Time for PTC to shift gears?
Earlier this week, the Food and Drug Administration released a scathing review of PTC Therapeutics’ Duchenne muscular dystrophy drug ataluren, known as Translarna in the EU.
The briefing documents came ahead of a Sept. 28 meeting of the Peripheral and Central Nervous System Drugs Advisory Committee, which ultimately, voted 10 to one against the approval of the drug. The only member of the committee to vote in favor of ataluren was a patient representative that has a child with DMD. While the FDA is not required to follow the opinion of its panels, it often does.
Even though the vote was not in PTC’s favor, the panel did not outright reject the drug, instead asking for more clinical studies to prove the drug works in the rare disease. The overwhelming view of the panel was ultimately that it’s just not clear whether the drug works.
It might seem strange that a drug could get this far in the regulatory process without having proven the fundamental issue of efficacy. But, PTC and ataluren are a strange case.
Ataluren has been in development for more than a decade yet has not been very impressive in that time. In fact, it has failed not just one, but two mid- and late-stage studies in the DMD patient population. It also failed a study in cystic fibrosis patients.
Despite the complete lack of clinical evidence, PTC has argued for the better part of a decade that post-hoc analysis of subgroups in the clinical trials show the drug is effective. There are a variety of problems with that approach.
DMD is already a rare disease that affects only one in 3,500 male births. Ataluren is meant to target an even smaller proportion of those patients that have what is called a nonsense mutation. According to the company, of the approximately 18,000 DMD patients in the U.S., there are only about 1,800 that have the nonsense mutation. That means subgroups of this population — which PTC argue ataluren definitively works for — is an even smaller group. Therefore, there is very little patient data supporting these analyses.
Secondly, these analyses were done after trial data was unblinded, and have not been tested in further clinical studies. Post-hoc analysis is often considered unreliable because it can be subject to bias.
All of these issues pushed the advisory committee to question whether the data PTC was presenting was even remotely reliable.
Bucking the system
All of this sketchy data isn’t the only problem with PTC and ataluren.
The company has been trying to garner approval of the drug since 2010. The FDA has actually refused to review the drug twice. When a drug company submits a New Drug Application (NDA) for approval, the FDA has 60 days from that initial submission to accept the application for review. In rare cases, the agency will issue a refusal-to-file (RTF) letter, telling a company that the application is incomplete and cannot be reviewed by the agency.
In the case of ataluren, FDA issued a RTF letter in 2011 and then again in 2016, explaining to the company that the data was incapable of supporting a conclusion of effectiveness. In both instances, PTC wouldn't take 'no' for an answer and appealed the decision.
Both of those appeals were denied as well. In an even rarer move — and one that is considered highly controversial — PTC filed the drug “over protest,” essentially forcing the FDA to review the application even if the NDA is still considered incomplete.
Time to make a pivot?
With all of this piling up against PTC, it is highly unlikely that ataluren is going to get the green light from the FDA. The most probable scenario is that the FDA rejects the drug and asks for further clinical studies.
This is where PTC has a decision to make: conduct further clinical trials that will likely costs hundreds of thousands (if not millions) of dollars and take years to complete (and may ultimately prove negative again), or abandon further development of the drug and shift gears.
While neither choice is ideal, sometimes drug companies are better off failing faster. The idea of failing faster is one that big pharma — which has dozens of clinical programs ongoing at once — understands well. The behemoths of the industry have learned that sometimes resources are better spent elsewhere. Take British pharma GlaxoSmithKline: the company recently culled its pipeline, eliminating its entire rare disease unit and selling off or dropping nearly 30 programs total.
There have been true success stories of companies making a pivot to another disease area or drug after a failure and eventually succeeding.
Medivation made headlines when its closely-watched Alzheimer’s disease drug dimebon failed to improve symptoms of the damaging neurological disease. CEO David Hung was cognizant enough to take the company in another direction and instead shift to oncology. The move resulted in the biotech being bought out for $14 billion.
Vertex Pharmaceuticals is another tale of new beginnings. The company was once a hot commodity due to its hepatitis C therapy. When its drug Incivek (telaprevir) was approved the company’s stock was at about $50 per share. But just two short years after approval, the drug became irrelevant after Gilead Sciences hit the market with its own curative hepatitis C drug. Vertex made the tough business decision to pull Incivek from the market in August 2014 and switched gears to cystic fibrosis. A recent late-stage study in cystic fibrosis proved Vertex made the right move, and now is on the verge of dominating this new market. Vertex now trades at more than $150 per share.
These sorts of business decisions are not always popular. Genocea Biosciences announced a pivot earlier this month, opting to drop its herpes vaccine that it has been developing since before 2010, and instead would shift to the development of immuno-oncology drugs. The move sent shares spiraling, and the biotech lost 75% of its value in an afternoon.
But what seems like a risky move now could pay off later. Immuno-oncology is a hot area today for a reason — the market opportunity is huge and, so far, this therapeutic approach is paying off.
Meanwhile, the development of a herpes vaccine was always a long shot. Physicians admit that they don’t know much about the disease and despite being highly prevalent (the World Health Organization estimates that more than 300 million American have the disease), most infected people never know they have it and are asymptomatic. Despite the high incidence, the fact that most people never know they have the disease means there isn’t a high unmet need for treatments and even if a vaccine was approved, there might not be any commercial opportunity.
While only time will tell what PTC will do, sometimes the tough calls are the right ones.
Follow Lisa LaMotta on Twitter