PTC To Appeal Translarna's Complete Response Letter From US FDA

PTC Therapeutics appears to be hoping that CDER Director Woodcock will do for ataluren what she did for Sarepta's exon-skipping Duchenne muscular dystrophy treatment Exondys 51 since dispute resolution request would first go to Office of New Drugs, where Woodcock is acting director.

PTC Therapeutics Inc.'s plans to appeal a US FDA complete response letter for Translarna (ataluren) could once again make Center for Drug Evaluation and Research (CDER) Director Janet Woodcock the decision-maker on a Duchenne muscular dystrophy drug that the agency's own clinical reviewers have concluded lacks substantial evidence of efficacy.

On Oct. 25, a day after the user fee goal date for ataluren, PTC announced that FDA's Office of Drug Evaluation I (ODE I) had issued a complete response for treatment of nonsense mutation dystrophinopathies, including Duchenne muscular dystrophy (DMD).

FDA's letter states that "evidence of effectiveness from an additional adequate and well-controlled clinical trial(s) will be necessary at a minimum to provide substantial evidence of effectiveness," PTC said.

FDA's complete response letter "indicated that evidence of effectiveness from an additional adequate and well-controlled clinical trial(s) will be necessary at a minimum to provide substantial evidence of effectiveness," PTC said. "The letter also mentioned other nonclinical and [chemistry, manufacturing and controls] matters that PTC is in the process of addressing."

In a press release, CEO Stuart Peltz said the company is extremely disappointed for the Duchenne community and strongly disagrees with the agency's conclusions.

"We believe that this decision fails to consider the benefit/risk of ataluren and the high unmet medical need," Peltz said. "Therefore, we plan to file a formal dispute resolution request next week."

Appealing To A Higher Authority …

The rejection of the new drug application is hardly a surprise given that FDA filed the NDA under protest after twice refusing to file it due to lack of substantial evidence of efficacy. (Also see "‘File Over Protest’ At US FDA: PTC To Pursue Rarely-Used Pathway For DMD Drug" - Pink Sheet, 9 Jan, 2017.)

In September, 10 of 11 members of FDA's Peripheral and Central Nervous System Drugs Advisory Committee voted that while it is possible ataluren may be effective in treating dystrophinopathies resulting from nonsense mutations in the dystrophin gene, the data are inconclusive and more work would be needed to establish efficacy. (Also see "Patients Can't Clear Translarna's Data Hurdles As PTC Falls Short At FDA Panel" - Pink Sheet, 28 Sep, 2017.)

Panelists pointed to the failure of two randomized, placebo-controlled trials to meet their prespecified primary endpoints. Although post hoc, exploratory analyses suggested benefit, they were not persuasive evidence of efficacy, committee members said, generally agreeing with agency reviewers' opinions of the data. (Also see "Exondys Revisited? Translarna Brings Efficacy Woes Into US Panel Review" - Pink Sheet, 26 Sep, 2017.))

With an appeal of the complete response letter, PTC will seek to move beyond the negative reviews by the advisory committee, the Division of Neurology Products and ODE I to a higher authority.

Woodcock has been serving as acting director of the Office of New Drugs since John Jenkins' retirement in January.

Pursuant to FDA's September 2015 draft guidance on formal dispute resolution appeals above the division level, an appeal of the ODE I complete response letter would first go to the Office of New Drugs (OND).

Woodcock has been serving as acting director of OND since long-time office head John Jenkins retired in January. Presumably, any appeal to OND would wind up on her desk or that of OND Deputy Director Peter Stein.

Even if Stein were to deny the appeal, PTC could continue up the chain of command to the CDER director's office and, ultimately, to Commissioner Scott Gottlieb.

… And Putting Their Faith In Woodcock?

PTC appears to be hoping that Woodcock will do for ataluren what she did for Sarepta Therapeutics Inc.'s exon-skipping DMD treatment Exondys 51 (eteplirsen).

In September 2016, Woodcock granted eteplirsen accelerated approval after overruling the objections of clinical review staff who believed substantial evidence of efficacy had not been demonstrated. Woodcock concluded that the quantity of dystrophin production produced in the eteplirsen clinical trials was reasonably likely to predict clinical benefit. (Also see "Sarepta's Eteplirsen Approved After Contentious Internal FDA Debate" - Pink Sheet, 19 Sep, 2016.)

The CDER director described her decision as representing the greatest flexibility possible while remaining within FDA's statutory framework. However, ODE I Director Ellis Unger said the approval would lower the evidentiary standard for effectiveness, and he appealed to then-Commissioner Robert Califf.

Califf ultimately deferred to Woodcock on the approval decision, concluding that the approval was "unique situation" that would not lower the bar for other drugs under the accelerated approval pathway. (Also see "Accelerated Approval After Eteplirsen: A Lowered Bar Or A Unique Event?" - Pink Sheet, 20 Sep, 2016.)

Nevertheless, at the ataluren advisory committee meeting PTC pointed to the eteplirsen approval as precedent for FDA's exercise of regulatory flexibility in considering the totality of the data for rare disease treatments.

In the eteplirsen proceedings, Woodcock drew internal criticism for her frequent interactions with the patient community and Sarepta, as well as her participation in the advisory committee review. In contrast, Woodcock did not attend the ataluren advisory committee meeting, although Stein did.

Also unlike with eteplirsen, accelerated approval does not appear to be a pathway for ataluren because FDA officials have described the dystrophin production data as uninterpretable due methodological shortcomings. (Also see "How Accelerated Approval Works – And How It Doesn't" - Pink Sheet, 28 Sep, 2017.)

Totality Of The Evidence

In its appeal, PTC can be expected to argue that regulatory flexibility is warranted given the rare disease setting, high unmet need and totality of efficacy and safety evidence.

Even though ataluren failed the prespecified endpoints in two clinical trials, subgroup and post hoc analyses showed evidence of benefit. At the advisory committee meeting, numerous patients and family members testified that the drug had slowed disease progression and maintained walking ability far longer than predicted based upon the natural history of the disease.

PTC also can be expected to highlight real-world experience in countries where the drug is approved and comparisons of ataluren patient outcomes against natural history data.

Ataluren is the second drug intended to treat DMD to receive an FDA complete response letter in the past few years. BioMarin Pharmaceutical Inc. terminated the development of Kyndrisa (drisapersen), an exon-skipping treatment, in 2016 following an FDA complete response letter. (Also see "BioMarin Kills Kyndrisa, But Duchenne Pursuit Not Over" - Pink Sheet, 1 Jun, 2016.)

BioMarin had considered appealing the drisapersen CRL following eteplirsen's approval, but apparently opted against it. "We continue to develop second-generation molecules, which we believe are substantially better compounds with potentially superior efficacy, and would therefore be more likely to succeed through all phases of development and registration," a company spokesperson said.

In early 2017, the agency approved Marathon Pharmaceuticals LLC's corticosteroid Emflaza (deflazacort), making it the second drug approved for DMD after eteplirsen. (Also see "Keeping Track: US FDA Approves Emflaza And Parsabiv, Turns Down Opioid/Anti-Emetic Combo CL-108" - Pink Sheet, 12 Feb, 2017.) PTC acquired the drug from Marathon in March after the launch was complicated by a pricing controversy.

Message To The DMD Community

In a statement to the Pink Sheet, FDA said it could not comment on questions about ataluren because information about an application that has yet to receive an approval, or has received a complete response, generally is not releasable by the agency.

FDA pledged to continue to work closely with the DMD community and sponsors to expedite development and approval of safe and effective treatments.

However, FDA "recognizes the unmet medical need of patients with Duchenne muscular dystrophy, a devastating disease for patients and their families. We remain committed to addressing the urgent need for new treatment options."

"We have taken a number of steps in recent months to advance and support the development of orphan drugs, and will continue to look for opportunities to specifically support the advancement of DMD treatments," FDA said. "In just over a year, the agency has approved two new treatments for DMD patients, but we understand that much more is needed and recognize the importance of bringing new treatment options to this community. We will continue to work closely with the community and all companies to expedite the development and approval of safe and effective drugs to treat this disease."