A Single Ascending and Repeated Dose Study of Oral ZF874 in Healthy Volunteers and PiXZ Subjects

• Status: Recruiting
• Trial end date: 2022-01-31
• Target enrollment: 0
• Participant gender: All

Summary

This study is composed of two parts. Part A: will test single doses of ZF874 in a double-blind, randomised, placebo-controlled and dose-escalating design (except Group 7, which will be open-label and without placebo). Up to 7 groups of 6-8 healthy volunteers will receive an oral dose of ZF874 or matching placebo (6 active: 2 placebo in Groups 1-6; 6 active in Group 7). The dosing of the first 2 subjects (1 active and 1 placebo) will take place before dosing of the remainder of the group in Groups 1-6, with morning doses given in the fasted state. The dose will be escalated only if the safety and tolerability of the previous highest dose are acceptable, and the plasma concentrations of ZF874 are predicted to remain below the toxicokinetic exposure limit, as determined by the Safety Review Group. Group 7 will consist of 6 subjects, all of whom will receive ZF874 after consuming a standard high-fat breakfast. Dosing of the first 2 subjects before the rest of the group is not required in Group 7, as 6 subjects have already safely received ZF874 at this dose in Group 3 and 12 subjects have already safely received higher doses in Groups 4 and 5.

The dose selected for Part A, Group 7 was chosen as the dose has previously been given to subjects fasted in Group 3, and it was safe and well tolerated, allowing for comparison for the food effect, and higher doses have been tested in Part A with no safety concerns.

Part B: Multiple Ascending Doses in subjects carrying at least one Z mutated alpha-1-antitrypsin (Z-A1AT) allele (PiXZ subjects): Up to 4 groups of up to 5 PiXZ subjects will be enrolled in Part B (Groups 1-4). In Group 1, up to 4 subjects will receive twice daily doses of either ZF874 or placebo on 28 consecutive days. The dose level (dose and dose regimen) selected for Part B Group 1 will be based on review of the available results from Part A. In Groups 2-4, up to 5 PiXZ subjects will receive ZF874 twice daily by mouth for 28 days; no subjects will receive placebo. The dose for Groups 2 - 4 will not exceed the doses already given in Part A.

• Phase: Phase 1
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: Z Factor Limited
• Collaborator: Hammersmith Medicines Research

Criteria

Inclusion Criteria:

• Part A: healthy Caucasian males or females, aged 18-65 years at the time of consent; Part B: males or females of general good health, aged 18-72 years at the time of consent.

• Body mass index of 18.0-30.0 kg/m^2 (Part A) and 18.0-35.0 kg/m^2 (Part B).

• Able to understand the nature of the trial and any hazards of participating in it. Able to communicate satisfactorily with the investigator and to participate in, and comply with the requirements of the entire trial

• Willing to give written fully informed consent to participate

• Agree to follow the contraception requirements of the trial

• Agree not to donate blood or blood products during the study and for up to 3 months after the trial medication

• Registered with a General Practitioner in the United Kingdom

• Willing to give written consent to have data entered into The Over-volunteering Prevention System [Part B only]

• Confirmed genotype with at least one Z alpha-1-antitrypsin allele (PiXZ)

Exclusion Criteria:

• Woman who is pregnant or lactating, or woman of child-bearing potential who is sexually active and not using a highly effective method of contraception

• Clinically relevant abnormal history, physical findings, ECG, or laboratory values at the pre-trial screening assessment that could interfere with the objectives of the trial or the safety of the volunteer

• Acute or chronic illness or history of chronic illness sufficient to invalidate the volunteer's participation in the trial or make it unnecessarily hazardous

• Impaired endocrine, thyroid, hepatic, respiratory or renal function, diabetes mellitus, coronary heart disease, or history of any psychotic mental illness

• Creatinine clearance <60 mL/min/1.73m2

• Active cancer or to be actively on cancer therapy, or diagnosis of cancer in 12 months before the first dose of trial medication

• Surgery (eg stomach bypass) or medical condition that might affect absorption of medicines

• Presence or history of severe adverse reaction to any relevant drug

• Use of prescription medicine, with the exception of inhalers and oral contraception in females (in Part B only), during the 28 days before the first dose of trial medication or use of an over-the-counter medicine, with the exception of ibuprofen, during the 7 days before the first dose of trial medication

• Receipt of a COVID-19 vaccine within 14 days before the first dose of trial medication.

• Receipt of an investigational product (including prescription medicines) as part of another clinical trial within 3 months before admission to this study; in the follow-up period of another clinical trial at the time of screening for this study

• Recent drug or alcohol abuse (within 2 years before screening), or intake of more than 21 units of alcohol weekly (for men) or 14 units of alcohol weekly (for women); or use of cigarettes or nicotine-containing products during 30 days before the first dose of trial medication until the end of the study

• Blood pressure and heart rate in supine position at the screening examination outside the ranges: blood pressure 90-140 mm Hg systolic, 40-90 mm Hg diastolic; heart rate 40-100 beats/min

• Possibility that the volunteer will not cooperate with the requirements of the protocol

• Evidence of drug abuse on urine testing

• Positive test for hepatitis B virus, hepatitis C virus or human immunodeficiency virus

• Loss of more than 400 mL blood during 3 months before the trial, eg as a blood donor

• Objection by General Practitioner to volunteer entering trial

Part A, Cohort 7 only:

• Vegans, vegetarians, or unwilling to eat a high-fat breakfast containing bacon.

Part B only:

• Undergone liver transplantation