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A Phase 1, Open-Label, Single Dose Study to Evaluate the Pharmacokinetics (PK), Safety, and Tolerability of Epetraborole Tablets and the Impact of Alcohol Dehydrogenase (ADH) Genotype on the PK of Epetraborole and Metabolite M3 in Healthy Japanese Adult Subjects

A Phase 1, Open-Label, Single Dose Study to Evaluate the Pharmacokinetics (PK), Safety, and Tolerability of Epetraborole Tablets and the Impact of Alcohol Dehydrogenase (ADH) Genotype on the PK of Epetraborole and Metabolite M3 in Healthy Japanese Adult Subjects

18

Ten subjects were male, 8 were female, and all 18 subjects were Japanese with a median age at the Pre-Study Genetic Test Period of 30.5 years (range: 19 to 55 years) and median body mass index at Screening of 21.6 kg/m2. Cohorts were defined by ADH1B genotype; therefore, 6 subjects were randomized into each of the 3 ADH1B cohorts (*1/*1, *1/*2, and *2/*2). Cohorts were not defined by aldehyde dehydrogenase (ALDH) genotype; however, ALDH genotype information was collected and 38.9% were ALDH *1/*1 and 61.1% were ALDH *1/*2, (no subject was ALDH *2/*2).

A total of 18 subjects were allocated to 1 of 3 cohorts (6 subjects each in Cohort 1 [ADH1B *1/*1], Cohort 2 [ADH1B *1/*2, and Cohort 3 [ADH1B *2/*2]). All 18 subjects received 1 dose of study drug (single 500 mg oral dose [two 250 mg tablets]) and completed the study. All 18 subjects were included in the Safety, PK Concentration, and PK Evaluable Populations.

No treatment-emergent adverse events (TEAEs) were reported in the 18 subjects dosed in this study. No CS results in clinical laboratory parameters, vital signs, physical examinations, or electrocardiograms were reported.

Epetraborole was rapidly absorbed following a single oral dose administration across all cohorts with median Tmax of 1.00 hours across all cohorts. The metabolite M3 appeared steadily in plasma and reached maximal observed concentration shortly after that of epetraborole with median Tmax of 2.5 to 3 hours across all cohorts. After reaching Cmax, plasma epetraborole and metabolite M3 concentrations declined with a geometric mean t1/2 of approximately 10.7 to 11.4 hours and 26.7 to 33.1 hours, respectively, across all cohorts. Exposure of epetraborole based on Cmax and AUCinf was similar between subjects with ADH1B genotypes *1/*1 (Cohort 1) and *1/*2 (Cohort 2). However, epetraborole Cmax and AUC were approximately 1.2- to 1.4-fold higher in Cohort 3 subjects with ADH1B *2/*2 genotype. Exposure of metabolite M3 based on Cmax and AUCinf was similar between subjects with ADH1B genotypes *1/*1 (Cohort 1), *1/*2 (Cohort 2), and *2/*2 (Cohort 3). Metabolite to parent ratios for Cohort 3 were generally similar for Cmax and were approximately 26% lower for AUCinf in Cohort 3 subjects with ADH1B *2/*2 genotype compared to Cohort 1 subjects with ADH1B *1/*1 genotype. There were no apparent differences in t1/2 in any of the 3 cohorts for either parent drug or metabolite M3. Given the exposure of epetraborole in Cohort 3 (ADH1B *2/*2 genotype) was approximately 1.2- to 1.4-fold higher than subjects in Cohort 1 (ADH1B *1/*1 genotype), target attainment was reached in all 3 ADH1B genotypes. The slightly increased epetraborole exposures associated with the 500 mg dosage in subjects with ADH1B *2/*2 genotype (AUC0-inf 26,100 h*ng/mL, Cmax 5040 ng/mL) were within the range of tolerable exposures. Note the maximum tolerated dosage of oral epetraborole was previously determined to be a single 4000 mg dose, with associated epetraborole exposures based on AUC0-inf of 94,363 h*ng/mL and Cmax of 12,672 ng/mL (GSK Study LRS114470).

Epetraborole (EBO) PK target attainment was not impacted by ADH1B genotypes associated with rapid ethanol metabolism. No underdosing of EBO is predicted in patients with ADH1B *1/*2 or *2/*2 genotypes. Slightly increased EBO exposures in the ADH1B *2/*2 cohort were within range of tolerable exposures. Single-dose 500 mg oral EBO was well tolerated in healthy Japanese subjects; no subject experienced an adverse event.

Dec. 31, 2023

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2071220004

Kanmuri Kazuhiro

Ascent Development Services, Inc.

Shibuya SOLASTA 3F, 1-21-1, Dogen-zaka, Shibuya-ku, Tokyo, Japan 150-0043

kazuhiro.kanmuri@ascent-dev.com

Kanmuri Kazuhiro

Ascent Development Services, Inc.

Shibuya SOLASTA 3F, 1-21-1, Dogen-zaka, Shibuya-ku, Tokyo, Japan 150-0043

+81-345909005

kazuhiro.kanmuri@ascent-dev.com

Complete

May. 10, 2022

Interventional

non-randomized controlled trial

open(masking not used)

active control

parallel assignment

basic science

1. Healthy adult male and/or female of 18 to 65 years of age at the time of signing of informed consent
2. Willing and able to provide written informed consent
3. Body mass index >=18.5 and <=28.0 kg/m2 and weight between 45.0 kg and 100.0 kg (inclusive) at Screening
4. Medically and hemodynamically stable without CS abnormalities at Screening and Day -1, based on physical examination, vital signs, 12 lead ECGs, and laboratory results
5. Light, non-, or ex-smoker (A light smoker is defined as someone using <= 5 cigarettes or less per day for at least 90 days prior to study drug administration. An ex-smoker is defined as someone who completely stopped using nicotine products for at least 180 days prior to study drug administration.)
6. Agrees not to consume alcohol throughout the study (through the F/U Visit)
7. Willing and able to comply with all study assessments and adhere to the protocol schedule, including the entire confinement period and through the F/U Visit
8. Has suitable venous access for blood sampling
9. Women of childbearing potential (WOCBP) must have a negative pregnancy test at Screening and on Day -1 and be willing to have additional pregnancy tests, as required, throughout the study. To be considered of nonchildbearing potential, a female must have either a tubal ligation, hysterectomy, bilateral salpingo-oophorectomy, or menopause (last menstruation >12 months and follicle-stimulating hormone levels >=40 mIU /mL at Screening); provision of written documentation is not required for female sterilization and oral confirmation is adequate.
10. WOCBP must agree to and comply with using 1 barrier method (eg, female condom or male partner using a condom) plus 1 other highly effective and approved method of birth control in Japan (eg, oral contraceptive pills [OCPs]), or sexual abstinence, for the duration of the study (from signing of consent through the F/U Visit) and for 30 days after study drug administration. Female subjects who are in same-sex relationships are not required to use contraception.
11. WOCBP must agree not to donate ova or oocytes (ie, human eggs) for the duration of the study (from signing of consent through the F/U Visit) and for 1 menstrual cycle after completion of the study.
12. Males must be surgically sterile (>30 days since vasectomy), abstinent, or if engaged in sexual relations with a WOCBP, the subject and his partner must be surgically sterile (eg, tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or using an acceptable, highly effective contraceptive method from Screening until study completion (through the F/U Visit). Acceptable methods of contraception include the use of condoms and the use of an effective contraceptive for the female partner that includes the following: OCPs, long-acting implantable hormones, injectable hormones, a vaginal ring, or an intrauterine device. Subjects with same-sex partners are eligible when this is their preferred and usual lifestyle.
13. Males must agree to not donate sperm for the duration of the study (from signing of consent through the F/U Visit) and for 90 days after study drug administration.
14. Subjects must agree to adhere to the current advice from the Japanese health authority of Ministry of Health, Labour and Welfare regarding minimizing exposure to coronavirus disease 2019 (COVID 19) from Screening through the F/U Visit.

1. History of significant cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, or neurological disease, including any acute illness or major surgery within the past 6 months determined by the Investigator to be CS
2. Unable to swallow solid, PO tablets whole with the aid of water
3. Positive test for HIV, hepatitis B surface antigen, or hepatitis C virus antibody, or test positive for COVID-19 infection
4. Positive drug/alcohol testing at Screening or prior to study drug administration unless the positive drug screen is due to prescription drug use that is approved by the Investigator and the Sponsors Medical Monitor.
5. History of regular alcohol consumption exceeding 7 drinks/week for females or 14 drinks/week for males (1 drink = 5 ounces [150 mL] of wine or 12 ounces [360 mL] of beer or 1.5 ounces [45 mL] of hard liquor) within 6 months prior to Screening
6. Use of any prescription medication or any over-the-counter medication, including erythropoietin-stimulating agents, herbal products, and vitamins, within 7 days prior to study drug administration
Note: An exception is made for hormonal contraceptives and intermittent, as-needed acetaminophen or nonsteroidal anti inflammatory drugs for the treatment of transient headache or any other minor ache/pain. Discussion between the Investigator and the Sponsors Medical Monitor is encouraged regarding the acceptability of the prior use of any medications during the study.
7. Any vaccinations or planned vaccinations (including COVID-19 and influenza) within 30 days (within 14 days only for COVID-19 vaccine) prior to dosing on Day 1 and for the duration of the study (through the F/U Visit)
8. Documented significant hypersensitivity reaction or anaphylaxis to any medication, which, in the opinion of the Investigator, could compromise subject safety
9. Subjects with hemoglobin <10.0 g/dL or <6.2 mmol/L (Grade 2 anemia or worse, based on Common Terminology Criteria for Adverse Events criteria) at Screening
10. Subjects who have donated blood or plasma within 28 days prior to Screening or have had symptomatic loss of blood or hemorrhage within 28 days prior to Screening
11. Subjects with severe hepatic impairment, as evidenced by alanine aminotransferase or aspartate aminotransferase > 3 x upper limit of normal (ULN) or total bilirubin > 2 x ULN, or clinical signs of cirrhosis or end stage hepatic disease (eg, ascites, hepatic encephalopathy)
12. Subjects who are pregnant or breastfeeding
13. Subjects with a mean QTcF >480 msec based on triplicate 12-lead ECGs at Screening
14. Received an investigational intervention (including an investigational vaccine) or used an invasive investigational medical device within 30 days (or 5 half-lives whichever is longer) prior to Day 1
15. Prior exposure to epetraborole
16. Any other condition or prior therapy, which, in the opinion of the Investigator, would make the subject unsuitable for this study, including unable to cooperate fully with the requirements of the protocol or likely to be noncompliant with any study requirements

Both

Mycobacterium avium complex (MAC) lung disease

ADH1B genotype *1/*1: A single Epetraborole 500 mg orally
ADH1B genotype *1/*2: A single Epetraborole 500 mg orally
ADH1B genotype *2/*2: A single Epetraborole 500 mg orally

To evaluate the PK of epetraborole and the impact of ADH genotype on the PK of epetraborole and metabolite M3 in healthy Japanese subjects.

To evaluate the safety and tolerability of epetraborole in healthy Japanese subjects, based on adverse events (AEs), laboratory tests, electrocardiograms (ECGs), physical examinations, and vital signs.

+81-92-283-7701

May. 06, 2022

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