Yesterday 10/04, at 7:00 am ET, Sarepta Therapeutics (SRPT) with Dr. Mendell released the biopsy data from the fourth patient including full 4 patients “Functional Data” from Argentina at #WMS2018 the 23rd International Annual World Muscle Society meeting
Link to the full slide deck: https://www.sec.gov/Archives/edgar/data/873303/000119312518292068/d616670dex992.htm
The after-hours share price reaction was wild swing, spiking up in the first few minutes, followed by a nose dive to reach the low of $ 131, and again bouncing back upward to close at $ 151!
This wild volatility shows the lack of understanding and interpretation of the data presented, and the fast response of traders and investors to any word dropped in the social media without understanding or even trying to read and understand the meaning of data.
The data from the 4th patient biopsy was amazing, something we never dreamed off a few months ago, where everyone back on June before the R&D day was looking for 5% to 25% as tremendous dystrophin expression, and today the market can’t get what the heck is the meaning of 182% of normal, and the bears start spreading fear whether the overexpression is bad!!!
Going back to the literature, at NCBI publication ”100-fold but not 50-fold dystrophin overexpression aggravates electrocardiographic defects in the mdx model of Duchenne muscular dystrophy” (Link) where mentioned:
Dystrophin gene replacement holds the promise of treating Duchenne muscular dystrophy. Supraphysiological expression is a concern for all gene therapy studies. In the case of Duchenne muscular dystrophy, Chamberlain and colleagues found that 50-fold overexpression did not cause deleterious side effect in skeletal muscle. To determine whether excessive dystrophin expression in the heart is safe, we studied two lines of transgenic mdx mice that selectively expressed a therapeutic minidystrophin gene in the heart at 50-fold and 100-fold of the normal levels. In the line with 50-fold overexpression, minidystrophin showed sarcolemmal localization and electrocardiogram abnormalities were corrected. However, in the line with 100-fold overexpression, we not only detected sarcolemmal minidystrophin expression but also observed accumulation of minidystrophin vesicles in the sarcoplasm. Excessive minidystrophin expression did not correct tachycardia, a characteristic feature of Duchenne muscular dystrophy. Importantly, several electrocardiogram parameters (QT interval, QRS duration and the cardiomyopathy index) became worse than that of mdx mice. Our data suggests that the mouse heart can tolerate 50-fold minidystrophin overexpression, but 100-fold overexpression leads to cardiac toxicity.
The micro-dystrophin expression data from the 4th patient biopsy is even more impressive than the first three presented back on the R&D day, with the western blot coming in at a staggering 182% of normal or 222% of normal adjusting for fat and fibrotic tissue. On the other hand the first three patients at 38.2% of normal expression (53.7% adjusted). 96.2% of fibers were positive for dystrophin expression on IHC. From the four patients, the average expression is 74.3% of normal (95.8% adjusted).
The CK levels also decreased in a similar amount with a new mean of 78% versus the prior 87%. The functional improvements were extremely robust and correlated to the dystrophin expression shown from the biopsy by WB. The NSAA increased by 12 linearized units in 90 days, well above historical controls which increased 4-6 linearised units over a year. Also, time to rise, stair climb and 100m walk all increased 13-30% over baseline in a similar fashion to NSAA.
In my eyes, the functional data is significantly better than what the market expectations, and SRPT need to continue with the Cohort C study where the placebo arm can be used as a comparator for the functional data and longer duration of follow up will confirm the substantial importance of the data, which give the hope to the kids and families to start dreaming of a “DMD cure” coming in the 2-3 years.
Disclosure: Author is Long SRPT
