Post Hoc Analysis Shows Consistent Efficacy With Givinostat for DMD


A recent post hoc analysis of the phase 3 EPIDYS trial presented at MDA 2024 revealed significant positive outcomes with givinostat, a histone deacetylase inhibitor, among patients with Duchenne muscular dystrophy.

Eugenio Maria Mercuri, MD, PhD, professor of pediatric neurology and head of the Pediatric Neurology and Psychiatry Unit at the Gemelli Hospital Catholic University Foundation, in Rome, Italy

Eugenio Maria Mercuri, MD, PhD

Credit: Gemelli Hospital Catholic University Foundation

In a new supportive post hoc analysis from the phase 3 EPIDYS trial (NCT02851797), findings showed a positive significant difference with givinostat (Italfarmaco SpA), a proprietary histone deacetylase (HDAC) inhibitor, in motor function among patients with Duchenne muscular dystrophy (DMD) in comparison with controls. These results are consistent with efficacy in the prespecified analyses and emphasize the potential efficacy of givinostat in a broader context.1

In the overall intention-to-treat (ITT) population (n = 179), investigators reported that givinostat displayed a statistically significant difference compared with the control in change from baseline at 18 months in the timed 4 stair climb (global longitudinal strain mean ratio, 0.84; SD, 0.069; P = .0116). Overall, investigators noted that the treatment effect estimates relating to the key secondary end points consistently favored givinostat over the control, which supports the primary end point result.

Top Clinical Takeaways

  • Givinostat demonstrated a statistically significant difference in the timed 4 stair climb compared with the control group in the overall intention to treat population.
  • Treatment effect estimates for key secondary endpoints consistently favored givinostat, supporting the primary end point result.
  • The analysis highlighted a less decline in NSAA Total Score with givinostat treatment, indicating its potential positive impact on patients with Duchenne muscular dystrophy.

These findings were presented at the 2024 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, held March 3-6, in Orlando, Florida, by lead author Eugenio Maria Mercuri, MD, PhD, a professor of pediatric neurology and head of the Pediatric Neurology and Psychiatry Unit at the Gemelli Hospital Catholic University Foundation, in Rome, Italy. EPIDYS was a randomized, double-blind, placebo-controlled, multicenter study to investigate the efficacy and safety of givinostat in patients with ambulant DMD. All the participants in the trial were treated with steroids and were randomly assigned to either givinostat or placebo in 2:1 fashion. The current analysis used an analysis of covariance (ANCOVA) to assess the impact of givinostat compared with the control on the overall ITT population. Thus, investigators analyzed both the primary end point, the time to climb 4 standard stairs, and 6 key secondary end points.

READ MORE: Duchenne Therapy Eteplirsen Safe in Infants as Young as 6 Months, Study Shows

In the analysis, the investigators used the North Star Ambulatory Assessment (NSAA) to evaluate both the change from baseline at 18 months of the total score and the cumulative loss of NSAA items. In the findings, authors observed an association between givinostat treatment and a less decline in NSAA Total Score (mean difference, 1.50 points; nominal P = .035). Researchers noted that givinostat treatment in patients with DMD showed a good tolerability profile, lining with findings in prior studies in DMD and other diseases.

Givinostat is designed to inhibit HDACs, enzymes that prevent gene translation by changing the 3-dimensional folding of DNA in the cell. Weeks before an approval decision was expected for givinostat in late 2023, the FDA informed the Italfarmaco it extended the review process, with a new scheduled PDUFA of March 21, 2024. The FDA accepted the new drug application submission for givinostat early last year, with data from EPIDYS as the supporting evidence. In the latest update, Italfarmaco noted that the agency needs more time to review the application, but that there were no issues with the data submitted.2

In the primary analysis, conducted on the target population (n = 120), findings showed a slower decline in givinostat-treated patients on the primary end point of climbing 4 stairs in comparison with placebo (difference, 1.78 seconds; P = .0345).3 In addition, fat infiltration in the vastus lateralis muscle of the thigh, considered a characteristic of disease progression in DMD, was assessed using a noninvasive objective imaging method called magnetic resonance spectroscopy. All told, givinostat treatment resulted in delayed fat infiltration by approximately 30% (difference vs placebo, –2.9%; nominal P = .035).

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 AE occurred in at least 1 of 10 participants with 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.

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1. Mercuri EM, Brogna C, Zaidman C, et al. The Epidys Givinostat Study in DMD: supportive results. Presented at: 2024 MDA Clinical and Scientific Conference; March 3-6; Poster M163.
2. Italfarmaco group announces new PDUFA date for givinostat DMD NDA. News release. November 29, 2023. Accessed March 4, 2024.
2. Italfarmaco group announces positive topline data from phase 3 trial showing beneficial effect of givinostat in patients with Duchenne muscular dystrophy. News release. June 25, 2022. Accessed March 4, 2024.
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