Sarepta Therapeutics said today it plans to acquire Myonexus Therapeutics for $165 million, exercising a purchase option under a gene therapy collaboration launched by the companies last year.

The deal is designed to broaden Sarepta’s pipeline with the five Myonexus candidates. All five use the same gene therapy platform licensed from Nationwide Children’s Hospital, designed to systemically and robustly deliver treatment to cardiac and skeletal muscle, including the diaphragm, without promiscuously crossing the blood-brain barrier.

All five gene therapy candidates are designed to offer the first-ever corrective treatment for five distinct forms of Limb-girdle muscular dystrophy (LGMD)—LGMD2B, LGMD2C, LGMD2D, LGMD2E, and LGMD2L.

Three of the five programs are in clinical phases. Furthest in development is Myonexus’ MYO-101 for LGMD2E, a gene therapy candidate designed to transfer a gene that codes for and restores beta-sarcoglycan protein, with the goal of restoring the dystrophin-associated protein complex.

MYO-101 uses the AAVrh.74 vector system, technology developed in the laboratory of Louise R. Rodino-Klapac, PhD, while she headed the lab for gene therapy research for Muscular Dystrophies at Nationwide Children’s Hospital; she was appointed by Sarepta in June 2018 as vice president, gene therapy. The hospital holds the gene therapy candidate’s IND application.

In addition to the AAVrh.74 vector system, MYO-101 uses the MHCK7 promoter, designed to only turn on the gene in muscle cells. According to Sarepta, the MHCK7 promoter has been chosen for three of the five LGMD programs because it is generally more productive in muscle than other muscle creatine kinase (MCK) promoters and robustly expresses in the heart, which is critically important for patients with LGMD2E as well as LGMD2B and LGMD2C, many of whom die from pulmonary or cardiac complications.

In November 2018, Myonexus announced the launch of a first-in-human, Phase I/IIa trial for MYO-101 (NCT03652259 ). The placebo-controlled study is designed to evaluate a single intravenous infusion of MYO-101 among children with LGMD2E between the ages of four and 15 years with significant symptoms of disease. The study is designed to evaluate up to two dose levels of the gene therapy candidate in two cohorts among nine patients whose baseline measurements were established based on a  recruitment study (NCT03492346).

Next-furthest advanced in Myonexus’ pipeline is MYO-102, a treatment for LGMD2D or alpha-sarcoglycanopathy. The FDA granted its Orphan Drug Designation for MYO-102 in January, and is requiring an initial intramuscular (IM) Phase I study and an Isolated Limb Perfusion (ILP) Phase I/IIa study to assess safety.

Myonexus has cited early clinical studies of MYO-102, which have shown safety and expression of alpha-sarcoglycan protein using the gene therapy candidate. After treatment with MYO-102, alpha-sarcoglycan expression increased versus baseline and the protein was present in muscles, as shown in biopsies six months after treatment, according to Myonexus.

Two-vector approach

Also reaching the clinic is MYO-201, a gene therapy for LGMD2B, also called dysferlinopathy, designed to permanently enable the muscle cells to produce the critical dysferlin protein, after simultaneous intravenous administration of two vectors, each containing approximately one-half of the gene.

MYO-201 is designed so the two halves self-assemble into a complete intact functional gene with a promoter that only turns on the gene in muscle cells, according to Myonexus. The company has cited studies in a dysferlin production deficient mouse model in Rodino-Klapac’s lab that showed widespread dysferlin expression in all muscles tested following treatment.

The FDA has approved an IND to allow IM administration of the dual vector gene therapy in LGMD2B patients. Myonexus says a request will be submitted to amend the IND to progress to systemic i.v. administration of LGMD2B patients

The remaining two programs in Sarepta’s collaboration with Myonexus are preclinical:

  • MYO-103, designed to treat LGMD2C or gamma-sarcoglycanopathy by permanently enabling the muscle cells to produce the critical gamma-sarcoglycan protein following intravenous administration of a vector containing the gamma-sarcoglycan gene and a promoter that only turns on the gene in muscle cells;
  • MYO-301, designed to treat LGMD2L or ANO5-related muscle disease or anoctaminopathy by permanently enabling the muscle cells to produce the critical anoctamin protein, after intravenous administration of a vector containing the anoctamin 5 gene and a promoter that only turns on the gene in muscle cells.

“We are excited to acquire Myonexus, which will allow us to move rapidly to find solutions for LGMD patients and continue to build out and validate our gene therapy engine,” Sarepta president and CEO Doug Ingram said in a statement. “The five LGMD gene therapies being developed fit brilliantly with Sarepta’s mission to develop therapies with the potential to rescue the lives of patients with serious life-limiting rare genetic diseases.”

Ingram stated that Sarepta’s confidence in the Myonexus programs stemmed from commonalities that has come from the fact that our micro-dystrophin gene therapy and the Myonexus programs have much in common, including inventors from Nationwide Children’s Hospital, a shared vector in AAVrh74 and, to date, similar preclinical safety data.

The Myonexus-partnered programs are five of 13 gene therapy candidates in Sarepta’s pipeline, which also includes six RNA-targeted therapies based on the company’s peptide phosphorodiamidate morpholino oligomer (PPMO) platform, and five RNA-targeted therapies based on its phosphorodiamidate morpholino oligomer (PMO) platform.

Among PMO therapies is Exondys 51™ (eteplirsen), which in 2016 won the FDA’s first approval of a treatment for Duchenne muscular dystrophy (DMD). Exondys 51 is indicated for DMD amenable to exon 51 skipping. The FDA approved Exondys 51 despite recommendations by two advisory committees against approving the treatment and over objections from some administrators—one of which subsequently retired from the federal government.

“We partnered with Sarepta less than a year ago, as we shared the mutual goal of developing LGMD therapies on behalf of patients with debilitating and fatal disease,” added Myonexus president and CEO Michael Triplett, PhD. “This acquisition solidifies a commitment to rapidly advance therapies on behalf of patients who currently don’t have treatment options.”

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