FDA Extends Review Time for Investigational Duchenne Agent Givinostat

NeuroLive^® first published this article. This version is lightly edited.

Paolo Bettica, MD, PhD

Image Credit: Italfarmaco

Weeks before a decision was expected to be made for Italfarmaco’s investigational agent givinostat, the FDA informed the company it has extended the review process, with a new scheduled Prescription Drug User Fee Act date of March 21, 2024. Givinostat, a proprietary histone deacetylase (HDAC) inhibitor, is currently in development for use in Duchenne muscular dystrophy (DMD), a severe neuromuscular genetic disease.¹

The FDA accepted the new drug application submission for givinostat earlier this year, with supporting data from the phase 3 EPIDYS trial (NCT02851797). Givinostat is designed to inhibit HDACs, which are enzymes that prevent gene translation by changing the 3-D folding of DNA in the cell. In the latest update, Italfarmaco noted the FDA needs more time to review the application, but that there was no issues with the data submitted.

EPIDYS, a randomized, double-blind, placebo-controlled, multicenter study, included 179 ambulant male individuals randomly assigned 2:1 to either oral givinostat or placebo for an 18-month treatment period. Of these, 120 boys formed the target population. At the conclusion of the study, results showed a slower decline in givinostat-treated patients vs those who received placebo on the primary end point of climbing 4 stairs (difference, 1.78 seconds; P = .0345).

At the time of the data release in June 2022, Paolo Bettica, MD, PhD, chief medical officer at Italfarmaco, said in a statement, "These topline phase 3 results in DMD add to the growing dataset we have collected over the last years, which have shown positive outcomes with our investigational therapeutic candidate, givinostat, when taken together with steroids in patients with DMD, providing new hope for boys with DMD, their families, and the medical community."²

In EPIDYS, results on a variety of secondary end points such as the North Star Ambulatory Assessment and time to rise test were consistent with the functional primary end point. In addition, fat infiltration in the vastus lateralis muscle of the thigh, considered a characteristic of disease progression in DMD, was assessed using magnetic resonance spectroscopy, a noninvasive objective imaging method. All told, givinostat treatment resulted in delayed fat infiltration by approximately 30% (difference vs placebo, –2.9%; nominal P = .035).

Craig McDonald, MD

Image Credit: UC Davis Health

In terms of safety, 95% of the adverse events (AEs) observed in EPIDYS were mild to moderate in severity, with 3 (2.5%) boys withdrawing treatment because of an AE. Similar to previous studies, the AEs occurring in at least 1 of 10 participants were diarrhea, abdominal pain, thrombocytopenia, hypertriglyceridemia, platelet decrease, and triglyceride increase. The therapy’s tolerability was managed with appropriate monitoring and dose adjustments, with no new safety concerns identified.

"I believe the EPIDYS study results are clinically meaningful, are consistent with previous findings, and further demonstrate that givinostat can slow down muscle deterioration leading to a reduction in the decline of muscle function," said Craig McDonald, MD, chair, Department of Pediatrics and Physical Medicine, and professor, departments of Pediatrics and Physical Medicine & Rehabilitation, UC Davis Health, in a statement.²

References
1. Italfarmaco group announces new PDUFA date for givinostat DMD NDA. News release. Yahoo Finance. November 29, 2023. Accessed November 30, 2023. https://finance.yahoo.com/news/italfarmaco-group-announces-pdufa-date-100000954.html
2. Italfarmaco group announces positive topline data from phase 3 trial showing beneficial effect of givinostat in patients with Duchenne muscular dystrophy. News release. BusinessWire. June 25, 2022. Accessed November 30, 2023. http://tinyurl.com/2b7exkkh