A Phase 2b Study to Evaluate the Safety and Efficacy of IMR-687 in Subjects with Sickle Cell Disease

Each subject must meet all the following criteria to be enrolled in the study:
1. Male or female aged *18 to *65 years at the time of informed consent form
(ICF) signing.
2. Confirmed diagnosis of SCD (HbSS, HbS*0 thalassemia, or HbS*+ thalassemia)
in the medical record; if not available, the diagnosis must be confirmed at the
site*s local laboratory instead.
3. Subjects must have had at least 2 and no more than 12 documented episodes of
VOC in the past 12 months at the time of ICF signing and at randomization (Day
1).
For study eligibility, VOC is defined as a documented episode of an acute
painful crisis (for which there was not an explanation other than VOC) that
involved moderate to severe pain lasting for at least 2 hours and at least one
of the following:
* Use of escalated analgesia (including healthcare professional-instructed use
of an analgesic prescription)
* A hospital, emergency department, or clinic visit and/or healthcare telephone
consultation at the time of occurrence
* Diagnosis of acute chest syndrome (ACS) (defined as an acute illness
characterized by fever and/or respiratory symptoms, accompanied by a new
pulmonary infiltrate on a chest X ray), hepatic sequestration, splenic
sequestration, or priapism (in males)
4. Hb of >5.5 and <10.5 g/dL; Hb values within 21 days post-transfusion will be
excluded.
5. This inclusion criterion has been removed.
6. Subjects receiving HU must have received it continuously for at least 6
months prior to signing the ICF, and must have been on a stable dose for at
least 3 months prior to signing the ICF, with no anticipated need for dose
adjustments during the study including the screening period, in the opinion of
the investigator.
7. Female subjects must not be pregnant or breastfeeding and be highly unlikely
to become pregnant. Male subjects must be unlikely to impregnate a partner.
Male or female subjects must meet at least one of the following criteria:
* A female subject who is not of reproductive potential is eligible without
requiring the use of contraception. A female subject who is not of reproductive
potential is defined as one who: (1) has reached natural menopause (defined as
12 months of spontaneous amenorrhea without an alternative medical cause, and
can be confirmed with serum follicle-stimulating hormone levels in the
postmenopausal range as determined by the central laboratory); (2) is 6 weeks
post surgical bilateral oophorectomy with or without hysterectomy; or (3) has
undergone bilateral tubal ligation. Spontaneous amenorrhea does not include
cases for which there is an underlying disease that causes amenorrhea (e.g.,
anorexia nervosa).
* A female of reproductive potential must have 2 negative pregnancy tests as
verified by the investigator prior to starting study therapy. She must agree to
ongoing pregnancy testing during the course of the study, at the EOT visit, and
at the EOS visit. This applies even if the subject practices true abstinence
from heterosexual contact.
* A male subject who is not of reproductive potential is eligible without
requiring the use of contraception. A male subject who is not of reproductive
potential is defined as one who has undergone a successful vasectomy. A
successful vasectomy is defined as (1) microscopic documentation of azoospermia
or (2) a vasectomy more than 2 years ago with no resultant pregnancy despite
sexual activity post vasectomy.
* A male or female subject who is of reproductive potential agrees to remain
truly abstinent or use (or have their partner use) acceptable methods of highly
effective contraception starting from the time of consent through 3 months
after the completion of study drug. True abstinence is defined as abstinence
that is in line with the preferred and usual lifestyle of the subject. Periodic
abstinence (e.g., calendar, ovulation, symptothermal, post ovulation methods),
declaration of abstinence for the duration of the study, and withdrawal are not
acceptable methods of contraception. Acceptable methods of highly effective
birth control are combined or progesterone-only hormonal contraception that is
associated with inhibition of ovulation, intrauterine device, and intrauterine
hormone releasing system.
8. Be capable of giving informed consent and reading and signing the ICF after
the nature of the study has been fully explained by the investigator or
investigator designee.
9. Be willing and able to complete all study assessments and procedures and to
communicate effectively with the investigator and site staff.

Subjects who meet any of the following criteria will be excluded from the study:
1. Hospital discharge for sickle cell crisis or other vaso occlusive event
within the 4 days prior to randomization (Day 1).
2. Subjects participating in a chronic/prophylactic RBC transfusion program
(i.e., regularly scheduled RBC transfusions); any transfusions within 21 days
of screening or baseline Hb measurements.
3. Subjects with HbF >25% at screening.
4. Subjects with known active hepatitis A, hepatitis B, or hepatitis C, with
active or acute event of malaria, or who are known to be positive for human
immunodeficiency virus (HIV).
5. For female subjects of childbearing potential, a positive serum human
chorionic gonadotropin (hCG) test (screening) or a positive urine hCG test at
randomization (Day 1).
6. Significant kidney disease as indicated by, for example, estimated
glomerular filtration rate (eGFR) <45 mL/min as calculated by the equation from
the Modification of Diet in Renal Disease (MDRD) Study using creatinine, age,
sex, and ethnicity (modified MDRD formula).
7. Alanine aminotransferase or aspartate aminotransferase >3× the upper limit
of normal.
8. Body mass index (BMI) <17.0 kg/m2 or >35 kg/m2; or total body weight <45 kg.
9. Current or history of malignancies (solid tumors and hematological
malignancies), unless the subject has been free of the disease (including
completion of any active or adjuvant treatment for prior malignancy) for *5
years. However, subjects with the following history of/concurrent conditions
are allowed if, in the opinion of the investigator, the condition has been
adequately diagnosed and is determined to be clinically in remission, and the
subject*s participation in the study would not represent a safety concern:
a. Basal or squamous cell carcinoma of the skin
b. Carcinoma in situ of the cervix
c. Carcinoma in situ of the breast
d. Incidental histologic finding of prostate cancer (T1a or T1b using the
tumor, nodes, metastasis clinical staging system)
10. History of a clinically significant allergic reaction or hypersensitivity,
as judged by the investigator, to any drug or any component of the study drug
formulations used in the study (see the Investigator*s Brochure).
11. History of unstable or deteriorating cardiac or pulmonary disease within 6
months before signing the ICF, including but not limited to the following:
a. Unstable angina pectoris or myocardial infarction or elective coronary
intervention
b. Congestive heart failure requiring hospitalization
c. Uncontrolled clinically significant arrhythmias
12. Any condition affecting drug absorption, such as major surgery involving
the stomach or small intestine (prior cholecystectomy is acceptable).
13. On ECG testing at ICF signing and/or randomization (Day 1), a corrected QT
interval, Fridericia*s formula (QTcF) >450 ms in men and >470 ms in women on 2
or more of the triplicate ECGs, or the presence of clinically significant ECG
abnormalities as determined by the investigator.
14. Major surgery within 8 weeks or minor surgery within 2 weeks of
randomization (Day 1).
15. Stroke requiring medical intervention within 24 weeks prior to
randomization (Day 1).
16. Subjects taking direct acting oral anti-coagulants (apixaban, dabigatran,
rivaroxaban, edoxaban, or ticagrelor) or taking warfarin, unless they stopped
the treatment at least 28 days prior to randomization (Day 1); low molecular
weight heparins are allowed in the peri operative period; aspirin use (<100 mg
per day) is allowed before and during the study.
17. Poorly controlled diabetes mellitus in the opinion of the investigator, for
example 1) Hb A1c >9.0% within 12 weeks prior to randomization (in the medical
history); 2) short term hyperglycemia leading to hyperosmolar or ketoacidotic
crisis; and/or 3) history of diabetic cardiovascular complications.
18. Subject has received chronic systemic glucocorticoids within 12 weeks prior
to randomization (*5 mg/day prednisone or equivalent). Physiologic replacement
therapy for adrenal insufficiency is allowed.
19. Any clinically significant bacterial, fungal, parasitic, or viral infection
requiring antibiotic therapy should delay screening/randomization (Day 1) until
the course of antibiotic therapy has been completed. This includes, but is not
limited to, long-term tuberculosis treatment.
20. Participated in another clinical study of an investigational agent (or
medical device) within 30 days or 5 half-lives of date of informed consent,
whichever is longer, or is currently participating in another study of an
investigational agent (or medical device).
21. Prior exposure to IMR 687.
22. History of crizanlizumab (Adakveo®) or voxelotor (Oxbryta®) use within 6
months prior to signing the ICF or anticipated need for such agents during the
study.
23. Consumption/use of the following drugs or other substances within the
specified time periods before randomization or plans to consume/use at any time
during the study. If there is any question as to whether a substance is
permitted, please review the product labeling (if applicable) and consult the
medical monitor and/or sponsor.
a. Phosphodiesterase type 5 inhibitors (including but not limited to
sildenafil, tadalafil, and vardenafil) within 7 days prior to randomization
(Day 1) or plans to use during the study.
b. Grapefruit, grapefruit juice, grapefruit products, or herbal supplements
with CYP altering abilities within 1 week prior to randomization (Day 1) or
plans to consume during the study.
c. CYP3A-sensitive substrates, including the opioids fentanyl and alfentanil,
or moderate to strong CYP3A inhibitors or inducers within 28 days prior to
randomization (Day 1) or plans to use during the study
d. Any drugs or substances known to be substrates or inhibitors of P
glycoprotein or breast cancer resistance protein within 28 days prior to
randomization (Day 1) or plans to use during the study.
24. Receipt of erythropoietin, luspatercept (Reblozyl®), or other
erythropoiesis-stimulating or erythroid maturation agent within 6 months prior
to signing the ICF or anticipated need for such agents during the study.
25. Prior gene therapy.
26. Any significant medical condition, laboratory abnormality, or psychiatric
illness that would prevent the subject from participating in the study,
including the presence of laboratory abnormalities that may place the subject
at unacceptable risk if he/she were to participate in the study.
27. Other prior or ongoing medical condition, physical findings, or laboratory
abnormality that, in the investigator*s opinion, could adversely affect the
safety of the subject, make it unlikely that the course of treatment or follow
up would be completed, or impair the assessment of study results (e.g., a
history of drug or alcohol abuse within the past 1 year, as judged by the
investigator).