Perhaps the most telling aspect of FDA's review of BioMarin Pharmaceutical Inc.’s proposed Duchenne muscular dystrophy treatment drisapersen is that no benefit-risk assessment was completed because staff found no benefit.

With FDA reviewers concluding there was no clear evidence of efficacy, as well as serious safety concerns, it appears the Nov. 24 Peripheral and Central Nervous Systems Drugs Advisory Committee meeting may wind up focusing more on how to improve the resubmission than the drug’s current approvability.

The product, proposed trade name Kyndrisa, would be used to treat Duchenne muscular dystrophy patients with mutations in the dystrophin gene that are amenable to treatment with exon 51 skipping as determined by genetic testing.

A benefit-risk assessment is a key part of FDA’s decision-making process where both positive and negative findings for a product are weighed, along with other factors, to help determine whether it should be approved.

But in a summary of all the benefits and risks of the treatment, FDA clinical efficacy reviewers Veneeta Tandon and Ashutosh Rao wrote in meeting briefing documents that “the benefit of drisapersen in exon 51 skip amenable patients is inconclusive at this time. Therefore, the benefit-risk assessments were not made.”

Tandon and Rao pointed out that the trials were structured such that “beneficial effects on biomarkers and clinical endpoints could have been detected if present.”

“The development program for drisapersen is extensive for a rare disease and exemplary,” the clinical reviewers said. “It is very disappointing that … both clinical and biomarker data for drisapersen are inconclusive at this time.”

Tandon and Rao are expected to present during the meeting.

Agency officials still seem very interested in advisory committee thoughts on the data presented as well as a potential path forward.

FDA Clinical Team Leader Ronald Farkas stated in his memo to the advisory committee that “no final decision has been made and the entire review team greatly looks forward to the insights that you can provide.”

Committee members will comment on eight questions, including four voting questions, but none will be on recommending approval.

The first three discussion and voting questions ask for opinions on issues found with the three drisapersen efficacy studies and whether they strengthen, weaken or have no effect on the persuasiveness of the trials.

The final two questions cover the evidence presented on dystrophin production, which is the primary function of drisapersen, and whether those results strengthen, weaken or have no effect on interpretation of the clinical results.

Restoring dystrophin production is thought to potentially provide a clinical benefit in Duchenne patients. The trials did not show a notable increase in dystrophin and a similar number of patients in the drisapersen and placebo groups had dystrophin increases.

FDA's review is a disappointing, although not entirely unexpected, development for the product.

Barclays analysts wrote in a Nov. 19 note that FDA briefing documents were expected to be negative given drisapersen’s failure in its Phase III DEMAND III trial.

FDA said it doubted the dystrophin biomarker is reliable as a predictor of clinical benefit following drisapersen’s negative trial results ([A#14131112004]).

BioMarin gained drisapersen as part of its acquisition of Prosensa Holding BV in November 2014.

Drisapersen is in a race with Sarepta Therapeutics Inc.’s eteplirsen to become the first approved exon-skipping Duchenne treatment. Drisapersen’s earlier advisory committee date was thought to put it in the lead ([A#14151014003]).

FDA’s user fee goal date for drisapersen is Dec. 27, based on a priority review.

Injection Site Reaction Could Lead To Bias, FDA Says

Drisapersen was evaluated for clinical endpoints in one Phase III and two Phase II randomized placebo-controlled studies with 290 patients in all.

The primary endpoint in the studies was change from baseline distance in the six-minute walk test.

But the results were characterized by FDA clinical reviewers as “inconsistent and in some cases contradictory” and not substantial.

Only one Phase II study showed a statistically significant treatment difference for drisapersen over placebo at week 25, but the change from baseline did not appear sustained at week 49, agency reviewers wrote.

The other studies did not verify the result. The second Phase II study was negative. An arm looking at a 3 mg/kg/week dose was numerically inferior to placebo, according to the briefing documents.

The larger Phase III study also was negative and a post-hoc analysis returned similar negative results.

None of the placebo-controlled studies had secondary endpoints with a significant treatment difference.

In addition, FDA concluded that there was a potential for bias among those receiving drisapersen in the trials because of an adverse event.

Farkas also wrote in his memo that patients could have been unblinded due to “outwardly obvious injection site reactions from drisapersen” and subsequently biased the results.

“The distance walked in six minutes is clearly related to effort and might have been affected by patient and investigator expectation bias if treatment assignments could be deduced,” he said.

No REMS, But Registry Recommended

In addition, the agency said the drisapersen safety profile is concerning, in part because of the potential for renal and vascular injury, thrombocytopenia and dermal toxicity.

Six drisapersen patients experienced thrombocytopenia levels where they were at risk of potentially fatal complications, including spontaneous intracranial or intrapulmonary hemorrhage, according to the FDA documents.

Renal toxicity was reported in 61% of drisapersen patients taking the 6 mg/kg/week dose, compared to 34% on placebo. Injection site reactions, such as ulceration, irreversible scarring and atrophy, were seen in 79% of patients on study drug, according to the documents.

If eventually approved, FDA staff recommended a boxed warning for labeling as well as a Medication Guide that suggested laboratory monitoring and rotation of injection sites.

No Risk Evaluation and Mitigation Strategy was recommended, but the agency said a patient registry should be required post-marketing to evaluate ongoing safety risks.

“Based on nonclinical findings and because of limitations due to the small number of patients exposed and duration of exposure in the clinical trials, it is likely that adverse reactions not identified to date will occur in the post-marketing setting,” the briefing documents state.

Heavy Meeting Interest Still Expected

The advisory committee meeting is expected to draw substantial interest from Duchenne patients and advocates.

The draft agenda includes two hours for the open public hearing, double the hour typically reserved.

Parent Project Muscular Dystrophy, a patient advocacy group, has worked with FDA to push a Duchenne treatment forward. The group submitted a proposed guidance for developing drugs in the disease in 2014 ([A#00140707011]).

FDA reviewed it and released its own draft guidance in June that included many of the group’s recommendations, such as increased use of biomarkers and consideration of patients’ risk tolerance ([A#14150609004]).

FDA Can’t Find Efficacy For BioMarin’s Drisapersen

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