Muscular dystrophies are a group of inherited genetic conditions that gradually cause the muscles to weaken. Duchenne muscular dystrophy is among the most severe forms of inherited muscular dystrophy.
It is caused by a genetic mutation in a gene that provides instructions for making dystrophin, a protein that helps stabilize and protect muscle fibers and is vital for muscle health. The condition is estimated to affect one in 3,500 male births worldwide.
In the past couple of years, therapeutic progress has seen drugs enter the market. Moreover, a variety of medicines are under evaluation ranging from gene therapies to myosin and HDAC inhibitors.
In this article, we take a look at six clinical-stage biotech companies that are fostering research and development (R&D) in Duchenne muscular dystrophy care.
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Wave Life Sciences
Headquartered in Cambridge, Massachusetts in the U.S., this RNA company has been making waves in the Duchenne muscular dystrophy R&D space. Its RNA medicines platform PRISM is used to develop medicines that can repair, restore, or reduce proteins, depending on the disease target.
Last week, it put out encouraging interim results from its phase trial testing WVE-N531 in boys with Duchenne muscular dystrophy who are amenable to exon 53 skipping. WVE-N531 is an exon skipping oligonucleotide.
One of the most common types of mutations in the dystrophin gene happens when a portion of the gene (the exon) is deleted, and this can affect the gene’s ability to be pieced together. For example, in Duchenne, if exon 52 is missing, exon 51 cannot join up with exon 53, and it prevents the rest from being assembled. So, an exon skipping drug like WVE-N531 can mask the exon that needs to be skipped – in this case, 52 – restore the mRNA reading frame and the function of the dystrophin protein.
The trial results showed that the candidate had a 5.5% mean absolute unadjusted dystrophin in patients after 24 weeks. Wave also reported mean absolute muscle content-adjusted dystrophin expression of 9%. Moreover, 89% of ambulatory participants achieved muscle content-adjusted dystrophin levels of at least 5%, and mean exon skipping was 57%, according to an RT-PCR.
These results were published after the FDA assigned Rare Pediatric Disease Designation for the drug candidate. Wave also snagged $200 million in a public offering in September.
Sarepta Therapeutics
Also based in Cambridge, Massachusetts, Sarepta Therapeutics is a big name in the Duchenne muscular dystrophy space. Its gene therapy Elevidys was greenlit to treat patients aged between four and five last year. In June, the FDA expanded its label to all patients aged four and older.
Elevidys works by delivering a gene that codes for a shortened form of dystrophin to the muscles. It is specifically for those patients with a mutation in the dystrophin gene.
But Sarepta’s Elevidys victory isn’t its first. Prior to Elevidys’ approval, the FDA had granted – rather controversially – another one of Sarepta’s Duchenne drugs Exondys 51 back in 2016, making it the first Duchenne drug to hit the market. This came after FDA officials were split about its effectiveness, with two against the approval.
Currently in the clinic, Sarepta has its RNA targeted therapy SRP-5051 (vesleteplirsen). The candidate is designed to bind to exon 51 of dystrophin pre-mRNA to aid exon skipping. Around 13% of children with Duchenne have mutations that make them amenable to skipping exon 51.
Phase 2 trial results testing SRP-5051 published earlier this year seem promising. The candidate showed mean dystrophin expression of 5.17% and mean exon skipping of 11.11% at 28 weeks. There were seven serious adverse events that occurred – four cases of hypomagnesemia (lower-than-normal level of magnesium in the blood) and three cases of hypokalemia (low potassium levels in the blood).
Capricor Therapeutics
The leading cause of death in patients with Duchenne muscular dystrophy is cardiomyopathy – conditions that affect the heart muscle. California-based company Capricor’s drug deramiocel is in phase 3 trials and the biotech intends to file a Biologics License Application (BLA) for full approval with the FDA, which, if it wins, would be the first to treat cardiomyopathy in patients with Duchenne muscular dystrophy.
Deramiocel is composed of cardiosphere-derived cells (CDCs), which are an endogenous population of stromal cells derived from cells of healthy human hearts. These CDCs have immunomodulatory, anti-inflammatory, pro-angiogenic, and anti-fibrotic properties that are mediated by secreted exosomes containing bioactive cargo.
The drug showed clinical benefit and was found to slow disease progression in patients with late-stage Duchenne. Improvements in heart function were observed in patients who had high ejection fractions at the start of the trial. Ejection fraction is the percentage of the total amount of blood in the heart that is pumped out with each heartbeat.
Capricor had sold the drug’s U.S. rights to Japanese multinational Nippon Shinyaku – another major stakeholder in the therapeutic field – and now it has handed over the Europe commercialization rights as well for $35 million.
Edgewise Therapeutics
Colorado-based Edgewise Therapeutics’ specializes in muscle dystrophies like Duchenne and Becker. While both are genetic diseases that cause progressive muscle weakness, Duchenne is more severe and progresses faster. Edgewise’s skeletal myosin inhibitor sevasemten is designed to protect unstable muscle against contraction-induced muscle damage in muscular dystrophies. It is currently in phase 2 trials.
The biotech is set to present drug data at the 29th International Annual Congress of the World Muscle Society in Prague, Czechia, next week. Earlier this year, the FDA granted Fast Track designation for the drug to treat Duchenne. It also secured $240 million in an offering in January.
Italfarmaco
Italian biotech Italfarmaco’s R&D is in the field of zinc-dependent histone deacetylase (HDAC) inhibitors. These drugs regulate gene expression and are being investigated to potentially treat cancer. But this class of medicines have also shown promise in addressing muscular dystrophies like Duchenne.
Italfarmaco’s lead candidate givinostat, now known by its brand name Duvyzat, was given the FDA stamp of approval for patients who are six years and older, back in March. This marks the first nonsteroidal drug approved to treat patients with all genetic variants of Duchenne in the U.S.
As HDAC inhibitors block enzymes called histone deacetylases, which are responsible for switching on and off genes in cells, Duvyzat inhibits HDAC activity in order to encourage muscle repair, regenerate muscle fibers, limit inflammation, and reduce fibrosis.
The thumbs up was based on a phase 3 trial conducted in 179 boys with Duchenne. It met its goal and the patients showed a “statistically significant and clinically meaningful difference” in time to complete the four-stair climb assessment. This test requires participants to climb four stairs as quickly as possible. It is used to measure leg muscle power, motor function, and heart health.
This drug is hoped to become part of the standard of care for people living with Duchenne. Italfarmaco’s pipeline is also focused on targeting other neuromuscular disorders, fibrosis, and cancer.
Avidity Biosciences
Situated in California, Avidity Biosciences’ pipeline comprises medicines to treat muscle disorders. The company’s Duchenne muscular dystrophy drug delpacibart zotadirsen (del-zota) showed positive effects in patients in a phase 1/2 trial.
Del-zota is designed to deliver phosphorodiamidate morpholino oligomers (PMOs) to skeletal muscle and heart tissue to specifically skip exon 44 of the dystrophin gene. PMOs are synthetic molecules created to alter gene expression. The drug is meant to enable dystrophin production through this mechanism.
Dystrophin production was up by 25% in patients and creatine kinase was brought down to near normal levels. Creatine kinase is an enzyme that helps produce energy in cells and is mainly found in the heart, skeletal muscles, and brain. High amounts of the enzyme are linked to the onset of Duchenne symptoms, even in newborns affected by the disease.
The investigational drug showed a 37% increase in exon 44 skipping and up to 66% skipping in a 5 mg/kg dosage after four months of treatment. The drug has been awarded Orphan designation by the FDA and the European Medicines Agency (EMA). The FDA has also authorized Rare Pediatric and Fast Track designations for del-zota.
In August, Avidity closed a $345.1 million public offering.
The Duchenne muscular dystrophy therapeutic landscape
The global Duchenne muscular dystrophy treatment market was valued at $3.2 billion in 2023 and is predicted to be $8.6 billion in 2032. This is largely owing to regulatory clearances for drugs such as Nippon’s exon skipper Viltepso, Sarepta’s Elevidys, Exondys 51, and Amondys 45, PTC Therapeutics’ corticosteroid Emflaza, and Italfarmaco’s Duvyzat, among others.
Besides, various other candidates are racing to the finish line. These include American company Myosana’s early-stage gene therapy, Canadian biotech Satellos Bioscience’ stem cell approach, and Massachusetts-based Dyne Therapeutics’ preclinical exon skippers. The Parent Project Muscular Dystrophy has taken a shine to Myosana’s gene therapy platform, and awarded it $500,000 to support the development of its Duchenne drug.