Sarepta’s Exon 53 Skipping Therapy, Golodirsen, Improves Dystrophin Expression in Phase 1/2 Trial

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by Alice Melão |

MD diagnostic tests

Sarepta Therapeutics says its lead candidate therapy for exon 53 skipping, golodirsen, showed potential to treat Duchenne muscular dystrophy (DMD) in a first clinical trial of DMD patients.

According to results of the Phase 1/2 clinical study, 4053-101 (NCT02310906), golodirsen significantly boosted dystrophin protein production in 25 boys with confirmed deletions of the DMD gene amenable to exon 53 skipping. About 8 percent of all DMD patients may benefit from this approach, Sarepta reports on its website.

DMD is caused by mutations on the gene that encodes the dystrophin protein. Although expressed in very small amounts — representing only 0.002 percent of total muscle proteins — dystrophin is essential for muscle cells to work as they should.

Golodirsen, also known as SRP-4053, is based on Sarepta’s exon-skipping technology and works by excluding, or skipping over exon 53 of the dystrophin sequence. This helps produce a smaller but functional form of dystrophin protein.

The trial evaluated the safety, tolerability, phamacokinetics and efficacy of golodirsen. French, Italian and British boys received weekly 30 mg/kg intravenous infusions of the investigative therapy for at least 48 weeks.

After roughly 11 months of treatment, muscle biopsies confirmed that all patients had responded, showing increased levels of exon 53 skipping compared to baseline measures. Importantly, a 10.7-fold increase in levels of the dystrophin protein from the study’s start was also seen in measures taken using Western blot, rising from an initial mean of 0.095 percent of normal protein levels to a mean of 1.019 percent.

These results, the company said in a press release, both confirm the validity of the therapeutic approach and golodirsen’s potential as a new therapy.

“This is now the second exon-skipping agent [the first was Exondys 51] to have shown a statistically significant increase in dystrophin production, validating the exon-skipping approach to treating DMD boys with amenable mutations,” said principal investigator Francesco Muntoni, who is also a pediatric neurologist at London’s Great Ormond Street Hospital for Children NHS Foundation Trust and the UCL Great Ormond Street Institute of Child Health.

In the Phase 2 initial study (NCT01396239) and follow-up trial (NCT01540409)  that led to the U.S. Food and Drug Administration granting Exondys 51  accelerated approval in September 2016, the dystrophin protein level in patients rose to 0.44 percent of normal levels after 48 weeks of treatment.

“These data demonstrate statistically significant exon skipping, dystrophin production and localization, which further validate the broad application of our exon-skipping platform and aligns with our strategic imperative to expand and improve the treatment choices for the majority of patients with DMD,” said Douglas Ingram, Sarepta’s president and CEO.

The 4053-101 clinical trial is part of the SKIP-NMD project, involving 10 academic partners across the United States and Europe. Its 25 patients will continue to be evaluated for a total of 144 weeks. The study will likely finish in May 2019, and Sarepta plans to release study data at a future scientific meeting.

The safety and efficacy of golodirsen is also being evaluated in the Phase 3 ESSENCE study (NCT02500381) in patients with DMD gene deletions amenable to exon 45 or 53 skipping. This trial is now recruiting about 100 DMD patients at sites across the United States, Canada and Europe.