Results were preliminary and the database included just three children, but Sarepta Therapeutics Inc. scored a solid win with investors and analysts by exceeding expectations in its first assessment of AAVrh74.MHCK7.micro-dystrophin in individuals with Duchenne muscular dystrophy (DMD).

"Nothing micro about it; expression handily surpasses 15 percent," Leerink Partners LLC's Joseph Schwartz penned in his flash note on the data. On the basis of immunohistochemistry (IHC) analysis, mean intensity of micro-dystrophin positive fibers was 74.5 percent (range 59 percent to 83 percent) compared to normal control. Mean gene expression, as measured by percentage of micro-dystrophin positive fibers, was 76.2 percent (range 73.5 percent to 78 percent).

Investors didn't take a micro stance on the Cambridge, Mass.-based company, either. Shares (NASDAQ:SRPT) soared more than 67 percent, to $176.50, early Tuesday, before finishing at $143.93 for a gain of $38.69, or 36.7 percent.

During Sarepta's inaugural investor's day, Jerry Mendell, director of the Center for Gene Therapy in The Research Institute, director of the Paul D. Wellstone Muscular Dystrophy Cooperative Research Center and chair of pediatric research at Nationwide Children's Hospital, presented additional data on the first three patients enrolled in the study. Post-treatment biopsies showed strong levels of micro-dystrophin as measured by Western blot, with a mean of 38.2 percent compared to normal using Sarepta's method or 53.7 percent compared to normal using Nationwide Children's quantification of Sarepta's method, which adjusts for fat and fibrotic tissue.

A mean of 1.6 vector copies per cell nucleus was measured in patients, consistent with micro-dystrophin expression levels that were observed, and the three patients showed a mean decrease of more than 87 percent in serum creatine kinase (CK) levels – a marker associated with muscle damage that is highly elevated in individuals with DMD – at day 60.

No serious adverse events were observed, although two of the three children had elevated gamma-glutamyl transferase that resolved within a week and returned to baseline levels following use of increased steroids. No other significant laboratory findings were seen. Patients had transient nausea during the first week of therapy, coincident with increased steroid dosing.

Sarepta's micro-dystrophin data from cohort B (ages 4-7) "far surpassed management's 'home-run' scenario of 15 percent and fulfilled our optimism of greater than a 50 percent level," Schwartz wrote. With strong expression and wide distribution across the biopsied sample and complemented by dystrophin-associated protein complexes, as indicated by alpha- and beta-sarcoglycan findings, the data "highlight the strong promise of the company's rh74-delivered gene therapy and should position Sarepta as a leader in this field."

Sarepta 'poised to transform care of these patients'

Mendell, the study's principal investigator, empirically optimized AVrh74.MHCK7 for DMD in collaboration with Louise Rodino-Klapac, Sarepta's newly recruited vice president of gene therapy, who co-founded Sarepta's Limb girdle muscular dystrophy partner Myonexus Therapeutics Inc. Rodino-Klapac previously headed the laboratory for gene therapy research for muscular dystrophies at Nationwide Children's, where she served as a principal investigator, and was associate professor in the department of pediatrics at the Ohio State University College of Medicine. (See BioWorld, Jan. 16, 2018.)

Dystrophin is the largest gene in the human genome, posing a critical obstacle for molecular manipulation, Rodino-Klapac explained during the investor presentation, as she outlined a pivotal DMD case dating back 30 years that provided a rational design for the micro-dystrophin construct optimized for use by Sarepta.

The company also reported preclinical findings suggesting the AAVrh74 vector can be systemically delivered to skeletal, diaphragm and cardiac muscle without crossing the blood brain barrier. As a rhesus monkey-derived AAV vector, AAVrh74 appeared to show lower immunogenicity rates in early-stage studies than expected with other human AAV vectors, according to the company.

The MHCK7 promoter was selected for its ability to express in the heart – a critical organ for individuals with DMD, who typically die from pulmonary or cardiac complications. In preclinical models, micro-dystrophin expression in the heart was observed to be up to 120 percent of the micro-dystrophin levels observed in skeletal muscles. The transgene also was designed to maintain spectrin-like repeats 2 and 3, reported to help maintain the protective functional characteristics of dystrophin.

"The micro-dystrophin gene therapy data, albeit early and limited to three patients (one more than was initially expected), did not disappoint," observed H. C. Wainwright's Debjit Chattopadhyay. "These are an immense positive for the DMD patient community and a shot in the arm for broader gene therapy approaches targeting a variety of neuromuscular disorders."

Evercore ISI's Josh Schimmer agreed, called Sarepta's report "some of the most dramatic gene therapy results we've seen to date" in DMD, adding, "If results are sustained (and so far durability to 12 weeks is very encouraging), they appear poised to transform care of these patients."

Sarepta also set a standard for presenting data by incorporating clinical results, serum biomarkers (CK levels) and tissue-level expression, Schimmer added.

"Where at all possible, this totality of data should be the first reveal to investors as opposed to laying it out piecemeal to try to guess/piece together over time," he maintained.

The findings achieved with AAVrh74 also set "a very high bar" for the vector field, "reminding us that in competitive settings, we need to watch for the 'WINNER' with the best transduction and best profile," Schimmer wrote. "As we contemplate this dynamic, we are watching for NOVEL vector constructs that are optimized for individual tissues and continue to believe that combining NOVEL vectors and NOVEL promoters could yield results superior to what some constructs are achieving to date. As such, we caution against 'read-throughs' from one vector to another. Anyone in the muscle-targeting field will now need to at least match [Sarepta]-type results."

Parent Project Muscular Dystrophy committed $2.2 million to the Sarepta trial, which also had financial support from additional Duchenne foundations and families.