Givinostat Receives Full FDA Approval for Duchenne Muscular Dystrophy

This article has been updated.

The FDA has approved givinostat (Duvyzat) from Italfarmaco, for use in boys 6 years and older who have all genetic variants of Duchenne muscular dystrophy (DMD).¹ The approval of the oral medication follows fast track, orphan drug, and rare pediatric designations, as well as an original Prescription Drug User Fee Act date of December 21, which the FDA pushed back to March 21 to have more time to review Italfarmaco’s application.²

Givinostat is a histone deacetylase (HDAC) inhibitor that works by blocking these enzymes from promoting muscle degeneration by preventing gene translation through changing the 3D folding of cell DNA. Inhibiting HDACs promotes muscle repair, reduces inflammation, and decreases both muscle fibrosis and fat accumulation in patients.³ It is the sixth targeted treatment approved by the FDA since 2016 for DMD, and the first nonsteroidal drug,¹ joining eteplirsen (Exondys 51; Sarepta Therapeutics), golodirsen (Vyondys 53; Sarepta Therapeutics), casimersen (Amondys; Sarepta Therapeutics), viltolarsen (Viltepso; NS Pharma), and delandistrogene moxeparvovec-rokl (Elevidys; Sarepta Therapeutics).⁴

"DMD denies the opportunity for a healthy life to the children it affects," Emily Freilich, MD, director, Division of Neurology, Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research, said in a statement. “This approval provides another treatment option to help reduce the burden of this progressive, devastating disease for individuals impacted by DMD regardless of genetic mutation.”¹

Italfarmaco’s new drug application for givinostat was originally accepted by the FDA and given priority review status on June 29, 2023,⁵ meaning the agency recognized the therapy’s potential to produce significant improvement in patients who have DMD,³ which is both the most common and most severe form of hereditary muscular dystrophy and the most common hereditary neuromuscular disease.^6,7

Givinostat was investigated in the phase 3 randomized double-blind placebo-controlled multicenter EPIDYS trial (NCT02851797), which enrolled 179 male patients across sites in North America and Europe who were aged 6 to 17 years—mean age, 9 years—and randomly assigned them 2:1 to receive givinostat or placebo plus their corticosteroid regimen over an 18-month treatment period; both treatments were administered twice daily at an oral dose of 10 mg/mL, and participants visited their study site every 12 weeks for evaluation on all study end points.^8,9 The primary study end point was mean change from baseline in time to climb 4 stairs, and secondary end points included scores on the North Star Ambulatory Assessment (NSAA) and the time to rise test and fat infiltration in the vastus lateralis thigh muscle, a common characteristic of DMD progression.¹⁰ There were 120 boys in the target population, which encompasses boys 6 years and older on chronic steroids.¹¹

Compared with those who received placebo, the boys who received givinostat took 1.78 fewer seconds to perform the functional task of climbing 4 stairs (P = .0345). Also, fat infiltration in the vastus lateralis was delayed by approximately 30% compared with placebo (nominal P = .035). Common adverse events—occurring in at least 10% of participants—were diarrhea, abdominal pain, thrombocytopenia, hypertriglyceridemia, platelet decrease, and triglyceride increase, and there were no new safety signals.²

Final EPIDYS study data published recently in The Lancet Neurology reiterate the benefits of givinostat administration. Measured over 72 weeks, the primary end point of improvement in the ability to climb 4 stairs was met. Participants who received givinostat also demonstrated 40% less decline overall in NSAA total score and item loss vs the control group, and the results of 30% reduction in vastus lateralis fat infiltration stood.⁸ Eligible EPIDYS participants could enroll in the open-label extension study, receiving givinostat on an ongoing basis; the overall median follow-up for both studies is 4.7 years.¹²

Along with the approval came guidance to conduct a baseline assessment of patient platelet count and triglycerides and to monitor each throughout treatment for potential dosage changes; the current recommended dosage is determined by the patient's weight, and the medication should be given twice daily with food. Contraindications exist for patients with a platelet count below 150 x 10⁹/L, who have certain types of heart disease, or who are taking medications that may cause QTc prolongation, as this is also a potential adverse effect of givinostat that can lead to an irregular heartbeat. Moderate or severe diarrhea may also necessitate dosage modification.¹

There is no known cure for DMD. All treatments are considered palliative.⁶

References

1. FDA approves nonsteroidal treatment for Duchenne muscular dystrophy. News release. FDA. March 21,2024. Accessed March 21, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-nonsteroidal-treatment-duchenne-muscular-dystrophy
2. Meglio M. FDA extends review time for Italfarmaco’s Duchenne agent givinostat. NeurologyLive^®. November 30, 2023. Accessed March 18, 2024. https://www.neurologylive.com/view/fda-extends-review-time-italfarmaco-duchenne-agent-givinostat
3. Lobo A. FDA gives priority review to oral givinostat in treating DMD. Muscular Dystrophy News Today. July 6, 2023. Accessed March 18, 2024. https://musculardystrophynews.com/news/fda-gives-priority-review-oral-givinostat-dmd-treatment/
4. Shaw M. Experts issue call for reform to DMD drug pricing, trial approval process. The American Journal of Managed Care^®. March 14, 2024. Accessed March 18, 2024. https://www.ajmc.com/view/experts-issue-call-for-reform-to-dmd-drug-pricing-trial-approval-process
5. Italfarmaco group completes FDA submission of new drug application for givinostat in Duchenne muscular dystrophy and receives priority review. News release. BusinessWire. June 29, 2023. Accessed March 18, 2024. https://www.businesswire.com/news/home/20230629900551/en/Italfarmaco-Group-Completes-FDA-Submission-of-New-Drug-Application-for-Givinostat-in-Duchenne-Muscular-Dystrophy-and-Receives-Priority-Review
6. Venugopal V, Pavlakis S. Duchenne muscular dystrophy. StatPearls. StatPearls Publishing; 2024. https://www.ncbi.nlm.nih.gov/books/NBK482346/#:~:text=Unfortunately%2C%20Duchenne%20muscular%20dystrophy%20(DMD,available%20treatment%20options%20are%20palliative
7. Office of Communications. What are the types and symptoms of muscular dystrophy (MD)? Eunice Kennedy Shriver National Institute of Child Health and Human Development. Accessed March 18, 2024. https://www.nichd.nih.gov/health/topics/musculardys/conditioninfo/types#:~:text=Duchenne%20MD%20(DMD),of%20age%2C%20and%20progresses%20rapidly
8. Clinical study to evaluate the efficacy and safety of givinostat in ambulant patients with Duchenne muscular dystrophy. ClinicalTrials.gov. Updated February 2, 2022.Accessed March 18, 2024. https://www.clinicaltrials.gov/study/NCT02851797
9. Henzi BC, Schmidt S, Nagy S. Safety and efficacy of givinostat in boys with Duchenne muscular dystrophy (EPIDYS): a multicentre, randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2023;22(10):890-899. doi:10.1016/S1474-4422(23)00285-5
10. Italfarmaco announces positive topline data from phase 3 trial showing beneficial effect of givinostat in Duchenne. News release. Parent Project Muscular Dystrophy. June 26, 2022. Accessed March 18, 2024. https://www.parentprojectmd.org/italfarmaco-group-announces-positive-topline-data-from-phase-3-trial-showing-beneficial-effect-of-givinostat-in-duchenne/
11. 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 March 18, 2024. https://www.businesswire.com/news/home/20220625005001/en/Italfarmaco-Group-Announces-Positive-Topline-Data-from-Phase-3-Trial-Showing-Beneficial-Effect-of-Givinostat-in-Patients-with-Duchenne-Muscular-Dystrophy
12. Results from Italfarmaco pivotal phase 3 EPIDYS study of givinostat in Duchenne muscular dystrophy (DMD) published in The Lancet Neurology. News release. Italfarmaco. March 19, 2024. Accessed March 19, 2024. https://www.businesswire.com/news/home/20240319626593/en/Results-from-Italfarmaco-Pivotal-Phase-3-EPIDYS-Study-of-Givinostat-in-Duchenne-Muscular-Dystrophy-DMD-Published-in-The-Lancet-Neurology