Sarepta announced successful results from a preliminary trial for Duchenne Muscular Dystrophy

Sarepta Therapeutics (SRPT) has news from preliminary Duchenne muscular dystrophy trials. Although the number of recruited patients was only three, the strong positive data excited the media and Wall Street investors who rushed to buy the stock, making it add over $50 in today’s morning trading.

The Story

At the Company’s R&D Day, Jerry Mendell, M.D. of Nationwide Children’s Hospital presented positive preliminary results from Phase 1/2a gene therapy in a clinical trial was assessing AAVrh74.MHCK7.micro-Dystrophin in individuals with DMD.

Following are the preliminary data presented by Dr. Mendell from the three patients’ trial:

– All patients showed robust expression of transduced micro-dystrophin, which is properly localized to the muscle sarcolemma, as measured by immunohistochemistry.

Mean gene expression of micro-dystrophin positive fibers was 76.2% and the mean intensity of the fibers was 74.5% compared to normal control.

All post-treatment biopsies showed robust levels of micro-dystrophin as measured by Western blot, with a mean of 38.2% compared to normal utilizing Sarepta’s method, or to 53.7% when compared to normal pursuant to Nationwide Children’s quantification of Sarepta’s method that adjusts for fat and fibrotic tissue.

A mean of 1.6 vector copies per cell nucleus was measured in patients, consistent with the high micro-dystrophin expression levels observed.

– All patients showed significant decreases in serum creatine kinase (CK) levels, with a mean reduction of CK of over 87% at Day 60.

CK is an enzyme associated with muscle damage and patients with DMD uniformly exhibit high levels of CK. Indeed, significantly elevated CK is often used as a preliminary diagnostic tool for DMD, which is then followed by confirmatory genetic testing.

No serious adverse events (SAEs) were observed in the study. Two patients had elevated gamma-glutamyl transferase (GGT) that resolved with increased steroids within a week and returned to baseline levels. There were no other significant laboratory findings. Patients had transient nausea generally during the first week of therapy coincident with increased steroid dosing.

Dr. Mendell, the study’s principal investigator, in collaboration with Louise Rodino-Klapac, Ph.D., empirically optimized the AAVrh74.MHCK7 specifically for DMD:

– The AAVrh74 vector can be systemically and robustly delivered to skeletal, diaphragm and cardiac muscle without promiscuously crossing the blood-brain barrier, making it an ideal candidate to treat neuromuscular diseases.

– As a rhesus monkey-derived AAV vector, AAVrh74 appears to show lower immunogenicity rates in existing early-stage clinical studies than expected based on other human AAV vectors.

The MHCK7 promoter has been chosen for its ability to robustly express in the heart, which is critically important for patients 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% of the micro-dystrophin levels observed in skeletal muscles.

– The transgene was designed to maintain spectrin-like repeats 2 and 3, which has been reported to be important for maintaining the protective functional characteristics of dystrophin.

Dr. Mendell said, “I have been waiting for my entire 49-year career to find a therapy that dramatically reduces CK levels and creates significant levels of dystrophin. Although the data are early and preliminary, these results, if they persist and are confirmed in additional patients, will represent an unprecedented advancement in the treatment of DMD. I look forward to treating more patients in the clinical study to generate the data necessary to bring this therapy to patients with DMD, with the goal of dramatically changing the course of the disease.”

Sarepta Therapeutics is a commercial-stage biopharmaceutical company focused on the discovery and development of precision genetic medicine to treat rare neuromuscular diseases. The Company is primarily focused on rapidly advancing the development of its potentially disease-modifying Duchenne muscular dystrophy (DMD) drug candidates.

Prohost Observations

The successful outcome of this dream story, if materialized, will be considered a historical achievement and a formidable gift offered to humanity represented this time by the DMD suffering patients and their parents and families. In case the small trial results are validated and confirmed by a large trial, the success would honor the unlimited capability of the human mind, which reached a stage where it can create miracles. This is what the worlds most famous masters have predicted and preached during many centuries.

We cross our fingers in hope that the results of the three preliminary cases will be confirmed in large trials.

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