3 DMD Exon-skipping Therapies Show Promise in Early Studies

Experimental treatments are targeting exons 53, 44, and 45

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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PGN-EDO53, an experimental therapy designed to treat Duchenne muscular dystrophy (DMD) in patients amenable to exon 53 skipping, showed promising effects in preclinical studies, the therapy’s developer PepGen announced.

The company also announced promising results from cell experiments for two other investigational exon-skipping therapies, PGN-EDO45 and PGN-EDO44.

“We believe that these data highlight the ability of our technology to enable the rapid development of PepGen’s pipeline programs,” Jaya Goyal, PhD, PepGen’s executive vice president of research and preclinical development, said in a press release.

DMD is caused by mutations in the DMD gene, which provides instructions for making the dystrophin protein. Like other protein-coding genes, the DMD gene contains exons — the parts that provide instructions for making protein — which are interspersed with noncoding regions known as introns.

When the gene is read, a temporary copy or transcript of the code is made in the form of messenger RNA. The introns are cut out and the exons are strung together to form the mature code, which is sent to the cell’s protein-making machines (ribosomes).

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Therapy skips disease-causing mutations

PepGen is developing a number of exon-skipping therapies for DMD. As the term suggests, the idea behind exon-skipping therapies is to skip over the disease-causing mutation by having certain exons removed from the transcript, allowing cells to produce a shortened but functional version of dystrophin protein.

Earlier this year, PepGen announced the initiation of a Phase 1 study of PGN-EDO51, the company’s exon-skipping treatment targeting mutations amenable to skipping exon 51 of the DMD gene.

PGN-EDO53 is designed for patients with mutations amenable to skipping exon 53 of the gene. This represents about 8% of DMD patients, according to James McArthur, PhD, president and CEO of PepGen.

“PepGen is driven by deep commitment to the DMD patient community, and we are very pleased to provide a comprehensive update on our DMD pipeline,” McArthur said.

Three doses of PGN-EDO53 were evaluated in nonhuman primates (NHPs). The experimental therapy was administered via infusion into the animals’ bloodstreams, and each NHP received three infusions, one month apart.

Results showed after the first dose of PGN-EDO53, mean exon skipping level in DMD transcripts was 36.4%. After three doses, the rate was 57.2%.

“We are particularly encouraged by the exon skipping levels we observed following a single dose of PGN-EDO53 in NHPs, and the subsequent accumulation of exon 53 skipped transcript with repeated administrations at a monthly interval. These results are consistent with our EDO51 program results to date,” McArthur said.

Other NHPs were treated with a comparator exon-skipping compound called R6G-PMO53, and results showed substantially less exon-skipping: 5.4% after one dose and 20.8% after three doses.

“Notably, repeat dosing of PGN-EDO53 afforded exon skipping levels that were almost three times higher than those observed for a comparator … approach, highlighting the potential of this candidate to deliver meaningful clinical benefits to the 8% of DMD patients who are amenable to an exon 53 skipping approach,” McArthur said.

PGN-EDO44 and PGN-EDO45 are designed for mutations amenable to skipping exons 44 and 45, respectively. PepGen shared studies of these compounds in early muscle cells called myoblasts.

“We are also excited to announce that we observed high, dose-dependent levels of exon skipping in wild-type human myoblasts for both our novel PGN-EDO45 and PGN-EDO44 nominated candidates for development, which could potentially address the 8% and 6% of DMD patients whose disease is amenable to an exon 45 and exon 44 skipping approach, respectively,” McArthur said.

Results showed PGN-EDO44 led to skipping of exon 44 at levels up to 93.4%. PGN-EDO45 led to skipping of exon 45 at levels up to 79.9%, and also outperformed a comparator that led to 54% skipping at the highest dose.

“We included a comparator … as a positive control in our PGN-EDO45 study and observed that our exon 45 candidate outperformed this approach at all dose levels assessed,” McArthur said, adding that the results indicate PepGen’s exon-skipping technology “has the potential to deliver meaningful clinical benefit to those living with this debilitating disease.”