Dose Escalation Study to Evaluate the Safety, Tolerability, PK and PD of Voxelotor in Patients With SCD
Condition: Sickle Cell Disease
MeSH terms: Anemia, Sickle Cell
Intervention: Voxelotor
Intervention description: synthetic small molecule supplied as 500 mg tablets
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 6.0
Sex: All
Minimum age: 18 Years
Maximum age: 60 Years
Healthy volunteers: No
Keywords: Sickle Cell Disease, SCD

Summary:

      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
    

Eligibility criteria:

        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