FDA Accepts Resubmitted NDA for Ataluren in Nonsense Duchenne Muscular Dystrophy

Matthew B. Klein, MD, chief executive officer at PTC

According to an announcement, the FDA has accepted PTC Therapeutics resubmitted new drug application (NDA) for its protein restoration therapy ataluren (Translarna) for the treatment of boys with nonsense mutation Duchenne muscular dystrophy (nmDMD). Because this was an NDA resubmission following a complete response letter (CRL) filed several years ago, the FDA is not obligated to follow PDUFA review timelines and thus, did not provide an action date for the therapy.¹

The resubmitted NDA was based on data from a phase 3 placebo-controlled trial, dubbed Study 041 (NCT03179631), which included an intent-to-treat population of 359 patients with nmDMD. In addition, the resubmission also included analyses from the STRIDE registry, an ongoing, multicenter, observational study of the safety and effectiveness of ataluren in routine care. Currently, the therapy is licensed in multiple countries, including the European Union and Brazil.

"The NDA acceptance for review is a significant milestone that brings us one step closer to providing this important treatment to boys and young men living with nonsense mutation Duchenne muscular dystrophy in the United States,” Matthew B. Klein, MD, chief executive officer at PTC, said in a statement.¹ "The totality of evidence clearly supports the favorable safety profile and short- and long-term benefits of Translarna for individuals with nmDMD. We look forward to working with FDA throughout the review process."

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Prior to the publication of study 041, PTC submitted a meeting request to the FDA in June 2022 to gain clarity on the regulatory pathway for a potential re-submission of a NDA for ataluren. The FDA provided initial written feedback that study 041 did not provide substantial evidence of effectiveness to support an NDA re-submission. Following an informal meeting, PTC released an update stating that it would prepare an additional type C meeting with the agency to review the totality of data collected to data, including dystrophin and other mechanistic data as well as additional analyses that could support the benefit of the therapy.²

In Study 041, significant improvements were observed in key study endpoints at 72 weeks, including six-minute walk distance (6MWD) (P =0.0248), North Star Ambulatory Assessment (P =0.0283), 10-meter walk/run (P =0.0422), four-stair climb (P =0.0293), and time to 10% worsening in 6MWD (P =0.0078). In STRIDE, treatment with the therapy resulted in a 3.5-year delay in loss of ambulation (P <.0001) and a 1.8-year delay in reaching a predicted forced vital capacity of less than 60% (P = .0028).¹

Debra Miller

"We are excited that the FDA has accepted the Translarna NDA for review,” Debra Miller, founder and chief executive officer at CureDuchenne, said in a statement.¹ "We believe that the totality of the data demonstrates the meaningful benefits and strong safety profile of Translarna for people with Duchenne muscular dystrophy caused by a nonsense mutation, which is approximately 13% of our community. Many of our boys and young men have participated in Translarna clinical trials over the years, and about 150 of them remain on therapy through extension studies and continue to experience the benefits of Translarna, including maintaining independence."

More recently, in May, the European Commission (EU) decided not to adopt the Committee for Medicinal Products for Human Use’s (CHMP) negative opinion of ataluren, allowing the therapy to stay on market. The committee’s negative opinion, issued in January 2024, came months after the group refused to convert ataluren’s conditional marketing authorization. In the latest update, the EU decided to refuse this opinion, factoring in data from patient registries and real-world evidence.³

At the 2024 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, investigators presented a large meta-analysis of three studies—Study 041, Study 007 (NCT00592553), and the ACT DMD study (NCT01826487)—highlighting ataluren's effects on muscle function in nmDMD. Among 354 patients treated with ataluren and 347 patients given placebo, significant differences were noted between groups in changes from baseline to week 48 in six-minute walk distance (6MWD), timed function tests (TFTs), and North Star Ambulatory Assessment (NSAA) scores.⁴

The results favored ataluren, with least-squares mean differences as follows: 6MWD: 15.8 meters (P = .0032); 10-meter walk/run: −1.1 seconds (P = .0026); climb four stairs: −1.3 seconds (P = .0025); descend four stairs: −1.3 seconds (P = .0021); NSAA total score: 1.1 (P = .0010); and NSAA linear score: 2.6 (P = .0036). Additionally, in the 6MWD 300 m to 400 m subgroup, ataluren significantly slowed the decline in 6MWD by 33.7 meters compared with the placebo group (P < .0001).

REFERENCES
1. PTC Therapeutics announces FDA acceptance of Translarna NDA resubmission. News release. PTC Therapeutics. October 30, 2024. Accessed November 5, 2024. https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-announces-fda-acceptance-translarnatm-nda
2. United States Securities and Exchange Commission. PTC Therapeutics. https://ir.ptcbio.com/node/15986/html. June 30, 2023. Accessed November 5, 2024.
3. PTC Therapeutics announces European Commission returns Translarna opinion to CHMP for re-evaluation. News release. PTC THerpeutics. May 20, 2024. Accessed November 5, 2024. https://www.prnewswire.com/news-releases/ptc-therapeutics-announces-european-commission-returns-translarna-opinion-to-chmp-for-re-evaluation-302149749.html
4. Werner C, Jong YJ, Karachunski P, et al. Ataluren slows the decline of muscle function in patients with nmDMD: a meta-analysis of three randomized, double-blind, placebo-controlled trials. Presented at: 2024 MDA Clinical and Scientific Conference; March 3-6; Poster M167.