Duchenne muscular dystrophy has several approved drugs, including a gene therapy that provides children who have the rare, inherited muscle-wasting disease the option of a one-time treatment. But each of these therapies only treats certain defined patient groups. While corticosteroids can reach more Duchenne patients, they introduce many side effects. The FDA just approved the first nonsteroidal Duchenne drug.
The late Thursday approval of Italfarmaco drug givinostat covers patients age 6 and older and spans all genetic variants that drive the inherited disease. The twice-daily oral suspension will be marketed under the brand name Duvyzat. In an email, Italfarmaco said Duvyzat’s price has not yet been set. The Milan, Italy-based company expects the product will become available in the third quarter of this year.
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In Duchenne, a genetic mutation leads to insufficient amounts of a key muscle protein called dystrophin. The disorder almost exclusively affects boys, showing its first signs when patients are between the ages of 2 and 5. Progressively worsening muscle function robs patients of the ability to walk. The disease’s muscle-weakening effects eventually reach the heart and lungs, typically leading to death when patients are in their 20s, though some live into their 30s. Though Duchenne is rare, it is the most common type of muscular dystrophy.
Privately held Italfarmaco discovered Duvyzat in partnership with the Telethon and Duchenne Parent Project in Italy. The drug is a small molecule designed to block an enzyme called histone deacetylase, or HDAC. While the precise way that this approach helps is not known, Italfarmaco has pointed to research showing that Duchenne patients have high HDAC activity. By blocking it, the drug is intended to inhibit excessive pathological activity associated with the enzyme.
The FDA’s approval of Duvyzat is based on the results of a placebo-controlled Phase 3 clinical trial enrolling 179 patients. The main goal of the 18-month study was to show a change in muscle function as measured by a stair-climbing test. Steroids are a standard first-line treatment for Duchenne and all study participants continued to receive these drugs during the clinical trial.
According to the results, patients in the study drug arm demonstrated statistically significant lower decline in the ability to climb four stairs compared to those in the placebo group. A secondary goal was measuring the change in physical function as scored according to a commonly used rating scale to measure motor function in Duchenne patients who can still walk. The FDA said patients treated with Duvyzat showed less worsening in scores at 18 months compared to those in the placebo arm.
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The most common side effects reported in the trial include diarrhea; abdominal pain; nausea and vomiting; a decrease in platelets; an increase in triglycerides, a type of body fat; and fever. Italfarmaco said the side effects were all mild to moderate. Duvyzat’s label advises physicians to monitor platelet counts and triglyceride levels. The dose may be adjusted to manage those side effects as well as moderate-to-severe diarrhea. The label also notes the drug may increase the risk of an irregular heartbeat. Full trial results were published online this week in The Lancet Neurology.
Corticosteroids have been used off-label for years as a Duchenne treatment. PTC Therapeutics’ Emflaza was approved for Duchenne in 2017, making it the first steroid approved specifically for Duchenne. This pill may be used by patients ages 2 to 5. Last October, FDA approval of Santhera’s oral suspension Agamree introduced another steroid option for patients age 2 and older. Adverse effects associated with the steroids used to treat Duchenne include weight gain, behavioral issues, gastrointestinal problems, and weakening of bones.
Sarepta and NS Pharma have commercialized Duchenne drugs, each one addressing a specific genetic mutation that drives the disease. Elevidys, a Sarepta gene therapy, won accelerated approval last year for treating Duchenne patients ages 4 and 5. Expansion of the approval to other age groups faces a tall hurdle. In a confirmatory Phase 3 study, Elevidys fell short of achieving statistical significance on the trial’s main goal. Nevertheless, Sarepta points to statistical significance according to the trial’s secondary goals.
A regulatory submission for Duvyzat is currently under review in Europe. Italfarmaco said it is also discussing the drug with regulatory agencies in other parts of the world. The company will commercialize Duvyzat through a newly established U.S. subsidiary, ITF Therapeutics.
“Duchenne muscular dystrophy is a disease with significant unmet medical need and Duvyzat has the potential to benefit a broad DMD patient population independent of the underlying gene mutation that causes the disease,” Francesco De Santis, president of Italfarmaco Holding and chairman of Italfarmaco Group, said in a prepared statement. “The FDA approval highlights the dedication of Italfarmaco’s research and clinical teams to achieve this milestone for the company.”
Photo: Getty Images, Sarah Silbiger
