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At Duchenne Panel, Parents Plead With Experts, FDA Decision Looms

Xconomy San Francisco — 

In one of the more dramatic biotech events in recent memory, the FDA convened an advisory panel on Tuesday to weigh the risks and benefits of a drug called drisapersen, which has the chance to be the first FDA-approved treatment for Duchenne muscular dystrophy—a progressive, fatal genetic disease.

The panel’s task was unusual, as far as these meetings go. Typically, panel members are asked whether they’d recommend approval of a drug. The agency then takes the panel results under consideration when it issues its final decision later on.

In this case, however, the agency did not ask the panel members for a yes or no recommendation. Instead, panelists were asked to assess the strength of the evidence accrued in the clinical trials of drisapersen, a Duchenne drug from San Rafael, CA-based BioMarin Pharmaceutical (NASDAQ: BMRN).

The panelists did so, and their commentary did not seem favorable, which stood out all the more because of the emotional pleas for the drug’s approval that came from many of the parents of Duchenne patients—and the patients themselves—who showed up at the meeting in Silver Spring, MD.

“Our children are fighting for their lives and they deserve therapies that can change their quality of life, and the outcome of their disease,” said one parent. “This should be the day that the ending of this tragic story is rewritten…please approve this drug.”

The panelists voted on whether the data from each of three different placebo-controlled clinical trials strengthened, weakened, or had no effect on BioMarin’s case for approval. They then wrapped up the panel by discussing—but not voting on—the drug’s benefits versus its risks.

By most accounts, it’s very unusual for the agency not to ask advisory panels for a yes-or-no vote about a drug. RBC Capital Markets analyst Michael Yee called this omission “unlike most panels” in a research note, and Leerink Partners’ Joseph Schwartz deemed it “unique and leaves the FDA open to do its own thing.” The FDA will make a decision on BioMarin’s drug by Dec. 27.

When asked why FDA did not want such a vote on drisapersen, FDA spokeswoman Sandy Walsh wrote in an email, “We want to gain input from the panel and will engage in substantive discussions today and discuss strength of evidence.”

When asked how often FDA tells an advisory panel not to weigh in with a yes-or-no vote on a drug, Walsh said FDA doesn’t keep track. Setting the questions up this way, Leerink’s Schwartz wrote, “should alleviate some of the intense pressure on [the] panel to reach overall conclusions.”

The FDA usually follows the guidance of its advisory panels, but not always. Since there wasn’t any voting directly for or against drisapersen—just on the relative strength and persuasiveness of the data—that guidance will be harder to read.

But the majority of panelists did vote that two of BioMarin’s studies “weakened” its case for approval. What’s more, some of them directly said they didn’t think drisapersen should be approved.

Justin Zivin, a professor from UC San Diego, noted that after reading the FDA’s briefing materials on drisapersen, “it was clear that this wasn’t going to get approved at this point. This just needs more work.”

Added Chiadi Onyike, a professor at Johns Hopkins: “What we have in front of us…is not yet ready.”

Still, this is a very complex issue. Duchenne patients, and parents of patients, are desperate for a drug for a deadly disease with no approved treatment. The drisapersen panel is as close as they’ve been to an FDA approved therapy, and many parents—and some young patients themselves—came to the hearing to make an impassioned plea for the drug before the panelists. One 16-year-old boy, for instance, claimed drisapersen had helped him walk longer without getting tired, and gave him the strength to swim and ride a bike. “Please don’t take this drug away from us,” he said. A round of applause followed.

But drugs are approved on empirical data, not powerful anecdotal evidence, and there are significant questions regarding BioMarin’s data. The key study of drisapersen, a Phase 3, 186-patient, placebo-controlled study, failed. It’s unclear whether the drug—as it’s designed to do—helps Duchenne patients produce enough dystrophin, the protein they lack, which normally helps keep muscles intact.

BioMarin is making the case that the study was flawed, that patients were enrolled too far along in their disease, and that a post-hoc analysis pooling data from subgroups of patients shows drisapersen does in fact help Duchenne patients. The totality of the data, BioMarin says, shows that there is a signal.

Today’s meeting on drisapersen will also likely affect the fortune of a rival drug from Sarepta Therapeutics (NASDAQ: SRPT), eteplirsen, that will be the subject of an FDA advisory panel in January. As with BioMarin, Sarepta’s case will also be flawed. It doesn’t have nearly the amount of data that BioMarin has on drisapersen. Even though the drug has so far looked safer than drisapersen, side effects could emerge as more patients are tested. When the FDA releases briefing documents for eteplirsen in the days leading up to the panel in February, new questions could face Sarepta as well.

Duchenne is a disease with no cure and no effective treatment. It sentences the roughly 300,000 boys who have it—the disease mostly affects boys—to a slow, progressive decline in muscle function. Many lose the ability to walk by their teens and die at a young age from one of a number of complications, such as respiratory failure.

Ilan Ganot is the father of a son with Duchenne and founded a company, Solid Biosciences, to fight the disease. Ganot told Xconomy recently, “This is a battle against time.” And that’s what made Tuesday’s panel so critical a point in the Duchenne battle. Every single FDA move either brings patients closer, or further away, from a potential treatment. Should the agency ultimately reject drisapersen, patients and their families will watch more time pass before a drug is available.

The severity of Duchenne and the significant need for treatments by nature lowers the bar for a drug’s safety and effectiveness. That’s why BioMarin paid $680 million to buy drisapersen, and the company that had developed it, Prosensa, even though the drug had already failed a Phase 3 trial. (GlaxoSmithKline had partnered with drisapersen on Prosensa in 2009, but severed its relationship with the company, and drisapersen, after the failed study.)

Similarly, PTC Therapeutics (NASDAQ: PTCT), another company with a prospective Duchenne drug, ataluren, has a failed trial on its resume, yet also expects to file for FDA approval. And ataluren is already approved on a conditional basis in Europe.

Both BioMarin and PTC have essentially argued that data pooled from patient subgroups in its studies prove that there is a positive drug effect. BioMarin, for instance, has used this pooled analysis to show that drisapersen helped patients walk about 31 meters farther, on average, than placebo patients on the standard six-minute walk test—a statistically significant result.

BioMarin did this by pooling groups of patients from three different placebo-controlled studies: two Phase 2 trials of about 50 patients each, and the larger Phase 3 study of 186 patients. The Phase 3 trial didn’t hit its primary goal—a benefit on the six-minute walk test. BioMarin chief medical officer Henry Fuchs said at the panel that the company was “surprised and initially puzzled” by those results, but he contended that it failed because the enrolled patients were too far along in their disease.

FDA scientists didn’t appear convinced. Briefing documents released on Friday called BioMarin’s efficacy evidence “inconsistent and in some cases contradictory,” and said that it “does not reach the level of substantial evidence.”

The reviewers continued the criticism during the panel. Said FDA statistician Sharon Yan: “There are an unlimited number of post hoc analyses we can perform. None of them can answer our question of whether the drug works, and none of them provide convincing evidence.”

The briefing documents also called drisapersen’s safety profile “concerning,” even in the context of a “disabling and fatal disease” like Duchenne. The document’s authors cited irreversible scars, skin discoloration, and ulcers at the drug injection sites, potential kidney damage due to high levels of protein in the urine, and other problems. The documents recommended a strict monitoring program to guard against such safety risks should drisapersen even be approved.

It’s important to note that, even though the criticism of drisapersen was, as Leerink’s Schwartz wrote in a note, “more intense than expected,” FDA briefing documents tend to strike this kind of tone. Just this year, briefing documents were very critical of Vertex Pharmaceuticals’s combination cystic fibrosis treatment, lumacaftor/ivacaftor (Orkambi), but an advisory panel later voted in its favor, and the agency approved it.

In other words, the criticism of the past several days doesn’t mean the agency will reject BioMarin’s drug. Still, the FDA presented a picture of a drug with a raft of safety concerns and doubts about how well it will actually work. That puts the agency in a precarious situation. Should it approve drisapersen because the need is so great and risk setting a bad precedent? Or reject it and be the villain to a patient group that desperately needs a drug?

The emotion was palpable at the panel. Craig McDonald, a neuromuscular disease expert from UC Davis who has treated hundreds of Duchenne patients—and who has been paid as a consultant to BioMarin, it should be noted—showed videos of Duchenne patients early, and late, in the progression of their disease, illustrating how devastating its effects are. He also added the video of a roughly 10-year-old patient treated with drisapersen who was put on the drug at five years of age, and was still able to run, jump, and hop on one leg. “I have never seen a nearly 10-year-old patient achieve this level of functioning,” he said.

Several parents pleaded for the drug, many describing the difference drisapersen had made in their sons’ lives. Some kids were able to climb stairs when they otherwise couldn’t, or continue walking longer than they otherwise would have. “This can not just be wishful thinking or a placebo effect,” said one parent. Many downplayed the skin reactions and other side effects when compared to the certain fate that awaits Duchenne patients.

Said panel member Cheri Gunvalson, a professor at the University of North Dakota and the mother of a son with Duchenne: “In the face of a lethal diagnosis, this is better than what we’ve got.”

Yet support for the drug wasn’t universal amongst the parents who spoke. One noted that injections were incredibly painful for her son, that he couldn’t tolerate them even if the drug were effective. Another parent said her nine-year-old son was on drisapersen for six months, and although progression of the disease “may have been slowed,” he decided not to keep taking it due to the side effects. “We must remember not to sacrifice the safety of our boys to the desperation of the disease,” she said.

All of which the FDA will have to work through as it weighs the pros and cons of drisapersen over the next month. Though the tenor of the panel made drisapersen’s approval prospects seem slim, some analysts still believe BioMarin has a fighting chance.

“Bottom line: overall, we still believe that this is difficult to call and continue to view…approval by Dec. 27 as largely a coin flip,” wrote analyst Mark Schoenebaum in a note following the panel.