Sarepta adds muscular dystrophy gene therapies via Myonexus pact

Sarepta is determined to stay at the forefront of genetic medicines for muscular dystrophies and to that end has signed another R&D deal—this time with Myonexus Therapeutics—and taken an option on buying the company.

The $60 million upfront deal comes just a few months after Sarepta got a green light from the FDA for the first trial of its gene therapy for Duchenne muscular dystrophy (DMD) partnered with Nationwide Children’s Hospital (NCH), and expands its focus to another group of rare, related diseases known as limb-girdle muscular dystrophies, or LGMD.

Sarepta CEO Doug Ingram told analysts on the company’s first-quarter results call that LGMDs cause similar muscle degeneration and wasting to that seen in DMD and progressively lead to wheelchair confinement and death, often before the age of 30, due to cardiopulmonary complications.

Sarepta has licensed five gene therapy candidates from Myonexus, headed by MYO-101 for LGMD2E or beta-sarcoglycanopathy, caused by a deficiency in the protein beta-sarcoglycan, which is due to start a phase 1/2 trial in mid-2018 with first gene expression data due later this year or in early 2019.

Sarepta has an option to acquire Myonexus at any time but will look more closely after it has reviewed the results of the trial, said Ingram. It has also agreed to make up to $45 million in milestone payments over the first two years of the collaboration.

MYO-101 delivers the sequence for beta-sarcoglycan and uses the same AAVrh.74 adeno-associated virus vector system deployed in Sarepta’s microdystrophin gene therapy for DMD, and the associations between the companies don’t end there. One of the co-inventors of the DMD therapy—Louise Rodino-Klapac, Ph.D.—is the co-founder of Myonexus and also its chief scientific officer, as well as being principal investigator at the Center for Gene Therapy at NCH.

Following after MYO-101 are four other candidates—MYO-102 for LGMD2D, MYO-103 for LGMD2C, MYO-201 for LGMD2B, and MYO-301 for LGMD2L—which all make use of the same AAVrh.74 vector.

Ingram said that the ultimate aim is to march "towards a future where many fatal genetic diseases which have robbed families first of hope and then have loved ones are transformed into … treatable obstacles."

Along with the NCH alliance, Sarepta previously signed a DMD gene therapy collaboration with French biotech Genethon, also focused on microdystrophin. The company said it will present more detail on all its pipeline programs at an R&D day on June 19.

Turning to near-term matters, Sarepta also revealed that its hopes of a speedy review for exon-skipping DMD drug Exondys 51 (eteplirsen) in Europe have hit a snag, after an interim review by the EMA’s CHMP.

According to the company, the negative trend vote from CHMP for the drug after an oral hearing last week "did not conclude that eteplirsen is ineffective for exon 51 amenable patients, but rather that Sarepta has not yet met the regulatory threshold for conditional approval, in part due to the use of external controls as comparators in the studies."

The company says it intends to ask for a meeting of a scientific advisory group comprised of DMD specialists to be convened and a re-examination of the verdict, covering "the validity of the external controls used and the importance of slowing pulmonary decline in patients with DMD," among other things.

"It is our understanding that the re-examination process will likely be completed by year-end 2018," said Ingram.

It’s not the first thing threatening to derail Sarepta’s plans in Europe. Earlier this year, the company was forced to suspend dosing in the ESSENCE pivotal trial of its next-generation DMD drugs golodirsen and casimersen after an adverse event in the U.K.

While there was no update on the U.K. situation in the first-quarter presentation, the company did say that it is still planning a rolling marketing application for golodirsen in the U.S. before the end of the year, with ESSENCE serving as a confirmatory study if the drug is approved on that basis.

Sarepta has licensed five gene therapy candidates from Myonexus, headed by MYO-101 for LGMD2E or beta-sarcoglycanopathy, caused by a deficiency in the protein beta-sarcoglycan, which is due to start a phase 1/2 trial in mid-2018 with first gene expression data due later this year or in early 2019.

Sarepta has an option to acquire Myonexus at any time but will look more closely after it has reviewed the results of the trial, said Ingram. It has also agreed to make up to $45 million in milestone payments over the first two years of the collaboration.

MYO-101 delivers the sequence for beta-sarcoglycan and uses the same AAVrh.74 adeno-associated virus vector system deployed in Sarepta’s microdystrophin gene therapy for DMD, and the associations between the companies don’t end there. One of the co-inventors of the DMD therapy—Louise Rodino-Klapac, Ph.D.—is the co-founder of Myonexus and also its chief scientific officer, as well as being principal investigator at the Center for Gene Therapy at NCH.

Following after MYO-101 are four other candidates—MYO-102 for LGMD2D, MYO-103 for LGMD2C, MYO-201 for LGMD2B, and MYO-301 for LGMD2L—which all make use of the same AAVrh.74 vector.

Ingram said that the ultimate aim is to march "towards a future where many fatal genetic diseases which have robbed families first of hope and then have loved ones are transformed into … treatable obstacles."

Along with the NCH alliance, Sarepta previously signed a DMD gene therapy collaboration with French biotech Genethon, also focused on microdystrophin. The company said it will present more detail on all its pipeline programs at an R&D day on June 19.

Turning to near-term matters, Sarepta also revealed that its hopes of a speedy review for exon-skipping DMD drug Exondys 51 (eteplirsen) in Europe have hit a snag, after an interim review by the EMA’s CHMP.

According to the company, the negative trend vote from CHMP for the drug after an oral hearing last week "did not conclude that eteplirsen is ineffective for exon 51 amenable patients, but rather that Sarepta has not yet met the regulatory threshold for conditional approval, in part due to the use of external controls as comparators in the studies."

The company says it intends to ask for a meeting of a scientific advisory group comprised of DMD specialists to be convened and a re-examination of the verdict, covering "the validity of the external controls used and the importance of slowing pulmonary decline in patients with DMD," among other things.

"It is our understanding that the re-examination process will likely be completed by year-end 2018," said Ingram.

It’s not the first thing threatening to derail Sarepta’s plans in Europe. Earlier this year, the company was forced to suspend dosing in the ESSENCE pivotal trial of its next-generation DMD drugs golodirsen and casimersen after an adverse event in the U.K.

While there was no update on the U.K. situation in the first-quarter presentation, the company did say that it is still planning a rolling marketing application for golodirsen in the U.S. before the end of the year, with ESSENCE serving as a confirmatory study if the drug is approved on that basis.