Safety, Tolerability and Pharmacokinetics of FTX-6058

This is an interventional treatment trial for Healthy Adult Subjects focused on measuring Healthy Adult Subjects, Sickle Cell Disease, Sickle Cell Anemia, Sickle Cell Disorder Read More

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

Exclusion Criteria: Sickle Cell Disease Subjects

1. Major surgery, hospitalization, infection, significant bleeding, cerebrovascular accident or seizure, or transfusion within 14 days prior to study enrollment through conclusion of study follow-up period; elective surgery planned for the time period of the trial.
2. Sickle cell complication requiring hospitalization in the past 14 days or > 6 total VOCs over the past 12 months requiring hospitalization.
3. Use of opioids and/or opiates (unless used for chronic pain management), anticoagulants, or medications that induce or inhibit CYP3A4 within 14 days prior to starting study drug or anticipated need for any of these agents during the study. (Pain meds for chronic pain management or VOC events occurring during the study may be administered at the discretion of the investigator.)
4. Use of voxelotor or hydroxyurea within 60 days prior to starting study drug.
5. Participation in any other investigative treatment studies within the past 60 days.
6. History of bone marrow transplant or human stem cell transplant or gene therapies.
7. Vaccination (including against COVID-19) in the previous 14 days.
8. Positive test for COVID-19 prior to admission to the study site, as required per local regulations.
9. Significant abnormalities in hepatic biochemical tests that, in the opinion of the investigator, are outside the typical range seen with SCD. Potential subjects are to be excluded if alanine aminotransferase (ALT) or aspartate transaminase (AST) ≥3× ULN or albumin <2.0 mg/dL or direct (conjugated) bilirubin ≥1.5 mg/dL or prothrombin time/international normalized ratio > 1.5 ULN.
10. Subjects with end stage renal disease defined as glomerular filtration rate <10 mL/min/1.73m², using Schwartz formula or serum creatinine >1.2 mg/dL and calculated creatinine clearance <30 mL/min. Subjects on dialysis are excluded.
11. Subjects with 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 or potentially obscure the interpretation of the scheduled assessments. Screening laboratory assessments may be repeated up to twice at the discretion of the investigator.
12. Subjects being treated with antiretroviral agents (such as didanosine and stavudine).
13. Infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C such that subjects are currently on therapy or will be placed on therapy during the trial
14. Subjects receiving regularly scheduled transfusions to reduce levels of HbS.
15. Clinically diagnosed substance use disorder for alcohol or other illicit drugs of abuse. Positive urine drug screen at screening or on day of admission for substances other than marijuana or prescribed opioids/opiates for chronic pain management is exclusionary.
16. Pregnant or lactating female; or female of childbearing age unable or unwilling to comply with birth control or abstinence during the course of the study.
17. Febrile illness in the 7 days prior to baseline visit.
18. Subject is investigative site personnel or member of their immediate family (spouse, parent, child or sibling whether biological or legally adopted).
19. Heart rate corrected QT interval-Frederica's method (QTcF) >450 msec male and >470 msec female.