Safety, Tolerability and Pharmacokinetics of FTX-6058

NCT04586985 | Completed Phase 1 FDA Drug

• 1 other identifier: FIS-002-2020
• Study Type: interventional
• Target: 109
• Locations: 1 country
• Sites: 2

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).

Conditions

Healthy Adult Subjects; Sickle Cell Disease

Keywords

Healthy Adult Subjects; Sickle Cell Disease; Sickle Cell Anemia; Sickle Cell Disorder

Outcome Measures

Primary Outcomes (1)

• Treatment-Emergent Adverse Events

  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.

  Up to approximately 4 weeks of monitoring

Secondary Outcomes (6)

• Plasma Concentrations of FTX-6058

  Study Part A: Days 1, 2, 3 and 4

• Plasma Concentrations of FTX-6058

  Study Part B: Days 1, 2, 7, 8-10, 11-14 and 15

• Plasma Concentrations of FTX-6058

  Study Part C: Days 1-4

• Plasma Concentrations of Midazolam

  Study Part D: Days 1, 2, 12 and 13

• Plasma Concentrations of for 1-OH-Midazolam

  Study Part D: Days 1, 2, 12 and 13

Other Outcomes (4)

• Predictive Model of the Relationship between FTX-6058 Concentration and QTc Intervals

  Study Part A: Days 1 and 2

• Predictive Model of the Relationship between FTX-6058 Concentration and QTc Intervals

  Study Part B: Days 1, 2, and 7-15

• Target Engagement of FTX-6058

  Study Part B: Days -1, 7, 11-14 and 7-10 days after last dose of study drug

Study Arms (5)

Single Ascending Dose (SAD) cohorts in Healthy Subjects (Part A)

EXPERIMENTAL

Subjects will be randomized to receive a single dose of FTX-6058 or placebo. Cohorts 1 and 2 will enroll 5 subjects per cohort randomized 3:2. Cohorts 3-8 will enroll 7 subjects per cohort randomized 5:2. Planned doses are 2 mg (Cohort 1), 4 mg (Cohort 2), 10 mg (Cohort 3), 20 mg (Cohort 4), 30 mg (Cohort 5), 40 mg (Cohort 6), 60 mg (Cohort 7), and 90 mg (Cohort 8).

Drug: FTX-6058/placebo oral capsule(s)

Multiple Ascending Dose (MAD) cohorts in Healthy Subjects (Part B)

EXPERIMENTAL

Subjects will be randomized 3:1 to receive once daily FTX-6058 or placebo by mouth for 14 days. Up to 6 cohorts of 8 subjects per cohort will be enrolled. Planned doses are 2 mg (Cohort 1), 6 mg (Cohort 2), 10 mg (Cohort 3), 20 mg (Cohort 4), 30 mg (Cohort 5), and 40 mg (Cohort 6).

Drug: FTX-6058/placebo oral capsule(s)

Pilot Food Effect Cohort in Healthy Subjects (Part C)

EXPERIMENTAL

Ten subjects will be randomized to receive a single 20 mg dose of FTX-6058 with and without a high-fat meal with a washout period of 4 days.

Drug: FTX-6058 - Two Dosing Periods

Potential for CYP3A Induction in Healthy Subjects (Part D)

EXPERIMENTAL

Sixteen subjects will receive 3 mg Midazolam once by mouth on Day 1. On Days 3-12, subjects will receive FTX-6058 by mouth once daily. On Day 12, a second dose of 3 mg Midazolam will be given once by mouth. The dose of FTX-6058 will be the highest tolerated dose from Part B.

Drug: FTX-6058 / Midazolam Syrup

Multiple Dose Cohort in Sickle Cell Disease Subjects (Part E)

EXPERIMENTAL

Subjects will be randomized 3:1 to receive FTX-6058 or placebo once daily by mouth for 14 days. Up to 8 subjects will be enrolled. The planned dose is 6mg.

Drug: FTX-6058/placebo oral capsule(s)

Interventions

FTX-6058/placebo oral capsule(s) DRUG

Subjects will receive FTX-6058 or matching placebo.

Single Ascending Dose (SAD) cohorts in Healthy Subjects (Part A)

FTX-6058 - Two Dosing Periods DRUG

Subjects will receive FTX-6058

Pilot Food Effect Cohort in Healthy Subjects (Part C)

FTX-6058 / Midazolam Syrup DRUG

Subjects will receive FTX-6058 and midazolam syrup

Potential for CYP3A Induction in Healthy Subjects (Part D)

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy male / female subjects, 18 to 55 years of age, inclusive at screening.
• 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.
• Body mass index (BMI) between 18 and 32 kg/m², inclusive at screening, and with a minimum weight of 50 kg.
• 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.
• Signed and dated written informed consent.
• Willing and able to comply with all study procedures.
• 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.

You may not qualify if:

• 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).
• History of febrile illness within 1 week prior to the baseline visit.
• 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).
• Known renal impairment (defined as glomerular filtration rate of \<60 mL/min/1.73 m²).
• 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.
• Any condition possibly affecting drug absorption (e.g., gastrectomy, cholecystectomy, or other gastrointestinal tract surgery, except appendectomy).
• 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.
• 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.
• 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.
• 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.
• 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.
• History of demonstrating an excess in xanthine or caffeine consumption (more than 8 cups of coffee or equivalent per day).
• 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.
• 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.
• 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.

Sponsors & Collaborators

• Fulcrum Therapeutics: lead

Study Sites (2)

Atlanta Center for Medical Research - Sickle Cell Subjects Only

Atlanta, Georgia, 30331, United States

Location

Altasciences Clinical Kansas, Inc. - Healthy Adults Subjects Only

Overland Park, Kansas, 66212, United States

Location

Related Publications (5)

• Ngo DA, Aygun B, Akinsheye I, Hankins JS, Bhan I, Luo HY, Steinberg MH, Chui DH. Fetal haemoglobin levels and haematological characteristics of compound heterozygotes for haemoglobin S and deletional hereditary persistence of fetal haemoglobin. Br J Haematol. 2012 Jan;156(2):259-64. doi: 10.1111/j.1365-2141.2011.08916.x. Epub 2011 Oct 24.

  PMID: 22017641 BACKGROUND

• Piel FB, Steinberg MH, Rees DC. Sickle Cell Disease. N Engl J Med. 2017 Apr 20;376(16):1561-1573. doi: 10.1056/NEJMra1510865. No abstract available.

  PMID: 28423290 BACKGROUND

• Sankaran VG, Orkin SH. The switch from fetal to adult hemoglobin. Cold Spring Harb Perspect Med. 2013 Jan 1;3(1):a011643. doi: 10.1101/cshperspect.a011643.

  PMID: 23209159 BACKGROUND

• Saraf SL, Molokie RE, Nouraie M, Sable CA, Luchtman-Jones L, Ensing GJ, Campbell AD, Rana SR, Niu XM, Machado RF, Gladwin MT, Gordeuk VR. Differences in the clinical and genotypic presentation of sickle cell disease around the world. Paediatr Respir Rev. 2014 Mar;15(1):4-12. doi: 10.1016/j.prrv.2013.11.003. Epub 2013 Nov 15.

  PMID: 24361300 BACKGROUND

• Steinberg MH, Chui DH, Dover GJ, Sebastiani P, Alsultan A. Fetal hemoglobin in sickle cell anemia: a glass half full? Blood. 2014 Jan 23;123(4):481-5. doi: 10.1182/blood-2013-09-528067. Epub 2013 Nov 12.

  PMID: 24222332 BACKGROUND

MeSH Terms

Conditions

Anemia, Sickle Cell

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• John Ziegler, MD, FASA

  Fulcrum Therapeutics

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Randomized double-blind, placebo-controlled
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Single ascending dose escalation and multiple ascending dose escalation study followed by an evaluation of food effects on absorption and CYP3A induction

Study Record Dates

• First Submitted: October 5, 2020
• First Posted: October 14, 2020
• Study Start: October 26, 2020
• Primary Completion: November 15, 2022
• Study Completion: November 15, 2022
• Last Updated: December 12, 2022

Record last verified: 2022-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)