Pharma Investors Look for Lessons After BioMarin FDA Defeat

  • Sarepta's eteplirsen gives investors different leap of faith
  • DMD's unmet need: Without treatment, `the boys all die'

The rejection of a BioMarin Pharmaceutical Inc. medication by U.S. regulators left patients and investors questioning how drugmakers could improve their chances for approval of treatments for diseases that afflict tiny segments of the population.

The urgency grew even greater Friday for the Duchenne muscular dystrophy community after a Food and Drug Administration staff report cast doubt on the future of a second medication, saying there isn’t enough evidence that Sarepta Therapeutics Inc.’s eteplirsen offers patients any real benefit. When the FDA chose not to approve BioMarin’s Kyndrisa on Thursday, they had missed out on the first treatment for their deadly disease.

Pharmaceutical companies are willing to go to great lengths to create medicine for rare diseases because they can charge hundreds of thousands of dollars per patient. Kyndrisa would have been eligible to treat about 2,300 boys and young men with Duchenne muscular dystrophy, a muscle-destroying disease that kills most patients by age 25. Eteplirsen aims to treat a similar population.

The FDA’s actions show it will continue to set a high bar for new medicines designed to be taken for a lifetime, even for children destined to die of their ailments who have no other treatment options.

In turning down BioMarin’s once-a-week injection of Kyndrisa, the FDA said there wasn’t enough evidence of its benefit and asked for additional research. Those questions were echoed by the agency staff reviewing Sarepta’s eteplirsen, which is betting on results from just a dozen boys who took the medicine for up to four years to sway the agency. While Sarepta is taking a different approach to regulatory approval for its drug, the staff review made it look like a long shot. FDA advisers meet Jan. 22 to discuss the drug.

“It’s a different leap of faith you have to take with Sarepta," said Ira Loss, an analyst with Washington Analysis. "They do have patients who are still walking around after three years. The risk is you don’t have a lot of patients.”

Investors, already skeptical that Sarepta could get approval, fled the stock. The drugmaker’s shares fell 56 percent to $13.83 at 12:29 p.m., the biggest drop in more than two years. PTC Therapeutics Inc., which is working on a rival medicine for DMD, plunged 11 percent to $21.18. BioMarin’s shares were down 2 percent at $82.76.

A Sarepta spokesman declined to comment.

Accelerated Approval

Sarepta, based in Cambridge, Massachusetts, is asking for accelerated approval, a program tailored to speed development of drugs that treat serious conditions that have few if any treatments. Rather than relying on conclusive evidence of a longer, healthier life, the agency approves the medicines based on trial results designed to produce a surrogate endpoint -- evidence that the drug is having an effect, such as a laboratory test or an intermediate signal like walking speed. After the drug is approved, additional studies, which Sarepta has under way, are required to confirm that patients improve with therapy.

BioMarin applied for full approval, giving the FDA a black-and-white choice based on studies that found side effects and yielded mixed results. While Sarepta’s drug hasn’t turned up serious side effects, the FDA staff questioned the company’s surrogate endpoint findings. Walking speeds were within what would be expected, they said. They also questioned how much the drug boosted production of dystrophin, a protein critical for muscle fibers that is missing in boys with Duchenne.

Accelerated approval doesn’t mean companies can turn in substandard evidence of effectiveness and shouldn’t be used to compensate for weak or inconsistent findings, the FDA staff report said.

"Although FDA is prepared to be flexible with respect to a devastating illness with no treatment options, we cannot approve drugs for which substantial evidence of effectiveness has not been established," they said.

‘Relentlessly Progressive’

Advocates working to get a treatment on the market for DMD, which affects about 1 in every 3,500 to 6,000 boys born each year in the U.S., will focus their efforts on getting the FDA to allow patients and families to decide for themselves if the medicine is worth any potential risks. They emphasized the fact that these boys and their families have no other options.

"This is a relentlessly progressive disease, with no ebbs and flows," said Debra Miller, founder and chief executive officer of CureDuchenne, a non-profit advocacy group that has invested in several experimental therapies for the disease. "We know what happens with no drug. The boys all die."

BioMarin said it still needs to discuss details with the FDA before it decides how to proceed with Kyndrisa. The company is also awaiting a regulatory decision in Europe, said company spokeswoman Debra Charlesworth, one that could allow the drug to reach an even bigger market than in the U.S. before the end of the year.

The FDA, which has come under intense pressure from families affected by the disease, said it is taking the concerns to heart. Laws passed to regulate the agency require it to take the patient’s perspective into account, and the FDA has worked with advocacy groups to provide guidance on drug development, said spokeswoman Sandy Walsh.

"We recognize the huge unmet medical need in Duchenne muscular dystrophy, the devastating nature of the disease for patients and their families, and the great urgency to make new treatments available," she said. "We will continue to work with sponsors to facilitate development and approval of effective treatments for DMD."

That doesn’t mean the FDA staff and outside reviewers won’t take a hard look at Sarepta’s eteplirsen, exposing any potential risks and detailing deficiencies in how the company developed the drug, Loss said.

"FDA is not going to write a review of Sarepta’s drug that says, ‘Let’s have a party and dance,’" Loss said. "It might not be as negative as BioMarin, but it’s not going to be a joyous celebration. There is a lot of negative stuff they can say."

Shying Away?

Advocates are also concerned about what might happen if the FDA’s standards keep potentially helpful medicines out of the hands of doctors and patients.

"It’s good to have a lot of interest by pharmaceutical and biotechnology companies in the Duchenne space, but there has to be flexibility in getting the drugs approved and to the kids," Miller said. "If there isn’t flexibility, companies will shy away from the space, and that would be a tragedy for Duchenne patients all over the world."

When FDA advisers met in November to discuss Kyndrisa, they heard heart-wrenching stories from patients and families about improvements the drug made in their lives during clinical trials -- being able to shower themselves, climb stairs, ride bikes, and roughhouse with their brothers.

But the panelists concluded that the data showed the drug wasn’t ready. Two of the three clinical trials that BioMarin relied on to try to persuade the FDA to approve Kyndrisa failed to meet their main goal, which was to help patients taking the drug to walk farther in six minutes -- a standard assessment used in treatments for similar diseases. And side effects were serious, including platelet levels low enough that they could cause serious bleeding complications, kidney toxicity and injection site reactions including ulceration, irreversible scarring and atrophy.

"It makes you want to cry, the history of this drug," Miller said.

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