Protocol No: ECCT/20/11/03 Date of Protocol: 29-01-2020

Study Title:
A Phase 2b Study to Evaluate the Safety and Efficacy of IMR-687 in Subjects with Sickle Cell Disease
Study Objectives:
Primary Objectives
• To evaluate the HbF response to IMR-687 versus placebo
• To evaluate the safety of IMR-687 versus placebo
Secondary Efficacy Objectives
• To evaluate the effect of IMR-687 versus placebo on HbF-associated biomarkers
• To evaluate the effect of IMR-687 versus placebo on indices of red cell hemolysis
• To evaluate the effect of IMR-687 versus placebo on indices of WBC adhesion
• To evaluate the effect of IMR-687 versus placebo on the incidence of VOCs
• To evaluate the effect of IMR-687 versus placebo on quality of life (QoL) measures
Pharmacokinetic Objectives
• To evaluate the PK of IMR-687 and any major circulating metabolites
Exploratory Efficacy Objectives
• To evaluate the effect of IMR-687 versus placebo on changes in RBC characteristics
and total Hb
• To evaluate the effect of IMR-687 versus placebo on renal function
• To evaluate the effect of IMR-687 versus placebo on indices associated with
cardiovascular pathophysiology and ischemic stroke risk
Laymans Summary:

Sickle Cell Disease is an uncommon disease that is inherited and affects the production of Hemoglobin (Hb). Hb is a protein in red blood cells that carries oxygen from the lungs to the rest of the body. In people who are living with Sickle Cell Disease, the hemoglobin deforms the red blood cell into a sticky and rigid sickle shaped cell, which may cause a lack of oxygen in many parts of the body. The disease may ultimately lead to the damage of many organs such as kidneys, liver, heart, brain, joints,  can ultimately lead to organ damage.  Currently there are very few treatments that are specifically approved for treatment of sickle cell disease.  Therefore, this study whose purpose is to evaluate how safe and well-tolerated a new drug called IMR-687 is in participants with Sickle Cell Disease. IMR-687 helps to stimulate the production of normal haemoglobin by inhibiting the production of abnormal haemoglobin. Participants will be randomly assigned (like flipping a coin) to 1 of 2 treatment groups which include treatment with a low dose of IMR-687 or placebo. Some participants may be given a higher dose of IMR-687 after reviewing safety data from 5 participants receiving the low dose of IMR-687.

The planned duration of study participation is approximately 60 weeks consisting of: screening period (4 weeks), treatment period (52 weeks) and safety follow-up assessment (4 weeks). Participants will be expected to take two tablets once a day for 52 weeks.  Safety assessments will be done throughout the study.

IMARA, Inc., is the pharmaceutical company that will be funding this research study.

Abstract of Study:

Background: SCD is caused by a specific point mutation in the gene encoding hemoglobin (Hb) sub unit beta that leads to the production of abnormal Hb (“sickle hemoglobin” or HbS). Under conditions of hypoxia, acidity, and/or dehydration, the intracellular concentration of

deoxygenated HbS increases, which favors its polymerization and causes RBCs to deform (i.e., sickle) or become rigid, leading to a complex cascade of hemolysis, inflammation, elevated cell adhesion, leukocytosis, oxidative stress, and endothelial dysfunction that culminates in the vascular obstruction and ischemia responsible for much of the observed morbidity in SCD.  The most common manifestations of SCD include vaso-occlusive crisis (VOC), chronic and acute severe pain, acute chest syndrome (ACS), stroke, priapism, acute anemia (particularly from aplastic crisis and splenic sequestration), increased susceptibility to infection, and progressive damage to major organs, including the spleen, brain, kidney, heart, lung, skin, retina, vestibular cochlear systems, and bone. In developed countries where there is prenatal screening and widespread access to prophylactic and acute interventions, the median age of death remains in the 40s to 50s.  In low resource countries, however, many patients succumb to the disease much earlier. Prior to July 2017, the only drug specifically approved for the treatment of SCD was hydroxyurea (HU).  In July 2017, L-glutamine oral powder (Endari™) was approved in the US to reduce complications of SCD. In November 2019, crizanlizumab and voxelotor were approved by the Food and Drug Administration (FDA). Due to the current cost of voxelotor and crizanlizumab, these therapies may not be accessible globally, especially for patients in resource-poor countries. Thus, additional accessible, novel, safe, and effective treatments to prevent the morbid complications of SCD in patients of all ages are still urgently needed. The sponsor, IMARA is developing IMR-687 for the treatment of patients with sickle cell disease (SCD) and β-thalassemia. IMR-687 is a potent, specific, and highly selective small molecule inhibitor of phosphodiesterase type 9 (PDE9); PDE9 mediates cellular signaling pathways by degrading cGMP to its inactive or monophosphate form. By inhibiting PDE9, IMR-687 is intended to increase cGMP levels and thus stimulate the production of HbF, which reduces the cellular concentration of abnormal Hb (HbS) within RBCs and its associated sequelae.


Objectives: To evaluate the HbF response to IMR-687 versus placebo and to evaluate the safety of IMR-687 versus placebo.


Methods: This is a phase 2b, randomized, double-blind, placebo-controlled, multicenter study of subjects aged 18 to 65 years with sickle cell disease (SCD; homozygous sickle hemoglobin [HbSS], sickle-β0 [HbSB0] thalassemia, or sickle-β+ [HbSB+] thalassemia) to evaluate the safety and efficacy of the phosphodiesterase type 9 (PDE9) inhibitor, IMR-687, administered once daily (qd) for 52 weeks. This study will enroll approximately 99 subjects with SCD. This study consists of a screening period (up to 4 weeks), a double-blind treatment period (52 weeks), and a safety follow-up period (4 weeks).

Screening: After providing documented informed consent, subjects fulfilling the inclusion criteria  will enter an up to 28-day screening period. The following information will be obtained and procedures will be performed for all potential subjects at the screening visit: medical/disease history, vital signs, electrocardiogram (ECG), complete physical examination (PE), laboratory tests (including safety, specialty hematology, and pharmacodynamic [PD] assessments). For a complete list of screening procedures, refer to the schedule of assessments.

Treatment Period: Subjects will receive either IMR-687 (lower dose [≥3.0 to ≤4.5 mg/kg] or higher dose [>4.5 to ≤6.7 mg/kg]) or placebo in a blinded fashion. Initially, subjects will be randomly assigned in a 2:1 ratio to receive either IMR-687 lower dose or placebo. Prior to the introduction of IMR-687 higher dose, the Data Monitoring Committee (DMC) will review safety data for at least 5 subjects who received IMR-687. If the DMC recommends inclusion of the higher dose, randomization will then proceed in a 1:2:1 ratio (IMR-687 lower dose, IMR-687 higher dose, or placebo). The DMC may request additional data and/or meeting(s) in order to make the recommendation on whether to move forward with inclusion of the higher dose.

Subjects may or may not be concomitantly receiving a stable dose of hydroxyurea (HU) according to

the subject’s established treatment plan. Randomization will be stratified by use of HU and by region. 

Subjects will return to the investigational site at Week 1 for a safety assessment, and qualified site

personnel will contact the subject by telephone at Week 2 and Week 6 to capture potential adverse

events (AEs) and concomitant medications. Subjects will be seen at the investigational site approximately every 4 weeks through Week 36 and then every 12 weeks through Week 52 (end of treatment), with a safety follow-up visit at Week 56 (end of study). Safety will be monitored throughout the study, and pharmacokinetics (PK), PD, quality of life (QoL), and clinical outcome measures will be performed at the visits shown in the schedule of assessments for (Table 1, in the protocol). QoL assessments include the Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me®), Patient-Reported Outcomes Measurements Information System - Preference (PROMIS® 29 + 2 Profile v2.1 [PROPr]), and Sickle Cell Self-Efficacy Scale (SCSES).

Data analysis: HbF response will be analyzed using a stratified Cochran-Mantel-Haenszel (CMH) test based on stratification factors of HU use and region to compare the proportion of patients achieving HbF response of each dose of IMR-687 to placebo. An interim analysis (IA) will be performed after 33 subjects have reached Week 24, and a primary analysis will be performed after all subjects have reached Week 24 or terminated early.  A final analysis will be conducted at study completion (i.e., when all subjects have reached Week 56 or terminated early).

Ethical considerations: The Gertrude’s Children’s Ethical Review Board has approved the study (

Open-label Extension: Subjects who complete this study may be eligible to enrol in an open-label extension (OLE) study. Details of the OLE study will be provided in a separate protocol.

Endpoints: The Primary Efficacy Endpoint will be Subject response as defined by an increase of ≥3% in HbF from baseline to Week 24.  The Safety Endpoints will be the AEs, SAEs, clinically significant changes in laboratory tests, clinically significant changes in vital signs, and clinically significant changes in ECGs