It appears that FDA's celebrated approval flexibility for rare disease treatments has its limits, especially when efficacy is questioned.

Agency officials issued a "complete response" letter for BioMarin Pharmaceutical Inc.'s proposed Duchenne muscular dystrophy treatment drisapersen, the company announced Jan. 14.

Drisapersen was proposed for use in Duchenne patients with mutations in the dystrophin gene that are amenable to treatment with exon 51 skipping.

BioMarin said in a written statement that "FDA has concluded that the standard of substantial evidence of effectiveness has not been met."

FDA told BioMarin in the letter that drisapersen, proposed trade name Kyndrisa, requires another clinical trial. The company said it needs to meet with agency officials to understand what the trial should include.

A decision on a path forward in the US will be determined after the meeting with FDA and a decision on the drisapersen marketing application in the EU, which is expected by June, a spokesperson said.

In the meantime, ongoing extension studies will continue, as well as ongoing clinical trials for other exon-skipping oligonucleotides.

Patients currently receiving drisapersen will remain on therapy, the company said.

FDA's decision cannot be considered much of a surprise.

Drisapersen faced a number of questions about efficacy and potentially serious safety problems.

One Phase II trial showed a statistically significant treatment difference for drisapersen over placebo after 25 weeks, but the baseline change was not sustained after 49 weeks.

A second Phase II study, as well as a Phase III study, were negative. And no secondary endpoints in the placebo-controlled trials showed a significant treatment difference.

FDA also concluded that an injection site reaction for those receiving drisapersen may have biased the trials. In addition, the agency said that renal and vascular injury along with thrombocytopenia were possible ([A#14151120004]).

Advisory committee members said drisapersen may help some patients, but it was unclear which ones ([A#14151124005]).

FDA also missed the Dec. 27 user fee goal.

The result shows once again that while FDA is willing to take substantial risks to make treatments available for rare diseases with unmet needs, it will continue to require some evidentiary basis for the decision.

FDA has long stated that it can be flexible with its standards, especially for orphan drugs Also see "Orphan Products Mostly Approved With Regulatory Flexibility, NORD "Catalog" Finds" - Pink Sheet, 17 October, 2011..

Next Treatment Candidate Up

Duchenne patients looking for the first FDA-approved exon-skipping therapy now shift their hopes to Sarepta Therapeutics Inc.'s eteplirsen, which will appear before the Peripheral and Central Nervous System Drugs Advisory Committee on Jan. 22.

Eteplirsen's user fee goal date is Feb. 26.

Eteplirsen has clearly pulled ahead in the race to market with drisapersen. Its path now may be easier if Sarepta can present data showing efficacy and safety.

BioMarin was thought to be leading after drisapersen had its advisory committee scheduled first and received an earlier user fee goal ([A#14151014003]).

A third product also is under review in the disease. PTC Therapeutics Inc. recently completed a rolling NDA for Translarna (ataluren) to treat the nonsense Duchenne mutation ([A#00160111014]).

Ex-US A Better Option Anyway?

While FDA denial certainly is a set-back, it is not expected to cripple drisapersen's potential.

BioMarin CEO Jean-Jacques Bienaimé said during the J.P. Morgan Healthcare Conference that 85% of the market for the product can be found outside the US.

He appeared to be preparing investors for a drisapersen "complete response" during a Jan. 11 session when he mentioned that there are 11,000 Duchenne patients worldwide that could receive drisapersen versus 2,000 in the US ([A#14160111006]).

But while the prospects for foreign prescriptions seem real, the product most likely would not command anything close to the price ex-US that it could charge in the US, even as orphan drugs draw increased pricing scrutiny in America.

Patients Disappointed, Feel Voice Not Heard

Patients, parents and advocates pushed hard for FDA approval at the advisory committee meeting, hoping personal testimony would help carry it across the finish line.

Debra Miller, president and founder of the patient group CureDuchenne, told "The Pink Sheet" DAILY that FDA did not hear the patient voice.

"This is a very sad day for the Duchenne community," Miller said. "The boys that have been on drisapersen, their parents, and their physicians, who are among the world's top Duchenne clinicians, all wanted to see this drug approved."

Miller also said in a press release on the decision that CureDuchenne remains hopeful that drisapersen can become a useful tool to treat Duchenne, which is unlikely to be cured with any one drug.

Patients and advocates stressed during and after the committee meeting that multiple treatment options are needed Also see "Drisapersen Advisory Committee Is Rough Welcome To FDA For Patient Groups" - Pink Sheet, 21 December, 2015..

BioMarin's Drisapersen 'Compete Response' Shows FDA Flexibility Still Limited

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