Ataluren Remains on Market Following European Commission Decision to Spurn CHMP’s Negative Opinion

Mathew B. Klein, MD

According to a recent announcement, the European Commission (EU) had decided not to adopt the Committee for Medicinal Products for Human Use’s (CHMP) negative opinion of ataluren (Translarna; PTC Therapeutics), a protein restoration therapy, and thus, the medication will remain on market. The EC asked the CHMP to further consider the totality of evidence of the therapy, which was conditionally approved in Europe in 2014.¹

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. Ataluren gained a conditional nod in Europe based on data from study 007 (NCT00592553), a phase 2b randomized, placebo-controlled trial of patients aged 5 years and older with nonsense mutation dystrophinopathy.

In the announcement, it was noted that the European Medicines Agency also informed PTC that the decision to refuse the negative opinion was not impacted by a Scientific Advisory Group (SAG) meeting for the agent in September 2023. Ultimately, that meeting, and all the procedural steps that followed, were considered invalid. Going forward, any future evaluation of the therapy will not include conversations from the SAG meeting held in September 2023 as well as the meeting held in January 2024.

"The maintenance of the current authorization of Translarna is a big win for boys and young men with nonsense mutation Duchenne muscular dystrophy in Europe," Mathew B. Klein, MD, chief executive officer at PTC, said in a statement.¹ "The efficacy and safety demonstrated in clinical trials and the long-term STRIDE registry support that Translarna fills an otherwise unmet need for nmDMD patients. We look forward to working collaboratively with CHMP on next steps once they are defined."

Strategic Targeting of Registries and International Database of Excellence, or STRIDE, is an ongoing, international, multicenter registry of real-world ataluren use in individuals with nonsense mutation Duchenne muscular dystrophy (nmDMD) in clinical practice. As of January 2022, 307 patients were enrolled from 14 countries. Published in the Journal of Neurology, an interim analysis of stride at the time showed that long-term, real-world treatment with ataluren plus standard of care delays several disease progression milestones in individuals with nmDMD.²

READ MORE: Duchenne Agent DYNE-251 Demonstrates Functional Improvement in Phase 1/2 DELIVER Trial

In the analysis, mean ages at first symptoms and at genetic diagnosis were 2.9 (SD, 1.7) years and 4.5 (SD, 3.7) years, respectively. Kaplain-Meier analyses demonstrated that the combination of ataluren with standard of care significantly delayed age at loss of ambulation by 4 years (P <.0001) and age at decline to percent-predicted forced vital capacity of less than 60% and less than 50% by 1.8 years (P = .0021) and 2.3 years (P = .0207), respectively, compared with standard of care alone.

At the 2024 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, investigators presented a large meta-analysis of 3 studies—Study 041 (NCT03179631), Study 007 (NCT00592553), and the ACT DMD study (NCT01826487)—further highlighting ataluren’s impact on muscle function in nmDMD. Among 354 patients treated with ataluren and 347 patients treated with the placebo, investigators observed statistically significant differences in change from baseline to week 48 in 6-minute walk distance (6MWD), timed function tests (TFTs), and the North Star Ambulatory Assessment (NSAA) scores between ataluren- and placebo-treated patients.

The differences observed favored ataluren (least-squares mean difference, 6MWD: 15.8m [P = .0032]; 10m walk/run: −1.1s [P = .0026]; climb 4 stairs: −1.3s [P = .0025]; descend 4 stairs: −1.3s [P = .0021]; NSAA total score: 1.1 [P = .0010]; NSAA linear score: 2.6 [P = .0036]). Additionally, in the 6MWD 300 m to 400 m subgroup, authors observed that ataluren significantly slowed 6MWD decline by 33.7 m compared with the placebo group (P <.0001).³

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 new drug application (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. It currently remains investigational in the US.⁴

REFERENCES
1. PTC Therapeutics announces European Commission returns Translarna opinion to CHMP for re-evaluation. News release. PTC THerpeutics. May 20, 2024. Accessed May 23, 2024. https://www.prnewswire.com/news-releases/ptc-therapeutics-announces-european-commission-returns-translarna-opinion-to-chmp-for-re-evaluation-302149749.html
2. Mercuri E, Osorio AN, Muntoni F, et al. Safety and effectiveness of ataluren in patients with nonsense mutation DMD in the STRIDE registry compared with the CINRG Duchenne Natural History Study (2015-2022): 2022 interim analysis. Journal of Neurol. 2023;270:3896-3913. doi:10.1007/s00415-023-11687-1
3. 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.
4. United States Securities and Exchange Commission. PTC Therapeutics. https://ir.ptcbio.com/node/15986/html. June 30, 2023. Accessed May 23, 2024.