213376 FTiH study for safety, tolerability, and PK of GSK3884464
Research type
Research Study
Full title
A Two-Part First Time in Human (FTIH) Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Repeat Oral Doses of GSK3884464 in a Randomized, Double Blind, Placebo-Controlled, Dose Escalation Study in Healthy Participants
IRAS ID
302063
Contact name
Nicolas Wisniacki MD, PhD
Contact email
Sponsor organisation
GlaxoSmithKline's Research and Development Limited
Eudract number
2021-001724-17
Duration of Study in the UK
0 years, 11 months, 12 days
Research summary
Research Summary
GlaxoSmithKline (GSK) is developing a drug (GSK3884464) to treat Heart Failure with reduced ejection Fraction (HFrEF) (reduced volume of blood pumped from the heart). Heart Failure is a disease which has many possible causes, for example disease of the heart valves or previous heart muscle injuries (heart attacks).
Despite current available treatments for Heart Failure improving the ability of the heart to pump blood, the death rate from Heart Failure patients remains at approximately 50% in a 5-year period.
In the body, GSK3884464 blocks the interaction of a particular protein, called KEAP1, with another protein called NRF2. This leads to an increase in the level of NRF2 in the cell nucleus. In animal studies, NRF2 activation has been shown to improve the heart’s ability to contract. If the study drug works, it will provide a good treatment option for patients with this type of heart failure, and potentially other patient populations.
This is the first time GSK3884464 is being studied in humans. The main objective is to test the safety and tolerability of single and repeat doses of orally administered GSK3884464 in healthy participants, and to measure concentrations of drug in the blood at various time intervals (pharmacokinetics).
Approximately 51 male and female (of non-childbearing potential) participants will be enrolled in the study, which consists of 2 parts:
• Part 1 (single dose) will consist of 27 participants (3 cohorts of 9).
• Part 2 (repeat dose) will consist of 24 participants (3 cohorts of 8). Participants will be allocated randomly to receive a dose of either GSK3884464 or placebo.
Participation has no direct benefit to participants. The study is sponsored by GSK and will be conducted in a Medicines and Health Care Products Regulatory Agency (MHRA) accredited clinical research unit in the United Kingdom.
Summary of Results
GSK3884464 was rapidly absorbed to the blood stream following single and repeat dose administration, with the highest measure concentrations in the blood observed at a median Tmax of 0.509 to 2 hours post-dose.
For the SAD (single ascending dose) data, a less than dose proportional increase in GSK3884464 exposure parameters was observed; however, it was not statistically significant.
Measurements of GSK3884464 almost 24 hours after receiving GSK3884464 that were measured over 14 days of repeated once daily dosing showed concentrations increasing gradually and approaching steady state.
Adequate and sustained dose dependent target engagement was observed with increases in NQO1 gene expression in whole blood following treatment with single ascending doses and repeat dosing of GSK3884464.
No deaths were reported.
In Part 1, one participant from Cohort 2 experienced a serious adverse event (SAE) of albuminuria (too much protein) following Placebo treatment. This SAE was reported by the Investigator as mild in intensity that led to withdrawal from the study. The event was reported to be resolved within 4 days. There were no other SAEs in Part 1 and Part 2 of the study.
No clinically significant changes to laboratory parameters, ECGs, or vital signs were observed.
However, 5 participants experienced elevated liver enzymes adverse events related to GSK3884464 which included ALT elevations (>1.5x – 4x ULN) and AST elevations (1.1x – 2.8x ULN); 1 of the 5 participant met individual liver stopping criteria (4x ULN ALT, 2.8x ULN AST). In consideration of these elevations, GSK put the study on temporary halt on 18 July 2022 to analyze data samples from the study in relation to the elevated liver enzymes. GSK consequently ended the trial early on 17 October 2022.
No other safety signals of note were recorded.
REC name
HSC REC A
REC reference
21/NI/0126
Date of REC Opinion
9 Sep 2021
REC opinion
Further Information Favourable Opinion