Tests of Duchenne muscular dystrophy drugs typically assess how patients with the muscle-wasting disorder performs tasks, such as walking. The key measure in a pivotal test of Italfarmaco Group’s Duchenne drug, givinostat, is climbing stairs. Less than two seconds may not seem like much time, but it could mean everything for the oral medication. Those seconds represent the time difference between those treated with the experimental therapy and those given a placebo. Italfarmaco says the results show its drug slows muscle decline and pave the way for discussions with regulators about seeking marketing approval.

The preliminary Phase 3 results were presented Saturday during the annual conference of Parent Project Muscular Dystrophy, a patient group.

Duchenne muscular dystrophy (DMD) is an inherited neuromuscular disorder that leads to insufficient amounts of dystrophin, a key muscle protein. The disease, which mainly affects boys, starts to show its muscle-weakening effects between the ages of 2 and 5. In time, patients lose the ability to walk. Duchenne’s effect on the heart and the lungs typically leads to death in a patient’s early 20s.

Givinostat is a small molecule designed to block histone deacetylase (HDAC). This enzyme changes the three-dimensional folding of DNA, which prevents gene translation. Privately held Italfarmaco points to research that shows Duchenne patients have higher than normal HDAC activity, which may prevent muscle regeneration and also cause inflammation. By blocking HDAC, givinostat is intended to slow Duchenne’s progression.

For the Phase 3 test of Italfarmaco’s drug, 179 boys age 6 and older were randomly assigned to receive the oral suspension or a placebo twice daily for 18 months. Those participants were already receiving chronic treatment with steroids, a standard Duchenne therapy. The anti-inflammatory and immunosuppressive effects of steroids are thought to slow the disease’s progression.

The study’s main goal is measuring the time it takes to climb four stairs. According to the results presented by Italfarmaco, patients treated with givinostat experienced a slower decline in the ability to perform the stair-climb task compared with those given a placebo. On average, the difference was 1.78 seconds. The study’s secondary goals included measuring time to rise from the floor and a six-minute walk test. Italfarmaco said that the time to rise was 3.28 second less in the givinostat group compared to the placebo arm. For the six minute walk test, the company said there was a small decline over time in both treatment groups.

The six minute walk test was the main goal of the pivotal test of Exondys 51, the first FDA-approved Duchenne therapy. In that small study, patients treated with the drug showed no significant difference compared to the control group. Exondys 51, an antisense oligonucleotide that get a cell’s protein-making machinery to produce a shorter but still functional version of dystrophin, won accelerated approval in 2016 on the surrogate endpoint of increased dystrophin production observed in some patients. The drug’s maker, Sarepta Therapeutics, has gone on to win approvals for two more Duchenne drugs. Each of Sarepta’s three approved Duchenne therapies addresses a different genetic subset of patients.

Italfarmaco, Sarepta, and other drug developers are working to expand the scope of Duchenne treatments with therapies that work differently and have the potential to help more patients. Sarepta, Solid Biosciences, and Pfizer have each reached clinical testing with gene therapies that deliver to cells a version of the dystrophin-producing gene.

Sarepta’s research also includes a next-generation drug that improves on Exondys 51 with technology that helps it penetrate tissue better and increase dystrophin production. But that experimental therapy, SRP-5051, has hit a setback. The Cambridge, Massachusetts-based biotech announced last Thursday that the FDA placed a clinical hold on Phase 2 testing after a patient was observed to have low levels of magnesium in the blood. Speaking during a conference call, Chief Scientific Officer Louise Rodino-Klapac said that the patient was treated with supplemental magnesium and the complication resolved within three days. The company is responding to the FDA’s request for safety information and the study is continuing outside of the U.S.

Italfarmaco said adverse effects observed in tests of givinostat were mild to moderate and include diarrhea, abdominal pain, low platelet levels in the blood, and elevated triglyceride levels in the blood. Based on the latest results of givinostat in Duchenne patients, the company plans to meet with U.S. and European authorities. Italfarmaco also plans to submit complete results from the Phase 3 study for publication in a peer-reviewed journal.

“There is a tremendous unmet medical need for additional drugs to treat this debilitating rare disease and with these positive results, we intend to meet with regulatory agencies to share these findings and discuss a path forward to submit the complete dataset in a marketing application for potential approval,” Italfarmaco Chief Medical Officer Paolo Bettica said in a prepared statement. “

Not all has gone well for givinostat. Italfarmaco previously tested the drug in another muscle disease, Becker muscular dystrophy. Last summer, the company reported a Phase 2 test in that indication failed to achieve the main goal of showing a change in fibrosis, or scar tissue, as measured according to a muscle biopsy. Despite failing to show a significant difference compared to a placebo on that endpoint, Italfarmaco pointed to significant differences from placebo in muscle deterioration as assessed by MRI scans of leg muscles.

Photo by Flickr user jmettraux via a Creative Commons license