Sarepta Therapeutics' (NASDAQ:SRPT) stock enjoyed a nice bounce after a disappointing first look at an experimental gene therapy from a potential competitor, Solid Biosciences (NASDAQ:SLDB). Although Solid's stock price tanked, the start-up biotech's muscular dystrophy program is a long way from washed up.
Initial results from Solid's lead candidate, SGT-001, were far from encouraging, but it's still too soon for Sarepta investors to assume Solid's similar approach isn't a threat anymore. Here's what you need to know about both clinical-stage programs.
Boys who inherit Duchenne muscular dystrophy can't produce enough dystrophin to protect their muscle tissue. Dystrophin is a relatively simple structural protein, but the complete gene is way too long to fit inside any delivery vehicle.
Solid Biosciences' gene therapy candidate, SGT-001, and another from Sarepta Therapeutics called AAVrh74.MHCK7.micro-dystrophin use a clever trick to get muscle cells to produce dystrophin on their own. Both deliver a relatively tiny micro-dystrophin gene to muscle cells that allows them to produce the protective scaffolding they need.
About mice and men
Grizzled biotech veterans know that successful results from trials with mice are just the first steps on the path to beginning trials with real patients. Solid Biosciences investors recently found out the hard way how dangerous it can be to make assumptions based on preclinical success.
Solid's lead candidate, SGT-001, produced striking improvements to the amount of functional dystrophin produced in the muscles of test mice at a dosage of 50 trillion vector genomes per kilogram of body weight (vg/kg). That might seem like a lot, but it wasn't enough to help the first three Duchenne muscular dystrophy (DMD) patients the same way it helped mice.
The best muscle biopsy result for patients three months after receiving a single infusion of SGT-001 was from one with micro-dystrophin present in around 10% of fibers, as determined by just one of two tests used. There was a detectable amount among all three patients, but the levels were too small to measure and almost certainly too small to make a difference for the patients.
The first three boys treated with Sarepta's candidate had micro-dystrophin in 81% of muscle fibers at an assessment 60 days after they received a single dose containing 200 trillion vg/kg, or four times as many copies of micro-dystrophin as patients received in Solid's trial with SGT-001. This might be a simple problem that Solid Biosciences can fix with a larger dosage, or there could be a serious problem with the promoter Solid used.
Transporting bazillions of micro-dystrophin genes from an IV bag and into muscle cells is only half the job for these treatments. Encouraging the right cells to actually do something with the new gene is the hard part. To promote expression of the micro-dystrophin gene, Solid used a muscle-specific promoter called CK8, while Sarepta went with MHCK7.
There really haven't been enough gene therapy trials to know if we should blame Solid's choice of promoter for the dismal results or bad luck with the first dosage strength. We know that Solid Biosciences began working on a next-generation promoter long before it saw any human proof-of-concept data for SGT-001, but that doesn't necessarily mean the company wasn't satisfied with CK8.
Solid Biosciences set out to test ascending doses of SGT-001 from the beginning. Following dismal results from the first dose, though, management promised to do what it can to shorten the time until the next group of patients receives a higher dose. The company hasn't enrolled any yet, so it's going to be more than a few months before we can be sure that Solid's first experimental gene therapy isn't a threat to Sarepta.
Last spring, Pfizer (NYSE:PFE) began the first clinical trial with a mini-dystrophin candidate for DMD patients called PF-06939926 that work the same way as Sarepta's and Solid's respective candidates. Pfizer will present results from an interim assessment in the first half of 2019, which could take the shine off Sarepta's program.
Recent guidance from the Food and Drug Administration (FDA) suggests the agency might be willing to grant Sarepta's treatment a speedy approval based on biomarkers that suggest the treatment works instead of waiting years to measure different rates of mobility loss. The first four patients showed micro-dystrophin expression in 81% of muscle fibers, and circulating levels of creatine kinase, an enzyme that signals muscle damage, fell 78% from baseline.
If the FDA is willing to approve a new DMD therapy based on efficacy signals instead of waiting years to measure outcomes, Sarepta's chances of a speedy approval seem pretty good. If incoming results fall in line with the first few patients, its micro-dystrophin candidate could start adding nine figures to Sarepta's top line in a few short years.
Check out the latest Sarepta earnings call transcript.