FDA Approval of New Therapy, Duvyzat, for Duchenne Muscular Dystrophy Represents Several Meaningful Firsts

On March 21st, FDA announced the approval of the first nonsteroidal therapy for the treatment of Duchenne Muscular Dystrophy (DMD) (FDA press release available here). Duvyzat (givinostat), a histone deacetylase (HDAC) inhibitor developed by Italfarmaco, S.p.A., represents a new class of therapeutics to slow progression of DMD and adds significantly to the armamentarium available to treat this relentlessly progressive and devastating condition.  Hyman, Phelps & McNamara, P.C.’s Frank Sasinowski, James Valentine and Charles Raver are honored to have aided Italfarmaco in the development and approval of this new drug, and to be part of the effort to expand treatment options for the young men and boys living with Duchenne, and the families of those affected by Duchenne.

Even with a growing list of therapies for DMD, this disease continues to cut short the lives of those with Duchenne and rob these young men and boys of the full functions of their bodies and autonomy that many of us take for granted. Several of the approved DMD therapies are available only to those with specific genetic variants, representing small portions of the overall population of people affected, and were approved and made available via Accelerated Approval while studies to confirm clinical benefit are ongoing. As Dr. Emily Freilich, Director of the Division of Neurology 1 in the Office of Neuroscience in CDER noted in FDA’s press release, Duvyzat is the first nonsteroidal DMD therapy approved regardless of genetic mutation.

Beyond the unmet medical needs that Duvyzat helps to address, we see this approval to be notable from a drug development and regulatory perspective. The primary basis for approval, like other drugs for DMD, was based on a single placebo-controlled randomized trial. However, it was the first of a nonsteroidal treatment of any product class to ever demonstrate an effect on a functional primary endpoint, here, the four-stair climb test (4SC). In addition, Duvyzat’s labeling also reports a nominal statistically significant effect on the North Star Ambulatory Assessment (NSAA), a secondary endpoint in the trial and is regarded by many in the field as the most widely accepted instrument for gauging the magnitude of benefit of a DMD therapy. It was also the first trial to be run with a placebo control over 18 months, whereas other DMD therapies have been tested in pivotal trials of 1 year or less.

The evidence reviewed by the FDA’s Office of Neuroscience and Division of Neurology 1 to support the approval of Duvyzat, however, goes beyond these traditional DMD functional endpoints. The underlying pathophysiological hallmarks of DMD are loss of muscle and its replacement with fibrotic and fatty tissue. While the mechanism by which Duvyzat and HDAC inhibition treats DMD likely involves multifaceted effects on the inflammatory and other pathophysiology processes set in motion by mutations in the dystrophin gene, Duvyzat showed an effect on muscle loss, the key pathogenic hallmark of DMD. Treatment with Duvyzat over 18 months resulted in a 30% reduction in fat fraction of major muscle groups in the thigh as measured by magnetic resonance spectroscopy.

Finally, each of the effects of Duvyzat were demonstrated on top of standard of care treatment with corticosteroids. All patients in the pivotal trial were required to be on a stable dose of corticosteroids for 6 months prior to enrollment and continued on corticosteroids throughout the study. While demonstrating an effect on top of an already effective therapy is impressive from a study design standpoint, it is most meaningful in that Duvyzat is not merely an alternative treatment option but it can be used on top of existing corticosteroid therapies to meaningfully delay disease progression for those with Duchenne.

We authors eagerly await the publication of FDA’s Summary Basis for Approval for the Duvyzat NDA so that we can better understand the basis for the Agency’s finding of substantial evidence of effectiveness, particularly in light of recent FDA guidance on the topic of single study approvals with confirmatory evidence, available here.

All the data described above can be found in Sections 12 and 14 of the FDA-approved prescribing information (see here). Additional data from studies of Duvyzat are available in the published literature (see e.g., Mercuri E, Vilchez JJ, Boespflug-Tanguy O, et al. Safety and efficacy of givinostat in boys with Duchenne muscular dystrophy (EPIDYS): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2024;23(4):393-403. doi:10.1016/S1474-4422(24)00036-X).