Exciting results from exon-skipping

CAMBRIDGE, Mass.—Sarepta Therapeutics Inc. has released results through week 144 of Study 202, the Phase 2b open-label extension study of its drug candidate eteplirsen in patients with Duchenne muscular dystrophy (DMD). After close to three years of follow-up, results on the six-minute walk test (6MWT)—one of the standard endpoints for DMD trials, as it tests cardio, pulmonary and muscle endurance simultaneously—demonstrated that walking ability declined at a slower rate than would be expected based on existing DMD natural history data.

Continued stabilization of respiratory muscle function was also observed. Sarepta previously reported that the study met its primary endpoint of increased novel dystrophin, as determined by muscle biopsy, and is now in its long-term extension phase as patients continue to be followed for clinical and safety outcomes.

“The long-term clinical data for eteplirsen showing a slowing in the decline of walking ability in a population now on average 12 years old are very encouraging, particularly when compared with the growing body of DMD natural history data which clearly show that similarly aged patients typically experience an increasingly rapid decline in walking ability and lose ambulation in their early teen years,” Dr. Jerry Mendell, director of the Centers for Gene Therapy and Muscular Dystrophy at Nationwide Children’s Hospital and principal investigator of the Phase 2b study, said in a news release.

Chris Garabedian, president and CEO of Sarepta, tells DDNews that there are no approved drugs for the treatment of DMD, and no disease-modifying drugs on the market. The current standard of care tends to be the use of corticosteroids, with prednisone as the most common choice in the United States. While there are horrible side effects, Garabedian says, the steroids do seem to help delay progression and mortality of the disease.

The benefit of Sarepta’s exon-skipping technology in Duchenne, according to Garabedian, is that it allows them to work at the disease’s origin. Eteplirsen is created with Sarepta’s novel phosphorodiamidate morpholino oligomer-based chemistry and proprietary exon-skipping technology. The compound skips exon 51 of the dystrophin gene, which enables the repair of specific genetic mutations that affect roughly 13 percent of the total DMD population. In skipping exon 51, eteplirsen may restore the ability to produce a shorter yet still functional version of dystrophin from messenger RNA.

“This disease is marked by the inability of these boys to produce this essential protein in muscles, dystrophin,” Garabedian explains. “And the reason they can’t produce dystrophin is they have errors—mutation, deletion—in the dystrophin gene that render it to be out of frame; it stops read-through where that deletion or mutation occurs. The beauty of our exon-skipping is that we can apply this, silence the mutated part of the gene that’s causing it to be out of frame and convert an out-of-frame mutation in the gene to an in-frame, which restores translation and production of the protein.”

He anticipates that eteplirsen could have even greater effects if it were to be administered earlier in the disease.

“Our clinical outcomes are the best outcomes we’ve seen in any Duchenne clinical study to date, and we have a safety profile that, after three years of dosing, has not produced any treatment-related significant adverse events,” Garabedian concludes. “So for all of these reasons, we think these are unprecedented results and very promising, and why the community has become very excited about this drug and this technology.”

DMD is one of the most common fatal genetic disorders, affecting approximately one in every 3,500 boys born worldwide. The disease causes progressive muscle wasting, beginning in the lower limbs before eventually affecting respiratory and cardiac muscles, and as a result, death generally occurs before the age of 30.

Looking more specifically at some of the trial results, the Phase 2b eteplirsen program was designed to consist of Studies 201 and 202. The former was a randomized, double-blind, placebo-controlled clinical study of 12 boys, aged seven to 13 years, who presented with a genotype amenable to treatment with an exon-51 skipping drug. The patients were split evenly into groups receiving 30 mg/kg of eteplirsen, 50 mg/kg of eteplirsen or a placebo/delayed treatment. At week 25, all patients were rolled over into Study 202.

At week 144, patients in the eteplirsen cohorts who could perform the 6MWT saw a decline of 33.2 meters, roughly 8.5 percent, from their baseline walking ability. A statistically significant treatment benefit of 75.1 meters was seen in this population compared to the placebo group; after seeing a decline of 68.4 meters from baseline to week 36 in the placebo group, which started treatment at week 25, that cohort demonstrated a decline of 39 meters in walking ability from week 36 to week 144.

Respiratory muscle function from baseline through week 144 in the intent-to-treat population showed a 14.7-percent mean increase in maximum inspiratory pressure and a 12.8-percent mean increase in maximum expiratory pressure. Additionally, there was also a mean increase in forced vital capacity (a measure of lung volume) of 11 percent.