Promising Phase 3 Data on DMD Hopeful Givinostat

When added to corticosteroids, treatment with the investigational agent givinostat led to statistically and clinical meaningful benefits in ambulatory children with Duchenne muscular dystrophy (DMD) compared with placebo, including reduced decline of muscle function and strength, results from the phase 3 EPIDYS trial show. 

Although results in the four-stair climb assessment from baseline to 72 weeks, the trial’s primary endpoint, worsened in both the treatment and placebo groups, the decline was significantly smaller with givinostat. 

These data provide “strong additional support for the use of givinostat in the treatment of DMD,” Matt Trudeau, head of ITF Therapeutics, part of Italfarmaco, which is developing the drug, told Medscape Medical News. 

The findings come on the eve of givinostat’s March 21 US Food and Drug Administration (FDA) Prescription Drug User Fee Act (PDUFA) date, which was originally scheduled for late last year. 

DMD is a “devastating disease that has only limited treatment options available,” Trudeau noted. “If givinostat is approved by the FDA, it could provide a large number of patients with a daily, orally administered therapeutic that could represent a significant advance in treatment of DMD.” 

The data were presented earlier this month at the Muscular Dystrophy Association (MDA) Clinical & Scientific Conference in Orlando, with the full results published online March 19 in The Lancet Neurology.  

HDAC Inhibitor

Treatment of DMD has historically included systemic corticosteroids, which can cause side effects, or therapy aimed at reducing individual symptoms.

A number of targeted therapies have been developed in recent years, “however, unlike givinostat, many are suitable only for specific subtypes of the disease,” the investigators wrote.

Givinostat inhibits histone deacetylases (HDACs), enzymes that modulate gene and protein expression in muscle. 

“Givinostat’s mechanism of action has the potential to inhibit HDAC pathological overactivity in an effort to address the cascade of events leading to muscle damage, thereby counteracting the disease pathology and slowing down muscle deterioration,” the company noted in a press release about the findings. 

The EPIDYS study was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial involving 179 ambulant boys aged 6 years or older with a diagnosis of DMD and on stable corticosteroid treatment for at least 6 months prior to treatment. 

A total of 118 patients received oral givinostat, and 61 received matching placebo twice daily along with corticosteroid treatment for 72 weeks. They were evaluated every 12 weeks for 72 weeks. 

‘Robust Evidence’

Treatment with givinostat was associated with a slower decline in performing the four-stair climb compared with the placebo group (difference vs placebo of 1.78 sec; P = .037).

Treatment with givinostat also resulted in a 40% lower decline on the North Star Ambulatory Assessment (NSAA), a 17-item rating scale that measures motor function, compared with placebo. 

In addition, compared with placebo, the treatment group showed a 30% reduction in vastus lateralis fat fraction (VLFF), a predictor of loss of ambulation and indicator of disease progression in DMD.

“When managing DMD, a primary goal is to maintain motor function for as long as possible. The results from EPIDYS provide robust evidence that givinostat has the potential to support this goal,” study investigator Craig M. McDonald, MD, with University of California Davis Health, said in a news release. 

Taken together, these data suggest givinostat could be an effective new treatment for DMD management,” McDonald continued.

An ‘Additional Therapy’

Givinostat was generally well tolerated. The most common treatment-related adverse events (frequency ≥ 1 in 10 boys) associated with givinostat were decreased platelet count/thrombocytopenia, increased blood triglyceride/hypertriglyceridemia, diarrhea, and abdominal pain; none of the severe or serious adverse events were treatment-related or resulted in study withdrawal. 

Givinostat tolerability was managed with appropriate monitoring and dose adjustments. Although dose reductions, mostly due to adverse events, were more common in the treatment group compared with placebo (48% vs 11%), 95% of participants completed the study, investigators noted. No other safety concerns were observed.

Commenting on the findings for Medscape Medical News, Nick Johnson, MD, professor and director of the Center for Inherited Muscle Research at Virginia Commonwealth University, Richmond, said that the findings demonstrate “modest impact on the rate of decline in boys with DMD.” 

“I think for clinicians, this will likely be an additional therapy that may be helpful over a long time,” he said. “As in the study, I would expect clinicians to consider a combination of steroids and givinostat across all boys with DMD, as well as exon skipping therapies or microdystrophin gene therapy for those boys that qualify.”

An ongoing extension study is evaluating the long-term safety and efficacy of givinostat in patients with DMD.

The FDA accepted the company’s new drug application and granted priority review for givinostat in June 2023. Italfarmaco announced in November that the original PDUFA date, set for Dec. 21, was extended to March 21 to allow the agency more time to review data submitted by the company. 

Funding was provided by Italfarmaco. Disclosures for the study team are listed with the original article.