A Phase 2 Study to Evaluate the Safety and Tolerability of IMR-687 in Subjects with Beta Thalassemia

Subjects must meet all of the following inclusion criteria to be eligible for
the study:
1. Subjects must understand and voluntarily provide informed consent and sign
an informed consent form (ICF) prior to any study-related
assessments/procedures being conducted. Although RBC transfusions and
associated Hb laboratory measurements prior to Screening are not study related,
the ICF will specifically request subject consent to collect these data.
2. Subjects must be >=18 to <=65 years of age at the time of signing the ICF.
3. Subjects must have documented diagnosis of β-thalassemia or HbE/β-
thalassemia in their medical history. Concomitant alpha gene deletion,
duplication, or triplication is allowed.
4. For TDT subjects only: Subjects must be regularly transfused, defined as >3
to 10 pRBC units (one RBC unit refers to one bag of packed RBCs) in the 12
weeks prior to the Baseline (Day 1) visit and no transfusion-free period for
>35 days during that period.
For NTDT subjects only: Subjects must be transfusion independent, defined as 0
to <=3 units1 of pRBCs received during the 12-week period prior to the Baseline
(Day 1) visit, must not be on a regular transfusion program, must be RBC
transfusion-free for at least >= 4 weeks prior to randomization, and must not be
scheduled to start a regular hematopoietic stem cell transplantation within 9
months.
5. Subjects must have documentation of the dates of transfusion events and the
number of pRBC units per event within the 12 weeks prior to the Baseline (Day
1) visit.
6. Subjects must be willing and able to complete all study assessments and
procedures, and to communicate effectively with the investigator and site staff.
7. Subjects must have Eastern Cooperative Oncology Group (ECOG) performance
score of 0 to 1 (Appendix 1).
8. Female subjects must not be pregnant or breastfeeding and be highly unlikely
to become pregnant. Male subjects must be unlikely to impregnate a partner.
Male or female subjects must meet at least one of the following criteria:
• A female subject who is not of reproductive potential is eligible without
requiring the use of contraception. A female subject who is not of reproductive
potential is defined as one who: (1) has reached natural menopause (defined as
12 months of spontaneous amenorrhea without an alternative medical cause, and
can be confirmed with serum follicle-stimulating hormone levels in the
postmenopausal range as determined by the central laboratory); (2) is 6 weeks
post-surgical bilateral oophorectomy with or without hysterectomy; or (3) has
undergone bilateral tubal ligation. Spontaneous amenorrhea does not include
cases for which there is an underlying disease that causes amenorrhea (e.g.,
anorexia nervosa).
• A female of reproductive potential must have 2 negative pregnancy tests as
verified by the investigator prior to starting study therapy. She must agree to
ongoing pregnancy testing during the course of the study, at the end of
treatment visit, and at the end of study visit. This applies even if the
subject practices true abstinence from heterosexual contact.
• A male subject who is not of reproductive potential is eligible without
requiring the use of contraception. A male subject who is not of reproductive
potential is defined as one who has undergone a successful vasectomy. A
successful vasectomy is defined as (1) microscopic documentation of
azoospermia, or (2) a vasectomy more than 2 years ago with no resultant
pregnancy despite sexual activity post-vasectomy.
• • A male or female subject who is of reproductive potential agrees to remain
truly abstinent or use (or have their partner use) acceptable methods of highly
effective contraception starting from the time of consent through 3 months
after the completion of study therapy. True abstinence is defined as abstinence
that is in line with the preferred and usual lifestyle of the subject. Periodic
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods),
declaration of abstinence for the duration of the study, and withdrawal are not
acceptable methods of contraception. Acceptable methods of highly effective
birth control are combined or progesterone-only hormonal contraception that is
associated with inhibition of ovulation, intrauterine device, and intrauterine
hormone releasing system.
9. Subjects receiving hydroxyurea must have received it continuously for at
least 6 months prior to signing the ICF, and must have been on a stable dose
for at least 3 months prior to signing the ICF, with no anticipated need for
dose adjustments during the study including the screening period, in the
opinion of the investigator.
10. For NTDT subjects only: Subjects must have Hb <=10.0 g/dL at Screening; the
screening Hb sample must be collected 7 to 28 days prior to randomization. Hb
values within 21 days post transfusion will be excluded.

Subjects meeting any of the following criteria must be excluded from the study:
1. Any significant medical condition, laboratory abnormality, or psychiatric
illness that would prevent the subject from participating in the study,
including the presence of laboratory abnormalities that may place the subject
at unacceptable risk if he/she were to participate in the study.
2. Any situation or condition that confounds the ability to interpret data from
the study (e.g., subjects also receiving RBC transfusions at centers not able
to obtain laboratory samples for central processing).
3. Diagnosis of α-thalassemia (e.g., hemoglobin H [HbH]) or hemoglobin S (HbS)/
β thalassemia.
4. Body mass index (BMI) <17.0 kg/m2 or a total body weight <45 kg; or BMI >35
kg/m2.
5. Subjects with known active hepatitis A, hepatitis B, or hepatitis C, with
active or acute event of malaria, or who are known to be positive for human
immunodeficiency virus (HIV).
6. Stroke requiring medical intervention <=24 weeks prior to randomization.
7. Subjects taking direct acting oral anti-coagulants (DOACs) apixaban,
dabigatran, rivaroxaban, edoxaban, or ticagrelor, or taking warfarin, are
excluded due to the possibility of a cytochrome P450 (CYP)3A-mediated drug
interaction, unless they stopped the treatment at least 28 days prior to
randomization (Day 1); other oral anti-coagulants and anti-platelet drugs are
permitted. Anti-coagulant therapies for prophylaxis of venous thromboembolism,
including pulmonary emboli including when undergoing surgery or high risk
procedures, are allowed if low molecular weight heparins are used in the peri
operative period. Aspirin use (<100 mg per day) is allowed before and during
the study.
8. Participated in another clinical study of an investigational agent (or
medical device) within 30 days or 5 half-lives of date of informed consent,
whichever is longer, or is currently participating in another study of an
investigational agent (or medical device).
9. Platelet count >1000 × 109/L.
10. For subjects on iron chelation therapy (ICT) at the time of ICF signing,
initiation of ICT less than 24 weeks before the predicted randomization date.
ICT can be initiated at any time during treatment and should be used according
to the label.
11. Subjects who have had treatment with erythropoietin-stimulating agents <=24
weeks prior to randomization.
12. Uncontrolled hypertension as defined by systolic BP >=160 mm Hg or diastolic
BP >=100 mm Hg, medical intervention indicated, and more than one drug or more
intensive therapy than previously used indicated.
13. Poorly controlled diabetes mellitus, in the opinion of the investigator,
for example 1) Hb A1c >9.0% within 12 weeks prior to randomization (in the
medical history); 2) short-term hyperglycemia leading to hyperosmolar or
ketoacidotic crisis; and/or 3) history of diabetic cardiovascular complications.
14. Subjects who have major organ damage, including:
a. Liver disease with ALT or AST >3× ULN; direct bilirubin >3× ULN with
proportion of direct/total bilirubin >0.3; or history/evidence of cirrhosis,
liver transplant, or presence of clinically significant mass/tumor.
b. Heart disease, heart failure as classified by the New York Heart Association
classification 3 or higher, or significant arrhythmia requiring treatment, or
recent myocardial infarction within 6 months of randomization, or significant
cardiac iron overload.
c. Severe lung disease, including pulmonary fibrosis or pulmonary hypertension,
i.e., >=Grade 3 NCI CTCAE version 5.0.
d. Significant kidney disease as indicated by, for example, estimated
glomerular filtration rate <45 mL/min/1.73 m2 (per Modification of Diet in
Renal Disease formula).
15. Subjects who have received chronic systemic glucocorticoids <=12 weeks prior
to randomization (>=5 mg/day prednisone or equivalent). Physiologic replacement
therapy for adrenal insufficiency is allowed.
16. Major surgery <=8 weeks prior to randomization.
17. A history of a clinically significant allergic reaction or
hypersensitivity, as judged by the investigator, to any drug or any component
of the study drug formulations used in the study (see Investigator*s Brochure).
18. History or current malignancies (solid tumors and hematological
malignancies) unless the subject has been free of the disease (including
completion of any active or adjuvant treatment for prior malignancy) for >=5
years. However, subjects with the following history/concurrent conditions are
allowed if, in the opinion of the investigator, the condition has been
adequately diagnosed and is determined to be clinically in remission, and the
subject*s participation in the study would not represent a safety concern:
a. Basal or squamous cell carcinoma of the skin
b. Carcinoma in situ of the cervix
c. Carcinoma in situ of the breast
d. Incidental histologic finding of prostate cancer (T1a or T1b using the
tumor, nodes, metastasis clinical staging system)
19. Screening or Baseline (Day 1) electrocardiogram (ECG) demonstrating a QTcF
>450 ms in men and >470 ms in women on 2 or more of the triplicate ECGs, or the
presence of clinically significant ECG abnormalities as determined by the
investigator.
20. Consumption/use of the following drugs or other substances within the
specified time periods before randomization or plans to consume/use at any time
during the study. If there is any question as to whether a substance is
permitted, please review the product labelling (if applicable) and consult the
medical monitor and/or sponsor.
a. PDE type 5 inhibitors (including but not limited to sildenafil, tadalafil,
and vardenafil) within 7 days prior to randomization (Day 1) or plans to use
during the study.
b. Grapefruit, grapefruit juice, grapefruit products, or herbal supplements
with CYP altering abilities within 1 week prior to randomization (Day 1) or
plans to consume during the study.
c. CYP3A sensitive substrates, including the synthetic opioid fentanyl and
alfentanil, or moderate to strong CYP3A inhibitors or inducers within 28 days
prior to randomization (Day 1) or plans to use during the study.
d. Any drugs or substances known to be substrates or inhibitors of P
glycoprotein (P gp) or breast cancer resistance protein (BCRP) within 28 days
prior to randomization (Day 1) or plans to use during the study.
21. Other prior or ongoing medical condition, physical findings, or laboratory
abnormality that, in the investigator's opinion, could adversely affect the
safety of the subject, make it unlikely that the course of treatment or follow
up would be completed, or impair the assessment of study results (e.g., a
history of drug or alcohol abuse as judged by the investigator within the past
1 year).
22. Any clinically significant bacterial, fungal, parasitic, or viral infection
requiring antibiotic therapy should delay screening/randomization (Day 1) until
the course of antibiotic therapy has been completed. This includes but is not
limited to long-term tuberculosis treatment.
23. Prior exposure to any of following:
a. IMR-687 or gene therapy
b. Sotatercept or luspatercept (Reblozyl®) within 6 months prior to
randomization (Day 1)
24. In the opinion of the investigator, the subject is unable to meet the
requirements of the study.