Dose Escalation Study to Evaluate the Safety, Tolerability, PK and PD of Voxelotor in Patients With SCD

A Phase 2, Open Label, Multiple Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Voxelotor in Patients With Sickle Cell Disease

Study participants will undergo up to four periods of voxelotor administered orally at progressively higher dose levels from 1500 mg until either a maximum tolerated dose (MTD) or 3000 mg/day dose is reached, whichever occurs first

Inclusion Criteria:

1. Male or female with SCD
2. Documentation of SCD genotype HbSS or HbSB0
3. Age 18 to < 60 years, inclusive
4. Hemoglobin ≥ 5.5 and ≤ 10.5 g/dL during Screening, and considered stable and close to Baseline by the Investigator
5. For participants taking HU, the dose in mg/kg must be stable for at least 90 days prior to signing the informed consent form (ICF) and with no anticipated need for dose adjustments during the study, in the opinion of the Investigator.
6. Participants, who if female and of child-bearing potential, agree to use highly effective methods of contraception or practicing abstinence from study start to 30 days after the last dose of study drug, and who if male, agree to use barrier methods of contraception or practice abstinence from study start to 30 days after the last dose of study drug
7. Participant has provided documented informed consent

Exclusion Criteria:

1. More than 10 VOCs within 12 months of screening that required a hospital, emergency room, or clinic visit

2. Female participant who is breast feeding or pregnant

3. Receiving regularly scheduled blood (RBC) transfusion therapy (also termed chronic, prophylactic, or preventive transfusion) or have received an RBC transfusion for any reason within 60 days of signing the ICF or at any time during the Screening Period

4. Hospitalized for sickle cell crisis or other vaso-occlusive event within 30 days prior to dosing (ie, a vaso-occlusive event cannot be within 30 days prior to dosing)

5. Screening laboratory test of alanine aminotransferase (ALT) > 4 × upper level of normal (ULN)

6. Clinically significant bacterial, fungal, parasitic, or viral infection which requires therapy, including acute bacterial infection requiring antibiotics

7. Known to be COVID-19 positive from within 3 weeks of screening through Day 1

8. Participants with active hepatitis A, B, or C or who are known to be human immunodeficiency virus (HIV) positive

9. Severe renal dysfunction (estimated glomerular filtration rate < 30 mL/min/1.73 m2 at the Screening visit; calculated by the local laboratory to assess safety) or is on chronic dialysis

10. History of malignancy within the past 2 years prior to treatment Day 1 requiring chemotherapy and/or radiation (with the exception of local therapy for non-melanoma skin malignancy)

11. History of unstable or deteriorating cardiac or pulmonary disease within 6 months prior to consent including but not limited to the following:

    1. Unstable angina pectoris or myocardial infarction or elective coronary intervention
    2. Congestive heart failure requiring hospitalization
    3. Uncontrolled clinically significant arrhythmias
    4. Pulmonary hypertension

12. Criteria related to ECG parameters:

    1. PR interval > 220 msec in any participant
    2. QRS interval > 120 msec or QT interval corrected using Fridericia's formula (QTcF) > 480 msec (both genders) in participants without bundle branch block
    3. QRS interval > 120 msec in participants with newly (within 3 months) emerged bundle branch block
    4. A participant with stable bundle branch block with or without stable cardiac disease may be enrolled; QRS interval > 120 msec and QTcF interval > 480 msec are acceptable in these participants.

13. Any condition affecting drug absorption, such as major surgery involving the stomach or small intestine (prior cholecystectomy is acceptable)

14. Participated in another clinical trial 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 trial of an investigational agent or medical device

15. Inadequate venous access as determined by the Investigator/site staff

16. Medical, psychological, or behavioral conditions, which, in the opinion of the Investigator, may preclude safe participation, confound study interpretation, interfere with compliance, or preclude informed consent

17. Received erythropoietin or other hematopoietic growth factor treatment within 28 days of signing ICF or is anticipated to require such agents during the study

18. Ongoing or recent (within 2 years) substance abuse

19. Known allergy to voxelotor

20. Use of herbal medications (eg, St. John's Wort), sensitive cytochrome P450 (CYP) 3A4 substrates with a narrow therapeutic index, strong CYP3A4 inhibitors, fluconazole, or moderate or strong CYP3A4 inducers