September 27, 2017
By Mark Terry, BioSpace.com Breaking News Staff
PTC Therapeutics , based in South Plainfield, NJ, may have found itself in a situation where pushing hard for a drug approval results in pushback from the regulatory agency.
PTC has a drug for Duchenne muscular dystrophy (DMD), ataluren, specifically for treatment for the nonsense mutation DMD (nmDMD), which has been approved in Europe for ambulatory patients with nmDMD. Originally, the U.S. Food and Drug Administration (FDA) refused PTC’s application for the drug, brand name Translama, citing lack of efficacy data. The European approval is dependent upon the company showing more data in a post-marketing study that is currently in progress.
The FDA’s independent panel is scheduled to meet on Thursday, Sept. 28 to discuss it. The FDA had already refused to review ataluren twice because of lack of effectiveness in clinical trials. Reuters notes, “PTC proceeded to file its application ‘over protest’ under a rarely used move that allows a company to have its application reviewed when there is a disagreement with regulators over the application’s acceptability.”
Yesterday, in a preliminary meeting, officials with the FDA didn’t show any signs they were any more interested in approving the drug, and, in fact, were clearly negative about it, which doesn’t bode well for Thursday’s meeting.
The FDA stated, “Ultimately, no positive results from any prospectively planned analyses that are persuasive have been provided with this application. The applicant has presented only the results from numerous post hoc and exploratory analyses that are intended to mitigate two negative clinical trials. In 2011, the applicant claimed that the effectiveness of ataluren had been established based on the post hoc analyses of the ADP population in Study 007. However, when this conclusion was prospectively evaluated in Study 020, the results were clearly negative.”
The agency then went on to bash the structure of the trials, undermine the way the analysis was performed, and express doubts that any further analysis or testing would provide any different result, ending with, “The analogous results from the applicant’s development of ataluren for the treatment of nmCF offer a similar cautionary tale. Overall, the data intended by the applicant to establish the effectiveness of ataluren for the treatment of nmDMD are not persuasive.”
John Carroll, with Endpoints News, writes, “That qualifies as one of the most conclusive rejections I’ve seen of any drug application at the FDA. Possibly PTC was emboldened by the agency’s accelerated OK of Sarepta’s drug [Exondys 51], even though the company never provided data that the drug could work. In this case, though, the agency feels they have plenty of data to conclude that ataluren doesn’t work. And there’s no evidence to suggest that Janet Woodcock will be riding to PTC’s defense. Even a big showing of support from Duchenne parents Thursday may prove unlikely to tip the scales in PTC’s favor.”
More eyes will be on Thursday’s meeting than usual because of Sarepta’s approval. Although Sarepta is unlikely to admit it, given that the $300,000 per year drug is selling well, but it was approved under a cloud of skepticism.
The release of documents by the FDA of Sarepta’s approval showed that Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER) took into account Sarepta’s financial problems. There was significant controversy within the agency over it, with at least three major opponents. Ronald Farkas, clinical team leader, left the agency just prior to approval after submitting a scathing report on the drug. Luciana Borio and Ellis Unger, the agency’s chief scientist and director of the office of drug evaluation, respectively, strongly opposed approval, arguing that Sarepta didn’t provide substantial evidence of Exondys 51’s effectiveness.
But Woodcock pushed it through, overruling her staff. The final decision went to then-commissioner Robert Califf, who expressed similar reservations as Borio and Unger, but punted the decision back to Woodcock.
As part of the approval, Sarepta is conducting a two-year, randomized controlled trial to verify the drug’s benefits. At its core, more data is needed to prove that the drug actually improves motor function. If it fails, FDA approval could be withdrawn.
Andrew Wood, writing for Seeking Alpha, says, “PTC Therapeutics is mirroring this past brouhaha, but with added vigor in all the wrong places. Translarna’s road to approval started off to a rocky start with an RTF due to a lack of efficacy data, then an appeal rejection. The finale to this rocky start culminated in the desperate use of the rarely used option of ‘filing under protest,’ forcing the FDA to consider Translarna for approval. The concerns of the FDA are not unwarranted as shone in the Phase III Lancet paper with the drug showing significance only in the middle severity subgroup.”
