking approval, where necessary, from the IRB/IEC/HREC.  Each Investigator will 
be responsible for allowing only those patients who have met all protocol eligibility criteria to be 
enrolled.   
Modifications to the protocol should not be made without agreement of the Investigators and Imago 
BioSciences.  Changes to the protocol will require written IRB/IEC/HREC approval / favorable 
opinion prior to implementation, except when the modification is needed to eliminate an immediate 
hazard(s) to patients.  The IRB/IEC/HREC may provide expedited review and approval/favorable 
opinion for minor change(s) in ongoing trials that have the approval/favorable opinion of the 
IRB/IEC/HREC.  The Investigator will submit all protocol modifications to the IRB/IEC/HREC in 
accordance with the governing regulations. 
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
patients, the Investigator will contact Sponsor, if circumstances permit, to discuss the planned course 
of action.  Any departures from the protocol must be fully documented in the eCRF and source 
documentation. 
14.2 Source Documentation 
The Investigator must maintain detailed records of all study participants who are enrolled in the 
study or who undergo screening. Source documents include patient medical records and 
Investigator’s patient study files, as well as all test results.  Information required for study purposes 
and any data recorded in the eCRF must be supported by appropriate source documentation. 
14.3 Direct Access to Source Documentation 
The Investigator will ensure that the Sponsor, IRB/IEC/HREC and regulatory authorities will have 
direct access to all trial-related sites, source data/documents, and reports for the purpose of 
monitoring and auditing (ICH[E6] 5.1.2 & 6.10).  This includes electronic source data.   
14.4 Case Report Forms 
Case report forms (or an electronic data capture system) will be provided to each investigational site 
for the collection of all study data for enrolled patients, with the exception of data that may be 
captured externally to the site (i.e., central laboratory data).  Study site personnel will record the data 
in the source documentation and enter it in the eCRF within, on average, 5 business days of the study 
visit, while carefully reviewing all information recorded for accuracy and consistency.  Any required 
data printouts should be filed in the patient’s source data, i.e., laboratory reports, etc. and 
signed/dated by appropriately designated site personnel as a true copy of the original. 
A clinical study monitor will review the eCRFs and compare the content to the source data. 
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The eCRFs for each patient must be reviewed and signed by the Investigator.  This should be done as 
soon as possible after the patient has completed the study and all data queries have been resolved.   
14.7 Training of Staff 
The PI is responsible for the conduct of the study at this study site, including delegation of specified 
study responsibilities, and training of study staff.  The PI shall ensure that the study is carried out in 
accordance with the protocol, ICH/GCP guidelines, and regulations. 
The PI will maintain a record of all individuals involved in the study (medical, nursing and other 
staff).  He or she will ensure that appropriate training relevant to the study is given to all of these 
staff, and that any new information of relevance to the performance of this study is forwarded to the 
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staff involved. 
14.8 Clinical Study Report 
The Coordinating or Lead Investigator will be designated to sign any interim clinical study reports 
and the final clinical study report at the end of this study.  The signatory Lead Investigator will be 
identified by the Sponsor in advance of study completion. 
14.9 Retention of Records 
Records and documents pertaining to the conduct of this study, including eCRFs, source documents, 
consent forms, laboratory test results, medication inventory records and Investigator Site File, must 
be retained by the Investigator in accordance with locally applicable regulatory requirements, and in 
any event for a period of at least 2 years after the last approval of a marketing application in an ICH 
region and until there are no pending or contemplated marketing applications in an ICH region or at 
least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product.  No study records shall be destroyed without notifying Sponsor and giving 
Sponsor the opportunity to take such study records or authorizing in writing the destruction of 
records after the required retention period. 
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Shi, Y., Lan, F., Matson, C., Mulligan, P., Whetstine, J.R., Cole, P.A., Casero, R.A., Shi, Y., 2004. Histone 
demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941-953. 
Shi, Y.J., Matson, C., Lan, F., Iwase, S., Baba, T., Shi, Y., 2005. Regulation of LSD1 histone demethylase 
activity by its associated factors. Mol Cell 19, 857-864. 
Somervaille, T.C., Cleary, M.L., 2006. Identification and characterization of leukemia stem cells in 
murine MLL-AF9 acute myeloid leukemia. Cancer Cell 10, 257-268. 
Somervaille, T.C., Matheny, C.J., Spencer, G.J., Iwasaki, M., Rinn, J.L., Witten, D.M., Chang, H.Y., Shurtleff, 
S.A., Downing, J.R., Cleary, M.L., 2009. Hierarchical maintenance of MLL myeloid leukemia 
stem cells employs a transcriptional program shared with embryonic rather than adult stem 
cells. Cell Stem Cell 4, 129-140. 
Spivak 2017 Myeloproliferative Neoplasms New Engl J Med 376(22), 2168-2181.  
Sprussel, A., Schulte, J.H., Weber, S., Necke, M., Handschke, K., Thor, T., Pajtler, K.W., Schramm, A., 
Konig, K., Diehl, L., Mestdagh, P., Vandesompele, J., Speleman, F., Jastrow, H., Heukamp, L.C., 
Schule, R., Duhrsen, U., Buettner, R., Eggert, A., Gothert, J.R., 2012. Lysine-specific demethylase 
1 restricts hematopoietic progenitor proliferation and is essential for terminal 
differentiation. Leukemia 26, 2039-2051. 
Thiele, J., Kvasnicka, H.M., Facchetti, F., Franco, V., van der Walt, J., Orazi, A. 2005. European consensus 
on grading bone marrow fibrosis and assessment of cellularity Haematologica 90(8), 1128-
1132 
Vannucchi, A.M., Guglielmelli, P., What are the current treatment approaches for patients with 
polycythemia vera and essential thrombocythemia? Hematology Am Soc Hemtol Educ 
Program, 2017. 17(1): p. 480-488. 
Wang, J., Hevi, S., Kurash, J.K., Lei, H., Gay, F., Bajko, J., Su, H., Sun, W., Chang, H., Xu, G., Gaudet, F., Li, 
E., Chen, T., 2009. The lysine demethylase LSD1 (KDM1) is required for maintenance of global 
DNA methylation. Nat Genet 41, 125-129. 
Wang, J., Scully, K., Zhu, X., Cai, L., Zhang, J., Prefontaine, G.G., Krones, A., Ohgi, K.A., Zhu, P., Garcia-
Bassets, I., Liu, F., Taylor, H., Lozach, J., Jayes, F.L., Korach, K.S., Glass, C.K., Fu, X.D., Rosenfeld, 
M.G., 2007. Opposing LSD1 complexes function in developmental gene activation and 
repression programmes. Nature 446, 882-887. 
Whyte, W.A., Bilodeau, S., Orlando, D.A., Hoke, H.A., Frampton, G.M., Foster, C.T., Cowley, S.M., Young, 
R.A., 2012. Enhancer decommissioning by LSD1 during embryonic stem cell differentiation. 
Nature 482, 221-225. 
Whyte, W.A., Orlando, D.A., Hnisz, D., Abraham, B.J., Lin, C.Y., Kagey, M.H., Rahl, P.B., Lee, T.I., Young, 
R.A., 2013. Master transcription factors and mediator establish super-enhancers at key cell 
identity genes. Cell 153, 307-319. 
Wouters, B.J., Lowenberg, B., Erpelinck-Verschueren, C.A., van Putten, W.L., Valk, P.J., Delwel, R., 2009. 
Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute 
myeloid leukemia with a distinctive gene expression profile that is uniquely associated with 
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a favorable outcome. Blood 113, 3088-3091. 
Yang. J., Huang, J., Dasgupta, M., Sears, N., Miyagi, M., Wang, B., Chance, M.R., Chen, X., Du, Y., Wang, Y., 
An, L., Wang, Q., Lu, T., Zhang, X., Wang, Z., Stark, G.R. 2010 Reversible methylation of 
promoter-bound STAT3 by histone-modifying enzymes Proc Nat Acad Sci 107(50), 21499-
21504Zhang, W., Zecca, L., Wilson, B., Ren, H.W., Wang, Y.J., Wang, X.M., Hong, J.S., 2013. 
Human neuromelanin: an endogenous microglial activator for dopaminergic neuron death. 
Front Biosci (Elite Ed) 5, 1-11. 
Zhang, W., Zecca, L., Wilson, B., Ren, H.W., Wang, Y.J., Wang, X.M., Hong, J.S., 2013. Human 
neuromelanin: an endogenous microglial activator for dopaminergic neuron death. Front 
Biosci (Elite Ed) 5, 1-11 
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16.2 ELN Criteria for Essential Thrombocythemia (Arber et al., 2016) 
Diagnostic Criteria for Essential Thrombocythemia† (WHO 2016) 
Major criteria: 
1. Platelet count ≥450 × 109/L 
2. BM biopsy showing proliferation mainly of the megakaryocyte lineage with increased numbers of enlarged, mature megakaryocytes 
with hyperlobulated nuclei. No significant left-shift of neutrophil granulopoiesis or erythropoiesis and very rarely minor (grade 1) 
increase in reticulin fibersɸ 
 
3. Not meeting WHO criteria for BCR-ABL1+ CML, PV, PMF, MDS, or other myeloid neoplasms 
 
4. Presence of JAK2, CALR, or MPL mutation 
Minor criterion:  
 
1. Presence of a clonal marker (e.g., abnormal karyotype) or absence of evidence for reactive thrombocytosis 
WHO indicates World Health Organization; PV, polycythemia vera; ET, essential thrombocythemia;  
PMF, primary myelofibrosis; CML, chronic myelogenous leukemia; MDS, myelodysplastic syndrome. 
† ET requires meeting all 4 major criteria or first three major criteria and one minor criterion. 
ɸGrading of BM fibers (Thiele et al., 2005) 
Criterion number 2 (BM biopsy) may not be required in cases with sustained absolute erythrocytosis: hemoglobin levels. 18.5 g/dL in men (hematocrit, 55.5%)  
or 16.5 g/dL in women (hematocrit, 49.5%) if major criterion 3 and the minor criterion are present. However, initial myelofibrosis (present in up to 20% of  
patients) can only be detected by performing a BM biopsy; this finding may predict a more rapid progression to overt myelofibrosis (post-PV MF) 
 
16.3 Criteria for Grading Myelofibrosis (Arber et al., 2016)*  
Fibrosis grade 
Definition 
MF-0 
Scattered linear reticulin with no intersections (crossovers) corresponding to normal bone marrow 
MF-1 
Loose network of reticulin with many intersections, especially in perivascular areas 
MF-2 
Diffuse and dense increase in reticulin with extensive intersections, occasionally with focal bundles of thick fibers 
mostly consistent with collagen, and/or focal osteosclerosisa  
MF-3 
Diffuse and dense increase in reticulin with extensive intersections and coarse bundles of thick fibers consistent 
with collagen, usually associated with osteosclerosis a  
*Slighly modified from the European Consensus Criteria as presented in Thiele et al., 2005 
Semiquantitative grading of BM fibrosis with minor modifications concerning collagen and osteosclerosis. Fiber density should be assessed only in hematopoietic areas.   
aIn grades MF-2 or MF-3 an additional trichrome stain is recommended.   
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16.4 Eastern Cooperative Group Performance Status 
Grade 
ECOG Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary 
nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% 
of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
5 
Dead 
 
16.5 Revised Response Criteria for ET:  IWG-MRT and ELN Consensus 2013 (Barosi et al., 2013) 
Response Categories 
Criteria 
 
 
Complete Remission 
 
A 
Durable* resolution of disease-related signs including palpable hepatosplenomegaly, large 
symptoms improvement, † AND  
B 
Durable* peripheral blood count remission, defined as:  
platelet count ≤400 x 109/L, WBC count <10 x 109/L, absence of leukoerythroblastosis, AND  
C 
Without signs of progressive disease, and absence of any hemorrhagic or thrombotic events, AND  
D 
Bone marrow histological remission defined as disappearance of megakaryocyte hyperplasia and 
absence of >grade 1 reticulin fibrosis. 
 
 
Partial Remission 
 
A 
Durable* resolution of disease-related signs including palpable hepatosplenomegaly, and large 
symptoms improvement, AND  
B 
Durable* peripheral blood count remission, defined as:  
platelet count ≤400 x 109/L, WBC count <10 x 109/L, absence of leukoerythroblastosis, AND  
C 
Without signs of progressive disease, and absence of any hemorrhagic or thrombotic events, AND  
D 
Without bone marrow histological remission, defined as the persistence of megakaryocyte 
hyperplasia. 
 
 
No Response 
Any response that does not satisfy partial remission  
 
 
Progressive Disease 
Transformation into PV, post-ET myelofibrosis, myelodysplastic syndrome or acute leukemia‡ 
 
 
Molecular response is not required for assignment as complete response or partial response. Molecular response evaluation requires 
analysis in peripheral blood granulocytes. Complete response is defined as eradication of a preexisting abnormality. Partial response 
applies only to patients with at least 20% mutant allele burden at baseline. Partial response is defined as ≥50% decrease in allele 
burden.  
WBC, white blood cell.  
*Lasting at least 12 wk.  
†Large symptom improvement (≥10-point decrease) in MPN-SAF TSS.  
‡For the diagnosis of PV see World Health Organization criteria (WHO); for the diagnosis of post-ET myelofibrosis, see the  
IWG-MRT criteria; for the diagnosis of myelodysplastic syndrome and acute leukemia, see WHO criteria. 
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16.6 Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF)  
 
  
 
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16.7 Patient Global Impression of Change (PGIC) 
 
 
 
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16.8 Criteria for Intolerance/Resistance to Hydroxyurea 
 
Intolerance/resistance to hydroxyurea defined using the ELN criteria for ET (Barosi et al., 2007) 
 
For patients with ET, intolerance / resistance to HU is  
defined as one of the following criteria: 
• 
Platelet count > 600 ×109/L after a daily dose of at least 2 g HU for at least 
3 months (2.5 g/day in patients with a body weight over 80 kg) 
• 
Platelet count > 400 × 109/L and WBC < 2.5 ×109/L at any dose of HU 
• 
Platelet count > 400 × 109/L and hemoglobin < 10 g/dl at any dose of HU 
• 
Presence of unacceptable HU-related non-hematologic toxicities, 
including fever, mucocutaneous manifestations or leg ulcers 
Note:  Updated based on Erratum published 25April2007. 
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16.9 Remote Data Review 
16.9.1 Risk Assessment 
Given the rapidly evolving COVID-19 pandemic, Imago will remain responsive to the changing 
requirements of each individual site, globally, to determine whether and how patient visits and 
monitoring visits can occur with minimal risk and in accordance with site policy.  A COVID-19 site 
management risk assessment form has been created to document site specific issues that could 
impact patient safety and data integrity. This tool will be used to highlight risks and document 
contingency plans for both the patient, and the monitor, to mitigate such risks.  As the patient 
population under study are those with a hematologic malignancy who require treatment for their 
disease and have failed at least one standard therapy, the benefit-risk is favourable for the patients 
to continue treatment during this pandemic, as long as the proper controls are in place and there is 
no government guidance to the contrary in individual countries. Note: This process will be 
implemented in Germany only in times of increased safety measures such as the COVID-19 
pandemic and only in special cases. 
16.9.2 Security Measures 
Monitors are only permitted to undertake remote data review through the processes detailed 
below in Sections 16.9.3.1 and 16.9.3.2 (EMR access or video call/conferencing) where the 
following security measures are in place: 
• 
Location of Monitor: remote data review activities may be performed in locations that do 
not allow access/viewing by unauthorized third parties: 
o 
Acceptable locations include: closed room in a Syneos Health office, at home in 
private area for home-based staff. 
o 
Examples of prohibited locations include: Open plan desk space in Syneos Health 
offices, on public transportation, in airport lounge or other public areas.  
• 
Internet connection: remote data review is permitted only through a secure internet 
connection i.e. Syneos Health office internet or secure personal internet after logging into 
Syneos Health virtual private network (VPN). Use of a public internet, hot spot or hotel 
internet is prohibited. 
• 
Device: remote data review is permitted only through Syneos Health registered device (e.g., 
laptop, iPad) or through a device provided by the site. 
• 
While the EMR system is accessed or video call/conference are ongoing, the computer must 
be locked if left unattended. 
16.9.3 Processes 
As outlined in Section 13.5, remote data review is intended to encompass as many activities 
performed in a routine on-site monitoring visit as is functionally possible, and as permitted by site 
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policy and procedure.  Remote data review has become critically important in the COVID-19 
environment as a measure of safeguarding patient safety, while also minimizing risks to trial data 
integrity and facilitating GCP compliance.  The source documents/source data to be made available 
for remote data review include those related to the primary endpoint and exploratory endpoints, 
safety, study drug dispensation and return and the reasons for exclusion of a subject from the trial. 
The remote review of data may be actioned via multiple pathways, often contingent on site’s 
capabilities.  Examples include: 
• 
Remote Source Data Review (via Electronic Medical Records (EMR) 
• 
Remote Source Data Review (via video call/conferencing) 
• 
Remote Data Verification (using redacted source documents) 
Additionally, to facilitate continued interaction with and support of the site, phone monitoring visits 
may also periodically be conducted. Remote review of data will not occur during phone visits. 
16.9.3.1 Direct, Controlled Remote Access to the Systems Used by the Trial Site to Manage the 
Source Documents/Source Data 
For data review whereby the monitor accesses the EMR system remotely, the following criteria are 
required to be met before this process can be implemented for any subject: 
• 
An audit trail is available in the Electronic Medical Records (EMR) system. 
• 
There is unique password access to the EMR system assigned to each member of site staff. 
• 
There is unique password, read-only access to the EMR system assigned to the Monitor. 
• 
EMR access has been granted only to trial subjects’ records and other patient data is not 
accessible to the Monitor (unless a procedure is in place to monitor the Monitor’s activity 
following each session).    
• 
US sites only: written procedure is in place for the use of EMR system. 
• 
US sites only: If the EMR system is certified by the Office of the National Coordinator for 
Health Information Technology (ONC) at the Department of Health and Human Services, it 
is sufficient to confirm this on the COVID-19 Remote Source Data Monitoring Site 
Agreement. 
16.9.3.2 For Passive Access to Original Documents/Original Data via Live Image Transmission 
The following controls will be applied for remote data review by video call/conferencing: 
• 
The video call/conference may only occur using a Syneos Health approved information and 
communication technology. 
• 
Video review of documentation only is permitted. 
• 
No recording of the interaction is permitted. 
• 
No document upload is permitted. 
• 
No Document storage is permitted. 
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• 
Usage must comply with applicable local regulations/regulatory guidance. 
• 
During remote data review by video call/conferencing care will be taken to avoid 
inadvertent viewing of individuals who should not be part of the interaction. 
16.9.3.3 Passing on Redacted Copies of Original Documents and Documents with Original Data 
Note:  In Germany, the sending of redacted source data is generally not permissible as a method for 
the remote review of data; however, single redacted documents may be used at times to confirm an 
individual data-point.  
The following controls will be applied during for passing on redacted copies of original documents: 
• 
Process must be allowed by local regulations and in compliance with applicable regulatory 
guidance 
• 
Principal Investigator to document the delegation of creation of Pseudonymized Certified 
Copies of the source documents on the Study Personnel Signature and Delegation Form 
• 
Site staff who will provide source documents to Monitor for remote data review will be 
trained on the role, responsibility, and process for providing pseudonymized Certified 
Copies of source documents to support remote review of data 
• 
Certified Copies of all required original source documents will be prepared 
Certified Copy: A copy (irrespective of the type of media used) of the original record that has 
been verified (i.e., by a dated signature or by generation through a validated process) to have 
the same information, including data that describe the context, content, and structure, as the 
original. (International Council for Harmonization (ICH) Guideline for Good Clinical Practice 
(GCP) Revision 2). 
Note: A copy is certified by signing and dating on the first page with a statement “certified 
copy” and adding a note on the first page that the certified copy package consists of # pages. 
Each page must be numbered so that, in total, the pages match the full # of pages documented 
on the first page of the package. 
• 
All subject direct identifiers (e.g. name, social security/national identification number, 
medical record number, initials, full date of birth, home address etc.) will be redacted/ 
obscured (i.e. pseudonymized) on the copies to protect subject confidentiality and personal 
data. 
• 
A quality check of the redacted Certified Copies will be performed by a second site staff 
member to confirm all subject directly identifiable information has been redacted, the 
correct subject identification code added and that the copies are legible.  
o The quality check will be documented by the second site staff member’s initials, 
dating of the first page of the package and addition of the statement “QC’d/Checked” 
• 
A transmittal form will be completed each time Pseudonymized Certified Copies of source 
documents are sent.  
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• 
The prepared source document package, including transmittal form, will be provided by one 
of the following methods:  
o Overnight Courier 
o Secure Fax Transmission  
o Scanned images via secure email (encrypted email or password protected email 
attachment. If the latter, the password will be provided to Monitor via telephone) 
o A secure platform for document exchange 
• 
A set of the prepared source document package, including transmittal form, will be retained 
in the Investigator’s Site File.  Note: These documents will not be retained in Germany. 
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SAP_001.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase 2 Multi-Center, Open Label Study to
Assess the Safety, Efficacy and
Pharmacodynamics of IMG-7289 in Patients
With Essential Thrombocythemia
NCT04254978 
December 21, 2020 


 
 
 
This document is confidential. 
SAP Version: V1.0 21-DEC-2020 
Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
Page 1 of 38 
Filing requirement: TMF 
Statistical Analysis Plan 
 
Sponsor Name: Imago BioSciences, Inc. 
 
 
Protocol Number: IMG-7289-CTP-201 
Protocol Title: A Phase 2 Multi-Center, Open Label Study to Assess the Safety, Efficacy and 
Pharmacodynamics of IMG-7289 in Patients with Essential Thrombocythemia 
 
 
Protocol Version and Date: Amendment 2 (09-Sep-2020) 
 
Syneos Health Project Code: 7010289 
 
Author(s) : 
, Senior Biostatistician 
, Biostatistician II 
 
 
 
 
 
 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Imago BioSciences, Inc. 
Acceptance of this document constitutes agreement by the recipient that no information contained herein 
will be published or disclosed without prior written authorization from an official of Imago BioSciences, 
Inc. However, this document may be disclosed to appropriate Institutional Review Board and Ethics 
Committees or duly authorized representatives of a national regulatory authority under the condition that 
they are requested to keep it confidential. In the event of an actual or suspected breach of this obligation, 
Syneos Health should be notified promptly. 
 
 
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Revision History 
Version # 
Date 
(DD-Mmm-YYYY) 
Document Owner 
Revision Summary 
0.1 
17-Jun-2020 
Initial Release Version 
0.2 
26-Oct-2020 
SAP Draft 2 
1.0 
21-Dec-2020 
Final Version 1 
 
 
 
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I confirm that I have reviewed this document and agree with the content.
APPROVALS
Syneos Health
Authoring Biostatistician
Senior Biostatistician
Date (dd-Mmm-yyyy)
Senior Reviewing Biostatistician
Senior Biostatistician
Date (dd-Mmm-yyyy)
Imago BioScience, Inc
Senior VP of Clinical Operations
Date (dd-Mmm-yyyy)
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Table of Contents 
Revision History ............................................................................................................................................ 2 
List of Abbreviations and Definition of Terms ............................................................................................... 6 
1. 
Introduction .......................................................................................................................................... 8 
2. 
Study Objectives ................................................................................................................................. 8 
2.1 
Primary Objectives ................................................................................................................. 8 
3. 
Study Design ....................................................................................................................................... 9 
3.1 
Initial Treatment Period (ITP) ................................................................................................. 9 
3.2 
Additional Treatment Period (ATP) for Qualifying Patients Only ......................................... 10 
 
 
5. 
Analysis Populations ......................................................................................................................... 17 
5.1 
Safety Population ................................................................................................................. 17 
5.2 
Modified Intent-to-Treat (mITT) Population .......................................................................... 17 
6. 
Statistical Methodology ..................................................................................................................... 18 
6.1 
Statistical and Analytical Issues ........................................................................................... 18 
6.1.1 
Statistical Methods ............................................................................................... 18 
6.1.2 
Handling of Dropouts and Missing Data .............................................................. 19 
6.1.3 
Pooling of Investigative Sites ............................................................................... 20 
6.1.4 
Determination of Sample Size ............................................................................. 20 
6.2 
Subject Characteristics ......................................................................................................... 21 
6.2.1 
Subject Disposition .............................................................................................. 21 
6.2.2 
Protocol Deviations .............................................................................................. 21 
6.2.3 
Background and Demographic Characteristics ................................................... 22 
6.2.4 
Treatment Exposure and Compliance ................................................................. 22 
6.2.5 
Prior and Concomitant Medications ..................................................................... 23 
6.2.6 
Medical and Surgical History (Non-Cancer Related) ........................................... 23 
6.2.7 
Disease History and Treatment ........................................................................... 23 
6.3 
Efficacy Analysis .................................................................................................................. 24 
6.3.1 
Primary Efficacy Analysis ..................................................................................... 24 
6.3.2 
ECOG Performance Status .................................................................................. 24 
6.4 
Safety Analysis ..................................................................................................................... 25 
6.4.1 
Adverse Events .................................................................................................... 25 
6.4.2 
Physical Examination ........................................................................................... 27 
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6.4.3 
Vital Signs ............................................................................................................ 27 
6.4.4 
Laboratory Parameters ........................................................................................ 27 
6.4.5 
Other Laboratory Assessments ........................................................................... 28 
6.4.6 
Pharmacodynamic Analysis ................................................................................. 28 
6.5 
Analysis of Other Assessments ........................................................................................... 32 
6.6 
Interim Analysis .................................................................................................................... 32 
6.7 
Data Monitoring Committee.................................................................................................. 32 
6.8 
Changes to Methods Planned in the Protocol ...................................................................... 33 
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1.
Introduction
This Phase 2 multi-center, open-label study will evaluate the safety, efficacy and pharmacodynamics of 
IMG-7289, an irreversible inhibitor of the enzyme lysine-specific demethylase 1 (LSD1) when administered 
orally once daily in patients with essential thrombocythemia (ET). ET is an indolent hematologic cancer 
characterized by reduced quality of life, thrombocytosis, elevated cytokines, and increased rates of 
thrombosis and bleeding that can evolve to myelofibrosis and/or acute myeloid leukemia. LSD1 is an 
enzyme that regulates the maturation of megakaryocytes from progenitor cells, as well as the function of 
mature megakaryocytes. In ET, acquired mutations in hematopoietic stem cells cause JAK/STAT activation, 
which results in an over-abundance of activated megakaryocytes that in turn produce an excess of platelets, 
growth factors, and inflammatory cytokines. 
2. 
Study Objectives 
The following primary and exploratory objectives will be evaluated in patients with ET treated with 
IMG-7289: 
2.1 Primary Objectives 
 
Safety and tolerability. 
 
9/L) in the absence of new thromboembolic 
events. 
 
 
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Statistical Analysis Plan
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3.
Study Design
This is a Phase 2 multi-center, open-label study evaluating the safety, efficacy, and pharmacodynamics of 
IMG-7289 administered orally once daily in patients with ET. 
The therapeutic goal for the treatment of ET is to inhibit the activity of LSD1 in hematopoietic cells for only 
a fraction of the 24-hour dosing cycle, sufficient to reduce the production of platelets, whose over-production 
characterizes this condition. Considerations leading to the choice of a safe starting dose include chronic 
toxicology studies in conjunction with the clinical experience of the patients who have received IMG-7289 
to date. Using all of the information available in conjunction with the therapeutic goal for the treatment of 
ET, an IMG-7289 starting dose of 0.6 mg/kg QD has been selected. 
To ensure patient safety, a Safety Advisory Board (SAB) will perform reviews at least quarterly of safety 
parameters and pharmacodynamic markers to draw conclusions around the safety and pharmacodynamic 
effect of IMG-7289. The SAB will also review patient dose titrations and may recommend adjustments. 
This study consists of 2 treatment periods: The Initial Treatment Period (ITP), followed by the Additional 
Treatment Period (ATP). In the ITP, patients will be treated daily for 169 days. In the ATP, which is iterative, 
treatment may continue for an additional 169 days in those patients deriving clinical benefit (defined as not 
m
Appendix 16.5 in the Protocol) and safely tolerating IMG-
7289; as determined by the Principal Investigator (PI). 
All patients will undergo follow-up period visits, including an End-of-Treatment (EoT) visit on the day of last 
dose or as soon as possible thereafter, a pre-End-of-Study (EoS) visit approximately 7 days post last dose, 
and an End-of-Study (EoS) visit approximately 14 days post last dose. Patients that do not enter the ATP, 
or discontinue early, will undergo follow-up beginning with an EoT visit. 
Patients will be followed closely throughout the study for both adverse events (AEs) and signs of toxicity by 
frequent monitoring of clinical signs and symptoms as well as safety laboratory parameters. Efficacy and 
pharmacodynamic effects will be closely monitored by frequent hematology assessments of peripheral 
blood, and requisite bone marrow aspirates and biopsies. Throughout dosing, transfusions may be 
administered if needed in accordance with standard institutional guidelines. 
3.1 Initial Treatment Period (ITP) 
Through the use of dose titration, the dose of IMG-7289 will be adjusted in each patient to that dose that 
provides sufficient exposure to safely inhibit thrombopoiesis for a fraction of the dosing cycle (designated 
as the Dpi). Treatment will begin on Day 1 at the IMG-7289 Ds of 0.6 mg/kg QD for all patients, with dose-
titration contigent on the comparison of hematology values from the prior visit. Up-titrations may begin on 
ITP Day 28 and occur no more frequently than every 4 weeks from the previous up- or down-titration. 
Down-titrations can be made at any time in the best interest of the patient.  Up-titrations will be made in 
increments of 0.2 mg/kg/d, and down-titrations in decrements of 0.1 or 0.15 mg/kg/d, as summarized in 
tabular form in Table 1. 
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Statistical Analysis Plan
Sponsor: Imago BioSciences, Inc; Protocol No.: IMG-7289-CTP-201  
 
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During the ITP, patients will initially return for study assessments every other week (bi-weekly) for the first 
12 weeks (ITP Days 15, 29, 43, 57, 71 and 85) and then monthly for 12 weeks (ITP Days 113, 141 and 
169). It is anticipated that by Week 12 (Day 85) the majority of patients will have achieved a stable dose. 
For safety purposes, bi-weekly visits may continue at the PI
will be made to determine whether the patient is deriving clinical benefit and safely tolerating IMG-7289. 
For the patients who qualify for entry into the ATP, transition should occur without interruption in dosing. 
Patients not deriving clinical benefit will discontinue IMG-7289 and undergo End of Treatment (EoT), pre-
End of Study (pre-EoS) and End of Study (EoS) visits. 
3.2 Additional Treatment Period (ATP) for Qualifying Patients Only 
In the ATP, treatment may continue for an additional 169 days in those patients deriving clinical benefit, as 
determined by the PI. For the purposes of clarity and efficiency, rather than continuing to present 
chronological days/
-
-7289 on ATP Day 1, with dose titration continuing as per the Titration 
and Re-challenge Rules (Table 1); there should be no interruption in dosing (Day 169 = Day 1 of the next 
ATP). Additional dose-titration may occur in consultation with the Medical Monitor. 
Qualifying patients will return for study assessments monthly (ATP Days 1, 29, 57, 85, 113, 141 and 169). 
It is anticipated that patients continuing in the ATP will have already achieved a stable dose, with every 
other week visits no longer necessary. For safety purposes, every other week visits may continue at the 
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Sponsor: Imago BioSciences, Inc; Protocol No.: IMG-7289-CTP-201  
 
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to determine whether the patient is continuing to derive clinical benefit. Such patients thereby qualify for re-
entry into the ATP, which is iterative; patients may continue to receive IMG-7289 for as long as they continue 
to qualify. Patients not deriving clinical benefit will discontinue IMG-7289 and undergo EoT, pre-EoS, and 
EoS visits.  
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Statistical Analysis Plan
Sponsor: Imago BioSciences, Inc; Protocol No.: IMG-7289-CTP-201  
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SAP Version: V1.0 21-DEC-2020 
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Statistical Analysis Plan
Sponsor: Imago BioSciences, Inc; Protocol No.: IMG-7289-CTP-201
This document is confidential. 
SAP Version: V1.0 21-DEC-2020 
Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
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Statistical Analysis Plan
Sponsor: Imago BioSciences, Inc; Protocol No.: IMG-7289-CTP-201
This document is confidential. 
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Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
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Statistical Analysis Plan
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SAP Version: V1.0 21-DEC-2020 
Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
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Statistical Analysis Plan
Sponsor: Imago BioSciences, Inc; Protocol No.: IMG-7289-CTP-201
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Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
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Statistical Analysis Plan
Sponsor: Imago BioSciences, Inc; Protocol No.: IMG-7289-CTP-201  
 
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Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
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5.
Analysis Populations
The following subject populations (i.e., analysis sets) will be evaluated and used for presentation of the 
data. 
5.1 
Safety Population 
The Safety Population will include all subjects who are enrolled in the study and receive at least 1 dose of 
study medication. Subjects will be analyzed according to treatment received in the study. The Safety 
Population will be used for all analyses of demographics, baseline characteristics, safety endpoints, and for 
subject disposition at the end of treatment. The Safety Population will be used for all data listings, with the 
exception of subject disposition at the end of study. 
5.2 
Modified Intent-to-Treat (mITT) Population 
The mITT Population will include all subjects who are enrolled in the study, receive at least 1 dose of 
study medication, and who have a non-missing baseline and at least 1 non-missing post-baseline efficacy 
assessment. Subjects will be analyzed according to treatment received in the study. The mITT Population 
will be used for all analyses of efficacy and pharmacodynamic endpoints. 
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Statistical Analysis Plan
Sponsor: Imago BioSciences, Inc; Protocol No.: IMG-7289-CTP-201  
 
This document is confidential. 
SAP Version: V1.0 21-DEC-2020 
Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
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6.
Statistical Methodology
6.1 Statistical and Analytical Issues 
6.1.1 Statistical Methods 
Tabulations will be produced for appropriate demographic, baseline, safety, pharmacodynamic, and 
efficacy parameters. 
 
 
 
 
 
 
 
 
 
  
By-subject data listings will be produced for data collected throughout the study.
 
 
 
 
 
 
Statistical analyses will be carried out by using SAS Version 9.4 or higher. Any deviations from the planned 
analysis as described in the SAP will be justified and recorded in the Clinical Study Report (CSR).  
Adverse events will be graded by the Investigator based on the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), Version 5, and will be coded for summarization using 
the Medical Dictionary for Regulatory Activities (MedDRA® Version 23.0 or later). Concomitant medications 
will be coded using the World Health Organization (WHO) Drug Dictionary (Global B3 March 2020 version 
or later). 
6.1.1.1 Dose and Study Part 
Many analyses will be presented by treatment period (ITP and ATP). Analyses on the ITP, ATP and overall 
will be presented.  
Data listings will be presented overall. 
Details regarding the presentation of the individual analyses will be described in the relevant sections of 
this SAP. 
6.1.1.2 Visit Windows 
All data will be tabulated per the evaluation visit as recorded on the eCRF, even if the assessment is outside 
of the visit window. Unless otherwise stated in the analysis sections below, unscheduled visits and data 
collected at suspected relapse will be included in data listings only.  
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Statistical Analysis Plan
Sponsor: Imago BioSciences, Inc; Protocol No.: IMG-7289-CTP-201  
 
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6.1.2 Handling of Dropouts and Missing Data 
6.1.2.1  Last Observation Carried Forward 
For the following endpoints, both as-observed analyses and imputed analyses will be performed. Missing 
data, including those not obtained because of death, will be imputed using the last observation carried 
forward (LOCF) method, up until the end of the given treatment period: 
 
MPN-SAF Total Symptom Score: 
 
 
 
Quality of Life (QoL): 
 
 
 
Spleen size by physical examination 
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Statistical Analysis Plan
Sponsor: Imago BioSciences, Inc; Protocol No.: IMG-7289-CTP-201  
 
This document is confidential. 
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Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
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6.1.3 Pooling of Investigative Sites 
No by-site analyses are planned.  
6.1.4 Determination of Sample Size 
This study is designed to make an assessment of the safety, tolerability, and efficacy of IMG-7289 for the 
treatment of essential thrombocythemia. This is a single-arm trial with a primary endpoint that is a proportion 
variable (proportion of subjects 
of new thromboembolic events). The test of significance is a 1-sided test at the alpha=0.025 level of 
significance (equivalent to a 2-sided test at the alpha=0.05 level of significance).
 
 
 
 
 
 
 
with a sample size of 21 subjects, there is an 80% probability that the study will be successful (where 
is increased to 30 subjects, the probability of study success is 90%. 
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Statistical Analysis Plan
Sponsor: Imago BioSciences, Inc; Protocol No.: IMG-7289-CTP-201  
 
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6.2 Subject Characteristics
6.2.1 Subject Disposition 
Subject disposition at EoS will be summarized for all subjects and presented overall. 
 
 
 
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Statistical Analysis Plan
Sponsor: Imago BioSciences, Inc; Protocol No.: IMG-7289-CTP-201  
 
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6.2.3 Background and Demographic Characteristics 
Demographics and baseline characteristics will be summarized overall on the Safety Population.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unless otherwise stated, percentages will be calculated based on the number of subjects in the Safety 
Population. 
 
 
 
6.2.4 Treatment Exposure and Compliance 
Study drug exposure will be presented cumulatively by treatment period, summarizing overall for both the 
ITP and ATP. The number of days dosed will be summarized by treatment period using both continuous 
 
  
 
 
n addition, the total cumulative dose (mg) received and the duration of exposure will be 
summarized by treatment period and overall. 
 
  
 
 
  
  
Study drug compliance will be presented for each scheduled study visit, presented by treatment period. 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan
Sponsor: Imago BioSciences, Inc; Protocol No.: IMG-7289-CTP-201  
 
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Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
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6.2.5 Prior and Concomitant Medications 
Prior medication will be defined as any medication with a start date prior to the date of first dose of study 
drug. Concomitant medication is defined as any medication that is ongoing or has a stop date on or after 
the first dose date of study drug. Medications can be classified in both categories if the start date is prior to 
the date of the first dose of study treatment and the medication continued after the first dose of study 
treatment. 
 
 
  
 
  
Prior and concomitant medications will be coded using the WHO Drug Dictionary, and subject incidence 
will be tabulated by Anatomic Therapeutic Class (ATC) and preferred term (PT) on the Safety Population. 
 
 Summaries will be presented overall for prior and concomitant 
medications separately. 
 
 
 
 
6.2.6 Medical and Surgical History (Non-Cancer Related) 
Medical and surgical history (non-cancer related) will be coded using MedDRA and listed only on the Safety 
Population. 
 
 
6.2.7 Disease History and Treatment 
Descriptive statistics of disease history characteristics will be presented overall on the Safety Population 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan
Sponsor: Imago BioSciences, Inc; Protocol No.: IMG-7289-CTP-201  
 
This document is confidential. 
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Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
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6.3 Efficacy Analysis 
All efficacy analyses will be performed using the mITT Population. 
 
 Summaries will be presented overall for the 
ITP and ATP, unless otherwise noted below. 
6.3.1 Primary Efficacy Analysis 
(400 x 109/L) in the absence of new thromboembolic events. The reduction of platelet counts will be 
evaluated and assessed based on local laboratory measurements of platelet counts from Day 1 to each 
visit where platelets are measured 
 
The primary efficacy endpoint is the proportion of subjects who achieve a reduction of platelet counts to 
 
9/L) in the absence of new thromboembolic events. This endpoint will be analyzed 
using an exact 1-sample binomial test. The proportions and corresponding 95% confidence intervals (CIs) 
based on the Clopper-Pearson method will be presented for each post-baseline study visit on the mITT 
Population. 2-sided p-values will be calculated for the Day 169 visit to test the null hypothesis assuming 
that the test statistic follows an exact binomial distribution. 
The null hypothesis tested for the primary efficacy endpoint is that the true response rate is 5%, where the 
response rate is defined as the proportion of subjects who achieve a reduction of platelet counts to 
 400 
9/L) in the absence of new thromboembolic events. The corresponding alternative 
hypothesis is that the true response rate is not 5%. The primary efficacy endpoint will be achieved if the 
null hypothesis is rejected at the 0.05 alpha level in favor of a higher (> 5%) response rate.  
 
6.3.2 ECOG Performance Status 
 
 
 
The frequency distribution of ECOG performance status at baseline (Screening) and the 
changes from baseline will be presented for each visit by treatment period. 
 
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Statistical Analysis Plan
Sponsor: Imago BioSciences, Inc; Protocol No.: IMG-7289-CTP-201  
 
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6.4 Safety Analysis 
For this study, the primary objectives involve safety and tolerability. The safety and tolerability of IMG-7289 
will be assessed by the analysis of adverse events (AEs), as well as changes in physical examinations, 
vital signs and laboratory values as detailed below. All safety analyses will be performed using the Safety 
Population. Summaries will be presented overall for the ITP and ATP, unless otherwise noted below. All 
 
6.4.1 Adverse Events 
 
 
AEs will be assessed post-first dose until 14 days post-last dose (Note for UK: Non-serious 
AEs will be assessed post-first dose, and SAEs post-consent, until 14 days post-last dose). Adverse events 
will be graded according to the NCI CTCAE Version 5, coded using the MedDRA coding system, and 
displayed in tables and data listings by system organ class (SOC) and preferred term (PT).  
Analyses of AEs will be performed for those events that are considered treatment-emergent. A treatment-
emergent AE (TEAE) is defined as any AE occurring or worsening after the first dose of study drug on 
Day 1 through the end of the study 
 
 
 
 
 
 
 
 
 
 
 
 
 
An overall TEAE incidence summary table will be produced and presented by treatment period, 
 
 
 
 
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Statistical Analysis Plan
Sponsor: Imago BioSciences, Inc; Protocol No.: IMG-7289-CTP-201  
 
This document is confidential. 
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Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
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Tabulations by SOC and PT will be produced for all TEAEs, TEAEs related to study drug, serious TEAEs, 
serious TEAEs related to study drug, TEAEs classified as DLTs (applicable for ITP only), TEAEs leading 
to study drug withdrawal, TEAEs leading to study discontinuation, TEAEs leading to death, and TEAEs by 
maximum severity. 
AE analyses by SOC and PT will be presented by treatment period. 
No formal hypothesis-testing analysis of AE incidence rates will be performed. 
 
 
 
 
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Statistical Analysis Plan
Sponsor: Imago BioSciences, Inc; Protocol No.: IMG-7289-CTP-201  
 
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Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
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Physical examination findings will be summarized on the Safety Population by means of a shift table from 
baseline (Screening/Day 1 pre-dose) until EoS/Early Termination for each body system. Summaries will be 
presented by treatment period 
 
 
6.4.3 Vital Signs 
The actual value and change from baseline (Screening/Day 1 pre-dose) to each post-baseline visit until 
EoS/Early Termination will be descriptively summarized by visit on the Safety Population. 
 
 
. Summaries will be presented by treatment 
period and sorted by study visit. 
 
  
6.4.4 Laboratory Parameters 
The absolute values and change from baseline (Screening/Day 1 pre-dose) to each post-baseline visit until 
EoS/Early Termination for each laboratory parameter
 will be descriptively summarized 
on the Safety Population. Summaries will be presented by treatment period
 
. 
All laboratory values will be categorized according to their normal ranges, where normal ranges exist. Shift 
tables from baseline will present the frequency counts and percentages of subjects 
 
 
 
 
 
 
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Statistical Analysis Plan
Sponsor: Imago BioSciences, Inc; Protocol No.: IMG-7289-CTP-201  
 
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Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
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6.4.6 Pharmacodynamic Analysis 
All pharmacodynamic analyses will be performed using the mITT Population. Summaries will be presented 
overall for the ITP and ATP. 
. 
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Sponsor: Imago BioSciences, Inc; Protocol No.: IMG-7289-CTP-201  
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Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
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Sponsor: Imago BioSciences, Inc; Protocol No.: IMG-7289-CTP-201  
 
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Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
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Sponsor: Imago BioSciences, Inc; Protocol No.: IMG-7289-CTP-201  
 
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Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
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6.7 Data Monitoring Committee  
To ensure patient safety, in accordance with a SAB Monitoring Plan (SABMP), a SAB will perform reviews 
at least quarterly of safety parameters and pharmacodynamic markers to draw conclusions around the 
safety and pharmacodynamic effect of IMG 7289. The SAB will also review patient dose titrations and 
may recommend adjustments. 
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Statistical Analysis Plan
Sponsor: Imago BioSciences, Inc; Protocol No.: IMG-7289-CTP-201  
 
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6.8 Changes to Methods Planned in the Protocol 
There are no changes in the planned methods in the SAP from those outlined in the protocol. 
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8.
References
Arber, A.A., Orazi, A., Hasserjian, R., Thiele, J., Borowitz, M.J., Le Beau, M.M., Bloomfield, C.D., 
Cazzola, M., Vardiman, J.W.  2016. The 2016 revision to the World Health Organization 
classification of myeloid neoplasms and acute leukemia Blood 127(20), 2391-2405 
Thiele, J., Kvasnicka, H.M., Facchetti, F., Franco, V., van der Walt, J., Orazi, A. 2005. European consensus 
on grading bone marrow fibrosis and assessment of cellularity Haematologica 90(8), 1128-1132 
 
 
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