Unknown Lungs & Breathing NIHR-supported project Cancer

A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single Oral Dose Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of BMN?349 in PiZZ and PiMZ/MASH Adult Participants

Funder NIHR (part of DHSC)
Recipient organisation NIHR Royal Free Clinical Research Facility
NIHR support Recorded as supported by this research centre
Period Feb 2025 — Ongoing

In plain English

AI plain-English summary

A small group of 12 adults with a genetic liver condition will each swallow a single 250 mg dose of an experimental drug called BMN 349, or a placebo, to see if it is safe. This trial targets a specific genetic flaw. People who carry two copies of the Z mutation in the alpha-1 antitrypsin gene (PiZZ genotype) produce a misfolded protein that clumps in the liver, causing damage. Many also develop metabolic dysfunction-associated steatohepatitis (MASH), a severe fatty liver disease. No approved treatment directly corrects the underlying protein misfolding. BMN 349 is designed to stabilise the faulty protein, potentially preventing the toxic buildup. If the drug proves safe and tolerable in this first human test, it would open the door to larger trials. Success could eventually lead to a daily oral therapy that halts liver scarring and prevents the need for transplantation in people with this specific genetic form of liver disease. The trial also includes PiMZ heterozygotes with MASH, a much larger patient group, to see if the drug works in milder genetic cases as well. The study is a necessary safety checkpoint before any efficacy testing can begin.

View original technical description
Study 349-102 is a Phase 1, randomized, double-blind, placebo-controlled study designed to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of BMN 349 in adult participants homozygous for the Z mutation of the alpha 1 antitrypsin (AAT) gene (hereafter referred to as protease inhibitor [Pi] ZZ [PiZZ]) or heterozygous for the Z mutation (hereafter referred to PiMZ) with presumed or biopsy-confirmed metabolic dysfunction-associated steatohepatisis (MASH). Participants will enter the study following a 28 to 42-day screening period. Approximately 12 participants are planned to be enrolled in the study in a single dose cohort: 6 participants with PiZZ genotype (PiZZ Group) and 6 participants with PiMZ genotype with biopsy-proven or presumed MASH (PiMZ/MASH Group). In each group, participants will be randomized to receive a single dose (250 mg) of BMN 349 or placebo in a 5:1 ratio. Each group will be divided into 2 subgroups for sequential dosing. The first subgroup (sentinel participants) will comprise 2 of the 6 randomized participants and will be dosed initially, 24 hours apart from each other. The second subgroup will comprise the remaining 4 non-sentinel participants and will be dosed at least 24 hours after the second sentinel. Study enrollment of non-sentinel participants and all dose administration will be halted to perform additional safety analyses and review if any dose-limiting toxicity (DLT) criteria are met by the sentinel participants. All participants will fast for ? 10 hours (overnight) before receiving BMN 349 on Day 1 and for ? 4 hours post-dose. Participants should refrain from consuming water for 1 hour pre-dose, and 1 hour post-dose (with the exception of the water used for dose administration). Participants will reside either at the study site or in close proximity to the study site from Day -1 through Day 2 of the Treatment Period. Participants will return to the study site on Day 8 (? 1 day) and on Day 36 (?1 day) for final study procedures. Assessments/procedures on Day 4 (? 1 day), Day 15 (? 1 day), Day 22 (? 1 day), and Day 29 (? 1 day) may be performed at the study site or by a home healthcare professional in combination with telemedicine where available.

Researchers

John Hurst (Principal Investigator)

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