ITF Gears Up for FDA Decision in Expanding DMD Market

Duchenne muscular dystrophy_Nicole Bean for BioSpace

Pictured: Illustration of a Duchenne muscular dystrophy patient alongside an FDA sign/Nicole Bean for BioSpace

The Muscular Dystrophy Association’s annual conference is taking place this week amid an expanding Duchenne muscular dystrophy treatment market. Sarepta Therapeutics recently reported strong demand for its gene therapy Elevidys, and Catalyst Pharmaceuticals is anticipating a first-quarter 2024 launch for the recently approved Agamree. Many other companies also hope to step into the fray, among them ITF Therapeutics. 

ITF, the newly minted U.S. subsidiary of Italian pharmaceutical company Italfarmaco Group, is gearing up for a March 21 FDA PDUFA date for its Duchenne muscular dystrophy (DMD) hopeful, givinostat. Italfarmaco had expected a decision by Dec. 21, 2023, but in November, the regulator extended the review period by three months. The company is banking on Phase III data showing that givinostat could reduce decline in mobility and muscle function, shared in two posters at this week’s conference.

Givinostat, a small molecule that acts by inhibiting histone deacetylases (HDACs), met the trial’s primary endpoint of mean time change from baseline to 18 months in the four-stair climb, Matt Trudeau, head of ITF, told BioSpace. The trial, which consisted of 179 ambulant boys with DMD who were six years and older, randomized patients into an active arm that received givinostat plus the current standard of care—steroids—and a placebo arm that received steroids alone.

HDACs are a group of enzymes that modulate gene and protein expression in the muscle, Trudeau told BioSpace in an email. “Deregulation of HDACs is a major consequence of the lack of dystrophin associated with DMD,” he explained. “We believe givinostat’s mode of action has the potential to inhibit HDAC pathological overactivity and thereby impact the cascade of events leading to muscle damage which, in turn, may counteract disease pathology and slow muscle deterioration.” 

Craig McDonald, chair of the Department of Physical Medicine & Rehabilitation at UC Davis Health and the lead U.S. investigator on givinostat’s Phase III trial, added that the drug also appears to have affected DNA methylation and gene expression in the muscle.

McDonald has treated nine patients with givinostat. “I’ve been really quite impressed with how they’ve done over time,” he told BioSpace.

An Evolving Treatment Landscape

If givinostat does win approval, it will be entering a growing market. Last June, the FDA approved Sarepta’s Elevidys as the first-ever gene therapy for DMD, despite its missing the primary functional endpoint in a randomized trial. Elevidys was greenlit under the FDA’s accelerated pathway for four- to five-year-old patients who are able to walk—but not all ambulatory patients, the indication the company had sought. Four months later, in October 2023, the therapy again failed to hit the primary efficacy endpoint in a Phase III confirmatory trial. 

Jeff Chamberlain, president of the American Society for Gene and Cell Therapy and the McCaw Chair in Muscular Dystrophy at the University of Washington School of Medicine, told BioSpace that the gene therapies currently in development are only somewhat effective.

“It’s far from a cure,” Chamberlain said. “With [Elevidys], we’re seeing most of the boys are doing better, but they’re not doing as much better as we were hoping they would. I think it’s fairly effective in slowing down the progression of the dystrophy, and some of the patients are showing increased strength, but a lot of them are not.” 

In animal models, Elevidys and other AAV-microdystrophin gene therapies currently in development are “very powerful and potent,” having a profound effect on the disease, Chamberlain said. He conjectured that they may not work as well in human patients, however, because “the AAV delivery vehicles are just not as efficient in human muscle as they were in the animal models.”

Meanwhile, Santhera Pharmaceuticals last fall won the FDA’s nod for Agamree, an oral suspension steroid that is indicated for DMD patients aged two years and older. Catalyst Pharmaceuticals, which will commercialize the drug in North America, anticipates launching it by the end of this month.

“I think that’s a really exciting and important development,” Chamberlain said. Steroid hormones can be used in conjunction with gene therapies to help reduce some of the inflammatory side effects caused by the high-dose vectors, he noted, but they have side effects of their own, including hyperactivity and weight gain. “[Agamree] was designed . . . to maintain all the benefits of a traditional steroid hormone while removing the parts of the molecule” that cause the side effects, Chamberlain said.

Michael Kelly, chief scientific advisor at CureDuchenne, which provided early financial backing for Agamree’s development, said he is “delighted” with the drug because it gives patients another choice alongside currently available steroids prednisone and deflazacort.

In terms of givinostat, Kelly said “it has clearly shown benefits in clinical trials. Patients we’ve talked to that have participated in those trials really continue to speak out highly in support of it. We’re hopeful that the agency will look upon this favorably.” 

The Diverse DMD Pipeline

As the recent approvals demonstrate, there’s more than one way to treat DMD. Ten years ago, steroids were the standard treatment, Trudeau said. “Today, the pipeline is quite rich.”

Kelly noted that there are several companies expecting data this year. On the gene therapy front, he highlighted Pfizer’s mini-dystrophin gene therapy fordadistrogene movaparvovec, for which Phase III data are anticipated in the second half of 2024, and REGENXBIO, which on Tuesday reported safety and efficacy data from the first patient to receive a higher dose level of its one-time gene therapy RGX-202 in a Phase I/II trial.

The 12-year-old patient had robust microdystrophin expression of 75.7% compared to someone without DMD at three months, according to the press release. At 10 weeks, the investigators observed a 77% reduction from baseline in serum creatinine kinase (CK) levels, which are associated with muscle injury and are uniformly elevated in patients with DMD. REGENXBIO is on track to launch a pivotal trial in the second half of this year, according to the press release.

Kelly also anticipates an exciting year for exon-skipping approaches, which he said involve a “much larger transcript of dystrophin.” In this space, he noted Dyne Therapeutics, Avidity Biosciences and Entrada Therapeutics, all of which have therapies in clinical trials. “We might expect if we’re able to put in dystrophin with much more efficacy and higher levels, that the benefit might be greater,” he said.

While there is no shortage of DMD therapies coming down the pike, Trudeau said, “every therapy that comes into this space is good news for these patients. Every new modality is important.”

Heather McKenzie is a senior editor at BioSpace. You can reach her at Also follow her on LinkedIn.

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