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

$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: [[ticker: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.