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

NCT04443192 | Terminated Phase 1 DMC

• 1 other identifier: ZF-0101
• Study Type: interventional
• Target: 69
• Locations: 1 country
• Sites: 5

Brief 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.

Conditions

Alpha1 Anti-Trypsin Deficiency

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment

  Safety and tolerability

  Part A: Day 1 to Day 8; Part B: Day 1 to Day 58

Secondary Outcomes (13)

• Pharmacokinetics of ZF874 and its metabolite ZF857 in healthy subjects and PiXZ subjects

  Part A: Day 1 to Day 3; Part B: Day 1 to Day 29

• Pharmacokinetics of ZF874 and its metabolite ZF857 in healthy subjects and PiXZ subjects

  Part A: Day 1 to Day 3; Part B: Day 1 to Day 29

• Pharmacokinetics of ZF874 and its metabolite ZF857 in healthy subjects and PiXZ subjects

  Part B: Day 1 to Day 29

• Pharmacokinetics of ZF874 and its metabolite ZF857 in healthy subjects and PiXZ subjects

  Part A: Day 1 to Day 3; Part B: Day 1 to Day 29

• Pharmacokinetics of ZF874 and its metabolite ZF857 in healthy subjects and PiXZ subjects

  Part A: Day 1 to Day 2

Other Outcomes (1)

• Pharmacodynamics (Exploratory)

  Part B: Day 1 to Day 58

Study Arms (14)

Part A Cohort 1 - ZF874

ACTIVE COMPARATOR

Single oral dose of ZF874 by mouth in the fasted state. Dose Level 1

Drug: ZF874

Part A - Placebo to ZF874 - Single Dose

PLACEBO COMPARATOR

Single oral dose of placebo by mouth in the fasted state

Drug: Placebo

Part A Cohort 2 - ZF874

ACTIVE COMPARATOR

Single oral dose of ZF874 by mouth in the fasted state. Dose Level 2

Drug: ZF874

Part A Cohort 3 - ZF874

ACTIVE COMPARATOR

Single oral dose of ZF874 by mouth in the fasted state. Dose Level 3

Drug: ZF874

Part A Cohort 4 - ZF874

ACTIVE COMPARATOR

Single oral dose of ZF874 by mouth in the fasted state. Dose Level 4

Drug: ZF874

Part A - Placebo to ZF874 - Two Doses

PLACEBO COMPARATOR

Two doses of placebo (12 h apart) by mouth in the fasted state

Drug: Placebo

Part A Cohort 5 - ZF874 - Two Doses

ACTIVE COMPARATOR

Two doses of ZF874 (12 h apart) by mouth in the fasted state. Dose Level 5

Drug: ZF874

Part A Cohort 6 - ZF874 - Two Doses

ACTIVE COMPARATOR

Two doses of ZF874 (12 h apart) by mouth in the fasted state. Dose Level 6

Drug: ZF874

Part A Cohort 7 - ZF874 - Single Dose

ACTIVE COMPARATOR

Single oral dose of ZF874 by mouth after consuming a high-fat breakfast. Dose Level 3

Drug: ZF874

Part B Cohort 1 - ZF874

ACTIVE COMPARATOR

Two doses of ZF874 (12 h apart) by mouth daily for 28 days.

Drug: ZF874

Part B Cohort 1 - Placebo to ZF874

PLACEBO COMPARATOR

Two doses of placebo (12 h apart) by mouth daily for 28 days.

Drug: Placebo

Part B Cohort 2 - ZF874

ACTIVE COMPARATOR

Two doses of ZF874 (12 h apart) by mouth daily for 28 days.

Drug: ZF874

Part B Cohort 3 - ZF874

ACTIVE COMPARATOR

Two doses of ZF874 (12 h apart) by mouth daily for 28 days.

Drug: ZF874

Part B Cohort 4 - ZF874

ACTIVE COMPARATOR

Two doses of ZF874 (12 h apart) by mouth daily for 28 days.

Drug: ZF874

Interventions

ZF874 DRUG

ZF874 is a novel chemical chaperone that is specifically designed to rescue the folding of the Z variant of alpha-1-antitrypsin (A1AT). It is being developed for the treatment of alpha-1-antitrypsin deficiency (AATD) caused by the Z-mutation.

Part A Cohort 1 - ZF874; Part A Cohort 2 - ZF874; Part A Cohort 3 - ZF874; Part A Cohort 4 - ZF874; Part A Cohort 5 - ZF874 - Two Doses; Part A Cohort 6 - ZF874 - Two Doses; Part A Cohort 7 - ZF874 - Single Dose; Part B Cohort 1 - ZF874; Part B Cohort 2 - ZF874; Part B Cohort 3 - ZF874; Part B Cohort 4 - ZF874

Placebo DRUG

Placebo to ZF874

Part A - Placebo to ZF874 - Single Dose; Part A - Placebo to ZF874 - Two Doses; Part B Cohort 1 - Placebo to ZF874

Eligibility Criteria

• Age: 18 Years - 72 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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 (except for Basal Cell Carcinoma, Squamous Cell Carcinoma (fully excised), or Cervical Intra-epithelial Neoplasia in situ) in the 5 years 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
• During the 28 days before the first dose of trial medication, the use of prescription medicine judged by the investigator to have the potential to influence the results of the study; or during the 7 days before the first dose of trial medication, the use of a herbal supplement or an over-the-counter medicine, with the exception of ibuprofen
• Receipt of a COVID-19 vaccine within 14 days before the first dose of trial medication; exhibition of symptoms suspected to be related to COVID-19 within 28 days before the first dose of trial medication; or receipt of a positive COVID-19 test during the 28 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 3 units of alcohol daily (for men) or 2 units of alcohol daily (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 90-160 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

Sponsors & Collaborators

• Z Factor Limited: lead
• Hammersmith Medicines Research: collaborator
• Centessa Pharmaceuticals plc: collaborator

Study Sites (5)

MAC Clinical Research Manchester

Manchester, Greater Manchester, M13 9NQ, United Kingdom

Location

MAC Clinical Research, Barnsley

Barnsley, S75 3DL, United Kingdom

Location

MAC Clinical Research, Leeds

Leeds, LS10 1DU, United Kingdom

Location

Hammersmith Medicines Research

London, NW10 7EW, United Kingdom

Location

MAC Clinical Research, Teesside

Stockton-on-Tees, TS17 6EW, United Kingdom

Location

MeSH Terms

Conditions

alpha 1-Antitrypsin Deficiency

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Subcutaneous Emphysema; Emphysema; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Malcolm Boyce, BSc MD FRCP FFPM

  HMR

  PRINCIPAL INVESTIGATOR

• Giuseppe Fiore, MSc MD

  MAC Clinical Research

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Part A Groups 1-6 and Part B Group 1 will be double-blind; Part A Group 7 (food effect) and Part B Groups 2-4 will be open label
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This is a double-blind, randomised, placebo-controlled, single ascending and repeat dose trial in healthy subjects and subjects carrying at least one Z-A1AT allele (PiXZ subjects)

Study Record Dates

• First Submitted: June 16, 2020
• First Posted: June 23, 2020
• Study Start: August 3, 2020
• Primary Completion: September 12, 2022
• Study Completion: September 12, 2022
• Last Updated: September 19, 2022

Record last verified: 2022-09

Data Sharing

• IPD Sharing: Will not share

Locations

GB (5)