SRPT Was and Still The DMD Gene Therapy Leader

Today after the market close, Solid Biosciences (SLDB) announced it has received notification from the U.S. Food and Drug Administration (FDA) that IGNITE DMD, its Phase I/II clinical trial for SGT-001 microdystrophin gene transfer in Duchenne muscular dystrophy (DMD), has been placed on Clinical Hold. The news sent SLDB share price down to $11.90 or -54% in the after-hours trading.
SLDB first patient dosed a month ago on February 14 in a non-ambulatory DMD patient with 5E13 vg/kg of SGT-001. But few days after administration, the patient was hospitalized due to laboratory findings that included a decrease in platelet count followed by a reduction in red blood cell count and evidence of complement activation.
Solid Bio mentioned that all lab parameters have subsequently improved or returned to normal. SLDB has halted enrollment and dosing in IGNITE DMD and is awaiting the formal Clinical Hold letter from the FDA to understand the requirements for resuming the clinical trial.

The whole story of SLDB looks bad, started with the story I wrote on January 30th  mentioning Dr. James Wilson paper that published online “Severe toxicity in nonhuman primates and piglets following high-dose intravenous administration of an AAV vector expressing human SMN” (link to the paper) highlighting the toxicity in NHP- non-human primate study.

Administration of 2×10^14 genome copies per kilogram body weight resulted in widespread transduction of spinal motor neurons in both species. However, severe toxicity   occurred in both NHPs and piglets.  All three NHPs exhibited marked transaminase elevations.
In two  NHPs the transaminase elevations resolved without clinical sequelae, while one NHP developed acute liver failure and shock and was    euthanized 4 days after vector injection.

Then the resignation of the head of SLDB’s Scientific Advisory Board, Dr. J. Wilson followed by the FDA putting a partial clinical hold on the SGT-001 higher dose. And today topped up by the news of the clinical hold on the lower dose!

On the other side, Sarepta Therapeutics (SRPT) went with the gene therapy leader Dr. Jerry Mendell, who had an extensive experience in the gene therapy, both preclinical and clinical trials, he brought in his success with the SMA treatment (with AVXS) to the DMD trial, at 20 months only 8%  of the SMA patients survive, while with Mendell’s gene therapy treatment, he has 15 out of 15 patients treated alive and respiratory event free for over 2 years. SRPT use RH74 (AAV8) because it is specifically designed to target muscle while SLDB using an AAV9 for DMD.

Sarepta and Dr. Mendell have an extensive preclinical program to support moving into high doses. As we already know the FDA has allowed Sarepta and Dr. Mendell to move into patients at therapeutic levels 2E14, and they start dosing the first patient back on January 04th, 2018,  followed with the second patient dosed a month later for safety precautions, while the third patient will start the treatment in few day.
At the MDA conference, Dr. Mendell said  both boys feeling well, no safety or SAE in both patients, while he is showing at the conference the picture of the first boy playing on scooter to emphasis the healthy state the boy is showing after almost 2.5 months of the gene therapy treatment with no safety issues, he said:

We had a very good success with our MACK7 muscles specific promoter, and have a very good success with that, also a very good delivery to the heart which frames very well as we move ahead. Good for older DMD patients, Becker disease and potential limb muscle treatment.
In preclinical trials in DMD, we have done many mice studies and big dose ranging studies to show safety and done toxicity studies for 6 months for every single organ, all the information presented to the FDA.
Also we had a very good success reducing fibrosis and that is very important for the DMD boys. We brought in the good and wide experience from the SMA trial into the DMD.


Sarepta’s share price spiked in the after-hours trading reaching the high $84.72, but we have to take it with a grain of salt as it was on a light volume. But tomorrow is gonna be very interesting to watch SRPT’s price action into the market hours, as the market received another proof of SRPT being  the leader of the DMD, if it was with the PMO, PPMO or gene therapy, and the investors who were looking to invest in the next generation DMD gene therapy will have to look again at SRPT and jump back on the winning horse. SLDB setback will leave them behind SRPT in the DMD gene therapy and their recovery might take long time to deal with the FDA, hope they can solve the issues and don’t cause any harm to any DMD patient in the future.

Disclosure: Author is long SRPT.

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