Spirits were not necessarily high among Duchenne muscular dystrophy patients and advocates heading into FDA’s advisory committee meeting on BioMarin Pharmaceutical Inc.’s drisapersen.

After reviewing FDA’s largely negative meeting briefing document, many of the attendees at the Nov. 24 Peripheral and Central Nervous System Advisory Committee meeting were concerned there could be a major setback for the development program.

Committee members did not do much to dissuade the fears, identifying many of the same concerns about the clinical evidence that the agency had.

It was an unwelcoming first foray into the advisory committee process for the Duchenne patient community, forcing it to defend, rather than confirm, drisapersen’s approvability.

Asked about her group’s strategy in the face of FDA concerns about a lack of drisapersen efficacy in its clinical trials and serious safety concerns, CureDuchenne Founder and President Debra Miller said the group wanted to communicate that the drug works.

“I knew going into it that the data wasn’t necessarily going to support the real-life experiences that I’ve seen with the actual patients,” Miller said in an interview with “The Pink Sheet.”

“I was hopeful that the advisory committee would hear the voice of the actual patients and that that would help them balance out some of the data points.”

Approval for drisapersen (proposed trade name Kyndrisa) appears to be in doubt following the committee meeting. BioMarin is seeking an indication for use in patients with Duchenne muscular dystrophy with mutations in the dystrophin gene that are amenable to treatment with exon 51 skipping.

But the product may prove an important case looking at the effect of FDA efforts to further involve patients in the drug review process and the impact they can have.

BioMarin Chief Medical Officer Henry Fuchs said in an interview that the patient testimony showed that drisapersen’s benefits were tangible, even though FDA questioned whether the clinical trial data showed it.

Fuchs said stories of regression and improvement from “going off drug, on drug, off drug, on drug because of the prior sponsor’s decision to stop the drug is exactly what you’d expect if there’s a real treatment effect.”

“That’s what you expect with a real drug,” he said.

Drisapersen was added to BioMarin’s portfolio as part of its acquisition of Prosensa Holding BV in November 2014.

Fuchs said BioMarin continues to believe in drisapersen and said the advisory committee comments will make the product better (see sidebar).

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Apply Knowledge To Eteplirsen

FDA has been collecting more patient and advocate positions in recent years to help reviewers understand their needs and risk tolerance.

In the upcoming prescription drug user fee reauthorization, agency and industry officials are hoping to enhance those efforts Also see "PDUFA VI: FDA Proposes Expanding Sentinel, Real-World Safety Data Sources" - Pink Sheet, 18 November, 2015..

The drisapersen advisory committee meeting should not be considered a step back for advocates of patient-focused drug development efforts, said Brian Daniels, former Bristol-Myers Squibb Co. senior VP of global development and medical affairs.

Daniels told YourEncore Executive Partner Peter Pitts in a post for the consultancy’s website that FDA will listen to patient groups in designing the development program, but still will require robust clinical evidence for approval.

“Don’t view this one episode as a step backwards in that approach,” Daniels said. “It reflects the chronic nature of Duchenne muscular dystrophy and the fact that you’re looking at years of therapy.”

The committee voted overwhelmingly against the evidence BioMarin presented, in every case saying issues raised had either no effect or weakened the persuasiveness of the findings (see box).

Advisory Committee Votes

What overall impact do the discrepant results of the two dosing regimens despite similar exposure to drisapersen and lack of statistically significant results on secondary endpoints have on the persuasiveness of Study 1 (phase II Study 117)? Strengthen-1, Weaken-9, No effect-7
What overall impact does the lack of statistical significance of the primary outcome measure, the 3 mg/kg group numerically inferior to placebo, and the 6 mg/kg group numerically inferior to placebo for most secondary endpoints have on the persuasiveness of Study 2 (phase II Study 876)? Strengthen-0, Weaken-5, No effect-12
What is the impact of the results of Study 3 (phase III Study 004) on the persuasiveness of the findings in Studies 1 and 2? Strengthen-0, Weaken-15, No effect-2
What is the impact of the dystrophin results on the interpretation of the clinical results? Strengthen-0, Weaken-6, No impact-10

Even Christopher Cassidy, the committee’s patient representative, who has Duchenne, voted against the persuasiveness of the evidence on three questions. He said that it had no effect on the fourth.

Interestingly, the committee was not asked to vote directly on efficacy and safety of the product.

Pat Furlong, president of the advocacy group Parent Project Muscular Dystrophy, said in an interview that patients and advocates walked away “deflated,” but still felt like their message came across clearly.

“I think that the committee had exposure to Duchenne that we all wanted them to have,” she said. “We have another one coming up and we’re hoping that we learn from the first one, apply it to the second one and come out of there celebrating.”

On Jan. 22, FDA's Peripheral and Central Nervous System Drugs Advisory Committee will consider drisapersen's competitor in the race to be the first approved exon-skipping Duchenne treatment – Sarepta Therapeutics Inc.’s eteplirsen.

Drisapersen’s user fee goal is Dec. 27. Its earlier advisory committee and goal date were thought to have pushed it to the lead ([A#14151014003]).

However, on Dec. 18 BioMarin announced that FDA had informed it that the agency would not make a decision by the goal date, but did "anticipate taking action in early January 2016."

Each Patient Is An N Of 1

Furlong decided to focus on the benefit-risk decision that Duchenne parents and patients are forced to make and how drisapersen fits into it.

When faced with a progressive disease with no cure, parents want choices, she said.

“There’s a fundamental issue of wanting options,” Furlong said. “I think they spoke to their quality of life and they felt that this drug was making a difference to them.”

Committee members heard numerous examples of young boys walking up stairs, attending school and buckling themselves into a car while on drisapersen, tasks that in most cases were not possible previously.

Patients and advocates also tried to persuade committee members to look beyond the unconvincing numbers found in the clinical trials and analyses. One man said that while on drisapersen, his son was able to go on hikes and play with his schoolmates.

“I’m not surprised that the six-minute walk test didn’t capture these improvements,” the man, whose son has Duchenne, said during the open public hearing portion of the meeting. “Balance and endurance are what we’re seeing. And they are making his life so much better.”

Another argued that all patients are unique.

“Ultimately, each person is an N of 1,” the parent said. “Recognizing that there’s a spectrum of progression in individuals, what this disorder highlights [is] a need for a number of therapies. Drisapersen could be one of those options. The [more] options that become available, the better the chances are that people will find a protocol that is right for them.”

Patients pleading for an approval is not new for advisory committee meetings, but in this case, it may have pushed advisory committee members to blunt some of their criticisms.

Advisory committee members agreed that the drug appeared to be working in some patients. A potential key for BioMarin may be determining how best to find responders.

Chiadi Onyike, associate professor of psychiatry and behavioral sciences at Johns Hopkins School of Medicine, said he could accept drisapersen’s safety problems because several Duchenne patients testified about the risks they were willing to take.

FDA said there was a potential for renal and vascular injury, thrombocytopenia and dermal toxicity associated with drisapersen.

Thrombocytopenia in particular could lead to fatal complications, the agency said ([A#14151120004]).

Holding Out For A Conditional Approval

Furlong said she is hoping for a conditional approval for drisapersen or some other way to continue allowing patients access to it.

Miller said the best route for a Duchenne treatment is approval with extensive post-marketing studies.

“We’re never going to get a drug approved for Duchenne unless they’re willing to provide flexibility and get some of these drugs to market and follow up with post-approval studies,” she said.

“There’s 7,000 rare diseases and most of them are childhood genetic diseases. And they’re not going to be easy. They’re not going to follow the path of a 3,000-person trial that’s powered for tremendous indicators.”

BioMarin said during the meeting that it was hesitant to make the drug available through an expanded access program because it did not want it to conflict with future clinical trials that may be required ([A#14151124005]).

‘Flexing’ FDA’s Approval Standards

Stakeholders and observers now will watch to see how much approval flexibility FDA is willing to use in determining drisapersen’s future.

In the rare disease setting, the agency has long approved drugs where there is a significant unmet need based on small trials or limited evidence Also see "Orphan Products Mostly Approved With Regulatory Flexibility, NORD "Catalog" Finds" - Pink Sheet, 17 October, 2011..

But with drisapersen, the opposite appears to be present. Reviewers have what they thought would be enough evidence to inform a decision – in FDA’s meeting briefing documents the development program was called extensive for a rare disease and exemplary – but now must decide what the evidence suggests.

Clinical Team Leader Ronald Farkas, of FDA’s Division of Neurology Products, told committee members that in some cases Duchenne patients did not worsen over time, which complicates the evidence for approving drisapersen.

“The critical thing is that patients, even in their teenage years, don’t only get worse,” he said. “That’s why this is difficult to figure out if the drug is working.”

Fuchs and Miller disputed that assertion, saying Duchenne patients will steadily weaken, lose function and eventually die. Fuchs also said patients can have ebbs and flows with their disease course, but the end result is certain.

Furlong and others also wanted to focus on the 10-meter improvement that patients showed in the six-minute walk test. She said a number of parents would take that improvement in exchange for the adverse events.

Farkas said FDA does not question the clinical meaningfulness of such an improvement, but cannot conclude drisapersen was the reason for it in the trials.

“There’s a question of if the 10-meter difference occurred due to drug or only by chance,” he said.

Exiting With More Ideas And Questions

Furlong said her group learned a lot about BioMarin, FDA and the committee members, as well as themselves during the advisory committee meeting.

And while most signs still point to a negative outcome or a longer wait for approval, Furlong said she left with several questions and ideas for additional small clinical trials to potentially push drisapersen over the finish line.

“I came away deflated for sure, but wishing that could we just do a do-over,” she said. “I walked away designing a very short small study in my head to say let’s get to a better yes or a no more quickly.”

Furlong’s group submitted a suggested Duchenne drug development guidance to FDA in 2014, which the agency issued earlier this year ([A#14150609004]).

Drisapersen Advisory Committee Is Rough Welcome To FDA For Patient Groups

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