FDA Grants Rare Pediatric Disease Designation to Duchenne Muscular Dystrophy Treatment Givinostat


Italfarmaco is expected to report topline data from the phase 3 EPYDIS trial in June 2022.

Paolo Bettica, MD, PhD, chief medical officer, Italfarmaco Group

Paolo Bettica, MD, PhD

The FDA has granted rare pediatric disease designation to givinostat, a histone deacetylase (HDAC) inhibitor, for the treatment of Duchenne muscular dystrophy (DMD).1

The investigational drug is the subject of the phase 3 EPIDYS clinical trial, which completed enrollment at the end of September and remains on track to read out topline data in June 2022. Notably, the last patient is expected to complete the 72-week treatment period in the first quarter of 2022.

"This is the third regulatory designation we have received from the FDA for givinostat after the orphan drug designation and fast track designation and reflects the agency’s recognition of givinostat’s potential to treat DMD, a devastating genetic disease,” Paolo Bettica, MD, PhD, chief medical officer, Italfarmaco Group, said in a statement.1

By inhibiting HDAC activity, givinostat may help to activate muscle repair mechanisms to increase muscle regeneration, reduce inflammation, and reduce fibrosis. Previous studies have shown that patients with DMD have higher than normal HDAC activity, which may prevent muscle regeneration and also trigger inflammation.

EPIDYS (NCT02851797) is a randomized, double-blind, placebo-controlled, multicenter study that is evaluating the efficacy and safety of givinostat in patients with DMD. The first 50 patients randomized in the “in-target” group were treated for 12 months, after which magnetic resonance spectroscopy (MRS) was used to measure muscle fat fraction (MFF) in the vastus lateralis muscle of the thigh. MFF was chosen as an objective end point because fat infiltration in these muscles is characteristic of disease progression in patients with DMD.

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Interim data from a prespecified futility analysis released in April 2020 showed a lower muscle fat infiltration with givinostat compared with placebo on MRS after 12 months of treatment. At the time, the company also announced that a blinded sample size re-estimation supported the reduction in the number of patients required for the phase 3 trial, with a new target enrollment of 169 from the original target of 242.2

Previously rpublished phase 2 results showed that treatment with givinostat significantly increased the fraction of muscle tissue seen in post-treatment musclebiopsies and reduced the amount of fibrotic tissue. It also substantially reduced tissue necrosis and fatty replacement. Overall, the drug significantly counteracted the histological disease progression typically seen in ambulant boys with DMD aged 7 to 10.3

Follow-up analyses in a long-term extension of the previously reported phase 2 trial showed a delay in disease progression in patients treated with givinostat and steroids for more than 6 years compared with published results from the natural history study by The Cooperative International Neuromuscular Research Group (CINRG).

Notably, mean age of loss of ambulation in those treated with givinostat plus corticosteroids was 15.20 years compared to 13.40 years in the CINRG study. Moreover, the yearly rate of decline of 2 respiratory parameters, forced vital capacity percentpredicted (FVC%) and peak expiratory flow percent predicted (PEF%) was 2.3% and 0%, respectively in subjects with DMD treated with givinostat and corticosteroids.2

1. Italfarmaco receives FDA rare pediatric disease designation for givinostat in Duchenne muscular dystrophy, announces completed enrollment in EPIDYS phase 3 trial. News release. Italfarmaco. October 9, 2020. Accessed October 13, 2020. https://www.biospace.com/article/releases/italfarmaco-receives-fda-rare-pediatric-disease-designation-for-givinostat-in-duchenne-muscular-dystrophy-announces-completed-enrollment-in-epidys-phase-3-trial/
2. Italfarmaco provides update on advanced-stage clinical development program with givinostat in Duchenne muscular dystrophy. News release. Italfarmaco. April 27, 2020. Accessed October 13, 2020. https://www.businesswire.com/news/home/20200427005274/en/Italfarmaco-Provides-Update-on-Advanced-Stage-Clinical-Development-Program-with-Givinostat-in-Duchenne-Muscular-Dystrophy
3. Bettica P, Petrini S, D'oria V, et al. Histological effects of givinostat in boys with Duchenne muscular dystrophy. Neuromuscul Disord. 2016;26(10):643-649. doi:10.1016/j.nmd.2016.07.002
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