I am not a scientist. I have been a clergyman since I was 23 and have earned no degrees in biochemistry whatsoever, but I possess a deep interest in science and biotechnology. I grew up watching the Jerry Lewis telethon and feeling incredibly blessed that I could run, jump, and play baseball. A few years ago I discovered Sarepta Therapeutics (NASDAQ:SRPT) and I have been investing and following the story religiously for the last several years. In full disclosure, I suffered a great deal of monetary loss on the release of the FDA's briefing documents (BD) Friday for the company's upcoming advisory committee meeting. But something tells me that the story is not over.
In college I got a lucky break and landed a job in the lab of one of the foremost scientists of our time, Dr. Francis Collins. It was an incredible time as scientists searching for a "needle in a haystack" were discovering the location and causes of major diseases in the human genome. Before you get too impressed, I want to point out that I began merely washing dishes, but the excitement and joy of being in the lab that discovered the genes whose mutations caused Cystic Fibrosis, Neurofibromatosis, and Huntington's disease (along with the many collaborators) was heady stuff. I fell in love with science and went on to work on the Human Genome project for a year after graduation from the University of Michigan. I ended up in a couple publications and even made the acknowledgements in a paper in Science. I remember believing that a cure for these diseases was within a decade away.
Obviously, things didn't work out how I imagined. From cloning the entire human genome to learning how to convert that epic accomplishment into viable treatments has proven to be much more difficult. But now we have a drug that the FDA concedes seems to produce the protein dystrophin. For a moment I want to set aside the fact that the agency is criticizing the amount being produced.
This is an epic accomplishment! A drug has been produced that interacts with the very machinery of the cell to produce a protein that can not be produced because of a significant mutation in the gene. This is exactly what scientists dreamed of thirty years ago when the genes associated with major genetic diseases were being located. Dystrophin was discovered in 1986 and it has taken just short of 30 years to be able to establish that a drug can manipulate the genome to produce dystrophin in boys with DMD. And the truly astonishing fact, is that the FDA acknowledged the drug's pristine safety profile. The problem of how to affect the genome while managing to target the correct locations without off-site interactions has been an incredible challenge. Just look no further than Biomarin's adcom. Sometimes incredible scientific accomplishments are only recognized in retrospect. Whether eteplirsen is approved or not within the next couple months, I believe we could be at an inflexion point in history regarding the treatment of genetic diseases.
I realize that it is not the FDA's job to recognize scientific paradigm shifts. The agency exists to approve drugs that are both safe and efficacious. But sometimes a larger historical perspective is important. The FDA BD's state, "For eteplirsen, the quantification of dystrophin present in the fourth muscle biopsy was assessed by Western Blot, and compared with treatment-naïve controls that were selected by the applicant. The apparent treatment effect could be expressed as a 3-fold increase over the trace amount present at baseline, but relative changes can be difficult to interpret. The mean dystrophin level in patients who had been treated with eteplirsen for some 180 weeks was on average 0.9% of normal, far below levels observed in a milder form of muscular dystrophy known as Becker-type muscular dystrophy (BMD). The minimum level of dystrophin that might be reasonably likely to predict clinical benefit in patients with BMD remains unknown, but experts in DMD9,10 have stated that levels less than 3% of that of normal healthy muscle are generally associated with the typical DMD phenotype, and have proposed that "induction of approximately 10% of normal dystrophin levels sets a minimum level to confer measurable clinical benefit."
But then later the documents state,"Rarely, patients with BMD are encountered who have dystrophin levels that are less than 1% of normal, which is as low as typical DMD patients. Importantly, however, rather than suggesting that very low levels of drug-induced dystrophin are likely to be beneficial, such patients highlight the complexity of the relationship between dystrophin levels and phenotype. The fact that such patients can have mild disease appears to be unrelated to, not necessarily the result of, low levels of dystrophin. In this context, the applicant selected three BMD patients as comparators for the Week 180 dystrophin studies, one of whom had low dystrophin level of about 2% of normal."
So the FDA admits that some BMD patients have dystrophin levels "less than 1%" but fail to lend any credence to the fact that some of the children on eteplirsen had measurements above 2%.
I want to remind you of the scientific fight against cancer. Drugs have been approved in the most advanced types and stages of cancer that improve mortality a mere matter of months. And yet those drugs have managed to pass the FDA's test of efficacy. DMD is a fatal disease that generally kills young people by their 20's. What if a mere 1% increase in dystrophin expression could increase the mortality by a matter of months or even years? Wouldn't it be worth an accelerated approval especially in light of the fact that eteplirsen has a far cleaner safety profile so far than many cancer drugs. What if this small increase in dystrophin could provide a month longer of ambulation or the ability to raise one's hands to care for oneself? If some BMD patients have a mild form of MD with only 2% dystrophin, does it stand to reason that if any dystrophin is being produced at all, lives should be improved? Is the FDA really willing to bet that the increase in dystrophin is either an artifact or it is so low that it will have no effect? The fight against cancer has been incredibly incremental. Can't we expect the fight against DMD to be the same? On October 1st 2015, DMD expert Dr Mendell suggested that steroids provided an incremental shift of 1-2 years in the course of disease progression. He suggested that eteplirsen may provide the next shift. Though I would like to see greater quantities of dystrophin being produced by eteplirsen, I rejoice that the drug seems to be working as it is designed. I would like to ask the FDA how confident they are that eteplirsen is not producing any dystrophin at all and how confident they are that there is a minimum level that needs to be produced to create any phenotypic benefits.
I also want to comment on the BD's discussion surrounding the historical control that Sarepta is proposing as a comparison to the eteplirsen patients. If you accept Sarepta's control comparison, it is impossible to argue against eteplirsen's efficacy-especially in light of the just-released 216 week data.
The BD's say that the "inability to control bias is the major and well-recognized limitation of externally- controlled trials, and it is always difficult, and in many cases impossible, to establish comparability of the treatment and control groups." Further, "Study 202 appeared to be receiving optimal care, including intensive physical therapy and intensive steroid regimens, and..."performance on the 6-minute walk test is strongly influenced by motivation and coaching, and open-label trials are susceptible to bias on the part of investigators, patients, and parents." In a September 2014 communication, FDA explained its concern that, as noted by DMD experts, "preservation of ambulation and other skills is affected by the value that families and caregivers put on maintaining those skills, with such factors as risk of falls and injury from continued ambulation weighed against the safety and speed of allowing patients to use a wheelchair."
Sometimes I think "scientific practices" can get in the way of common sense. Does the FDA really believe that the pressure to perform well in a 6 minute walk test in an office is greater than the desire to live your life outside of a wheelchair? Are these kids really more motivated to perform well in a test than they are to not stand out like a sore thumb among their peers because they are forced to be in a wheelchair with all the dependence that involves? In cancer, death is a clear endpoint for a study. The loss of ambulation seems to me to be a pretty clear endpoint in children. Ten of the 12 children on eteplirsen are still walking after four years while the two who aren't walking lost ambulation so early in the study that it is arguable whether the drug had time to take effect. Dr. Wilton in the October 1st Sarepta presentation even put forth the possibility that they (the twins who lost ambulation) may have had a second mutation that could have prevented eteplirsen from working. In the historical comparison, 89.7% of the children lost ambulation. Does the FDA really believe that they may still be walking if they were merely in some kind of study where the test itself, or extra care, or extra effort would have willed them to stay out of a wheelchair? Does anyone think children aged 8-16 need more motivation to stay ambulatory than life, peers, convenience, and discomfort naturally provide? Is the FDA so confident of this bias that they can explain away the difference between 17% and 90% in children who have no hope and a drug with a thus far excellent safety profile? As a pastor, I recognize that the power of hope that these kids on eteplirsen possess can power them to higher achievement, but really, am I to believe hope alone propelled them over a four year period against a devastating disease like DMD? Morality demands that we error on the side of the kids. If I am the FDA, I'd much rather be proven wrong and find out that these 10 wonder-kids willed themselves to stay ambulate for four years rather than discover that eteplirsen works in the future and cause, through my decision to deny, the loss of ambulation and death of possibly hundreds of children.
As to the claim of "optimal care" it's odd that the FDA didn't do it's homework when only 12 patients were involved and thus must face the wrath of the parents who are already refuting that claim.
I want to restate that I am no scientist and I'm certainly not a statistician, but I hope the agency will approach the adcom with the same liberality that we have seen with cancer drugs that get approved with minimal efficacy while ignoring arguably barbaric side-effects. The children with DMD deserve no less. When the FDA BD's say, "In the context of this considerable variability among patients, the clinical course of eteplirsen patients over more than 3 1⁄2 years of treatment with eteplirsen has been generally similar to expected natural history of patients.." I am deeply troubled by the word 'generally'. After minimizing the potential effects of dystrophin production and discounting the natural history control group, the word "generally" disturbs me. The next few months will tell us how history unfolds.
Disclosure: I am/we are long SRPT.