Healthy Adult Subjects, Sickle Cell Disease
Conditions
Keywords
Healthy Adult Subjects, Sickle Cell Disease, Sickle Cell Anemia, Sickle Cell Disorder
Brief summary
This is a study to evaluate the safety, tolerability and pharmacokinetics of FTX-6058 in healthy adult subjects and adult subjects with sickle cell disease (SCD).
Detailed description
This study is a Phase 1 randomized, double-blind, placebo-controlled, single- and multiple-dose study evaluating safety, tolerability, and pharmacokinetics, with an open-label initial food effect and CYP3A drug-drug interaction study, of FTX-6058 in healthy adult subjects and a randomized, double-blind, placebo-controlled, multiple-dose study in adult subjects with sickle cell disease (SCD). This study will comprise 5 parts and will be conducted in healthy adult subjects and adult subjects with sickle cell disease (SCD) (Part E only). Part A will be a randomized, double-blind, placebo-controlled, single ascending dose (SAD) study in up to 8 cohorts of healthy adult subjects. Part B will be a randomized, double-blind, placebo-controlled, multiple ascending dose (MAD) study in up to 6 cohorts of healthy adult subjects dosed once daily for 14 days. Part C will be an open-label pilot food effect study in healthy adult subjects randomized to take FTX-6058 with and without a high-fat meal, and Part D will be an open-label study to evaluate the potential of FTX-6058 to induce CYP3A (using midazolam) in healthy adult subjects. Part E will be a randomized, double-blind, placebo-controlled, multiple dose study in adult subjects with sickle cell disease (SCD). Subjects in Part E may enroll into Study 6058-SCD-101 (NCT 05169580) Part A (6 mg cohort) at the Day 15 visit; subjects that enroll into 6058-SCD-101 will not need to undergo the Safety Follow-up visit. The primary endpoint of the study is to evaluate the safety and tolerability of FTX-6058 in healthy adult subjects and adult subjects with sickle cell disease as measured by the frequency of adverse events. Secondary endpoints include evaluation of the pharmacokinetics of single dose and multiple dose FTX-6058 in healthy adult subjects, pharmacokinetics of multiple dose FTX-6058 in adult subjects with sickle cell disease, evaluation of the potential effect of food on FTX-6058 and evaluation of the potential for CYP3A induction by FTX-6058 in healthy adult subjects.
Interventions
DRUGFTX-6058/placebo oral capsule(s)
Subjects will receive FTX-6058 or matching placebo.
DRUGFTX-6058 - Two Dosing Periods
Subjects will receive FTX-6058
DRUGFTX-6058 / Midazolam Syrup
Subjects will receive FTX-6058 and midazolam syrup
Sponsors
Fulcrum Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Randomized double-blind, placebo-controlled
Intervention model description
Single ascending dose escalation and multiple ascending dose escalation study followed by an evaluation of food effects on absorption and CYP3A induction
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
Healthy Subjects 1. Healthy male / female subjects, 18 to 55 years of age, inclusive at screening. 2. Good health, based upon the opinion of the investigator and the results of medical history, physical examination, vital signs, ECG, and laboratory profiles of both blood and urine at screening. 3. Body mass index (BMI) between 18 and 32 kg/m², inclusive at screening, and with a minimum weight of 50 kg. 4. Willingness of men and women of reproductive potential to agree to use two effective means of contraception throughout study participation until 90 days after dose administration. 5. Signed and dated written informed consent. 6. Willing and able to comply with all study procedures. 7. Females with hematocrit \>35% and \<45% or hemoglobin \>11.7/dL and \<15.5/dL and males with hematocrit \>38.5% and \<50% or hemoglobin \>13.2/dL and \<17.1/dL.
Exclusion criteria
Healthy Subjects 1. History of any illness or any clinical condition that, in the opinion of the investigator/sub-investigator, might confound the results of the study or pose an additional risk in administering study drug to the subject. This may include, but is not limited to, history or presence of gastrointestinal conditions including Crohn's disease, ulcerative colitis, frequent episodes of diarrhea, or irritable bowel syndrome; history of relevant drug or food allergies; history of cardiovascular or central nervous system disease; history or presence of clinically significant pathology; clinically significant history of mental disease; concurrent active malignancy; and history of cancer, except for squamous cell skin cancer, basal cell skin cancer, and Stage 0 cervical carcinoma in situ (all 3 with no recurrence for the last 5 years). 2. History of febrile illness within 1 week prior to the baseline visit. 3. Acute or chronic history of liver disease or current alanine aminotransferase ≥ 2 × ULN or total bilirubin \>1.5 × ULN at screening (Note: Subjects with Gilbert's syndrome are permitted to enroll in the trial). 4. Known renal impairment (defined as glomerular filtration rate of \<60 mL/min/1.73 m²). 5. Positive screen for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, or antibodies against human immunodeficiency viruses 1 and 2 (HIV1/HIV2 Abs) at screening. 6. Any condition possibly affecting drug absorption (e.g., gastrectomy, cholecystectomy, or other gastrointestinal tract surgery, except appendectomy). 7. Standard 12 lead ECG demonstrating QTcF \>450 msec for male subjects and QTcF \>470 msec for female subjects at screening. If QTcF exceeds 450 msec for males or 470 msec for females, the ECG will be repeated 2 more times, and the average of the 3 QTcF values will be used to determine the subject's eligibility. 8. History of cardiac dysrhythmias requiring anti-arrhythmia treatment(s) or history or evidence of abnormal ECGs that, in the opinion of the investigator or medical monitor, would preclude the subject's participation in the study. 9. Blood or blood product (e.g., plasma/serum) donation (of approximately 1 pint \[500 mL\] or more) or any significant loss of blood within 8 weeks prior to screening or intention to donate blood or blood products during the study as determined by the investigator. 10. History of abuse of addictive substances such as drug abuse, or regular user of sedatives, hypnotics, tranquilizers, or any other addictive agent within 6 months prior to screening. 11. History of regular alcohol consumption within 6 months prior to screening defined as: (a) An average weekly intake of greater than 21 units. One unit is equivalent to a 285 mL glass of full-strength beer or 425 mL of light beer or 1 (30 mL) measure of spirits or 1 glass (100 mL) of wine. 12. History of demonstrating an excess in xanthine or caffeine consumption (more than 8 cups of coffee or equivalent per day). 13. Use of another investigational product within 30 days or 5 half-lives (whichever is longer), or according to local regulations, or currently participating in a prospective study with an investigational product or medical device. 14. Use of any medication (prescription or over-the-counter \[OTC\]) within 14 days of study drug administration, or use of herbal supplements, dietary supplements or multivitamins within 7 days of study drug administration or less than 5 half-lives (whichever is longer), with the exception of paracetamol (up to 3 g/day). Other exceptions will only be made if the rationale is clearly documented by the investigator (a) Note: Any vaccination, including COVID-19 vaccine, cannot be administered within 14 days prior to initial dose of study drug until the end of study participation. 15. History of sensitivity to the study drug or placebo, or a history of drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates their participation. 16. Female subject who is pregnant, trying to become pregnant, or is breastfeeding or male subject whose partner is pregnant, trying to become pregnant, or is breastfeeding. 17. Subject is mentally or legally incapacitated. 18. Abnormal laboratory results indicative of any significant medical disease that, in the opinion of the investigator, would preclude the subject's participation in the study at screening or prior to first dose. 19. Subject, or close relative of the subject, is the investigator or a sub-investigator, research assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of the study at that site. 20. Positive test for drugs of abuse at screening or baseline. 21. Positive test for COVID-19 prior to admission to the study site, as required per local regulations. 22. Subject smokes cigarettes (or equivalent) and/or has used nicotine-based products within 3 months prior to screening. (a) Note: Cotinine test is not required per protocol but may be performed at the discretion of the Investigator to confirm non-smoker status. 23. Consumption of any alcohol within the 48-hour period prior to study drug administration. 24. Plans for hospitalization, surgery, or other major procedures during the study duration or between screening and baseline. 25. Part D Only: Any contraindication to the use of midazolam. Inclusion Criteria: Sickle Cell Disease Subjects 1. Subject is 18 to 55 years of age at the time informed consent is obtained. Subject has provided consent before any study-specific procedures are performed and is willing and able to comply with the study procedures and restrictions. 2. Body mass index (BMI) between 18 and 32 kg/m², inclusive at screening, and with a minimum weight of 50 kg 3. Willingness of men and women of reproductive potential must agree to use 2 effective means of contraception throughout study participation until 90 days after dose administration. 4. Signed and dated written informed consent. 5. Confirmed Sickle Cell Disease (SCD) at the time of screening (SS and S/β⁰) by high performance liquid chromatography (HPLC). 6. HbF ≤20% of total hemoglobin (Hb) at screening by HPLC 7. SCD characterized by both of the following: (a) Total hemoglobin between 5.5 and 10.5 g/dL at screening; (b) 0-6 vaso-occlusive crisis (VOC) episodes over the 12 months prior to screening (VOC is defined as pain crises (defined as an acute onset of pain for which there is no other medically determined explanation other than vaso- occlusion and which requires therapy with oral or parenteral opioids or parenteral NSAIDs) as well as other complicated crises, such as acute chest syndrome (ACS), priapism, and hepatic or splenic sequestration.). 8. Subject must meet both of the following laboratory values at screening: (a) Absolute neutrophil count ≥1.5/ × 10⁹/L; (b) Platelets ≥80 × 10⁹/L 9. Absolute reticulocyte count at screening higher than 100 × 10⁹/L
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment-Emergent Adverse Events | Up to approximately 4 weeks of monitoring | To evaluate the safety and tolerability of FTX-6058 in healthy adult subjects and adult subjects with sickle cell disease based on the frequency of adverse events (AEs), frequency of serious adverse events (SAEs), and clinically significant laboratory test results, electrocardiograms (ECGs), and vital signs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Concentrations of FTX-6058 | Study Part A: Days 1, 2, 3 and 4 | Blood samples will be collected to measure the plasma concentration of FTX-6058 at specified timepoints by liquid chromatography with tandem mass spectrometry. |
| Plasma Concentrations of Midazolam | Study Part D: Days 1, 2, 12 and 13 | Blood samples will be collected to measure the plasma concentration of Midazolam at specified timepoints by liquid chromatography with tandem mass spectrometry |
| Plasma Concentrations of for 1-OH-Midazolam | Study Part D: Days 1, 2, 12 and 13 | Blood samples will be collected to measure the plasma concentration of 1-OH-Midazolam at specified timepoints by liquid chromatography with tandem mass spectrometry. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Target Engagement of FTX-6058 | Study Part B: Days -1, 7, 11-14 and 7-10 days after last dose of study drug | Change from baseline in H3K27me3/Total Histone H3 ratio in circulating monocytes will be evaluated by fluorescence-activated cell sorting (FACS). |
| Predictive Model of the Relationship between FTX-6058 Concentration and QTc Intervals | Study Part A: Days 1 and 2 | A model of the relationship between time-match FTX-6058 plasma concentrations and QTc intervals may be developed and will include simulations to predict potential QT risk. |
Countries
United States
Outcome results
None listed