CHMP Issues Negative Opinion for Renewal of Conditionally Approved Therapy Ataluren


Despite conditional approval in Europe since 2014, ataluren's authorization has faced rejections and is still investigational in the US.

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

Matthew B. Klein, MD

Months after the Committee for Medicinal Products for Human Use (CHMP) refused to convert ataluren’s (Translarna; PTC Therapeutics) conditional marketing authorization, the committee has now issued a negative opinion following its re-examination procedure. Ataluren, a protein restoration therapy for patients with nonsense mutation Duchenne muscular dystrophy (DMD), was originally approved in Europe under conditional circumstances in 2014.1

Per European regulations, the European Commission has 67 days to adopt the opinion. Ataluren is a small molecule treatment that allows for stop-codon read-through to produce dystrophin in patients with nonsense mutations, which affects up to 15% of DMD diagnoses.

"We are disappointed that the CHMP has maintained its negative opinion on the Translarna authorization which will result in the withdrawal of a therapy for patients in Europe with nonsense mutation Duchenne Muscular Dystrophy that the data support is safe and effective," Matthew B. Klein, MD, chief executive officer at PTC, said in a statement.1 "The CHMP's decision, which is against the stated wishes of the patient community and expert physicians, will be devastating for children and young men in Europe for whom no other disease-modifying therapies are available."

Ataluren gained a conditional nod in Europe based on data from study 007 (NCT00592553), a phase 2b randomized placebo-controlled of patients aged 5 years and older with nonsense mutation dystrophinopathy. In the trial, those on ataluren 10, 10, 20 mg/kg (n = 57) showed favorable, but not statistically significant, differences vs placebo on the primary end point of change in 6-minute walk distance (6MWD) at week 48. Secondary end points, which included timed function tests, showed meaningful differences between ataluren 10, 10, 20 mg/kg and placebo.2

READ MORE: Positive Phase 2 Data Announced for MOMENTUM Study of Duchenne Agent SRP-5051

In 2017, when the European Medicines Agency (EMA) renewed ataluren’s conditional clearance, PTC agreed to use data from a third trial, study 041 (NCT03179631), to confirm the drug’s benefit-risk profile. Published in Neurology in 2023, the placebo-controlled trial randomly assigned boys with nonsense mutation DMD to either ataluren or placebo for a 72-week period, followed by a 72-week open-label extension. Intended to assess ataluren’s effect on ambulatory function, the trial included a predefined subgroup of boys aged between 7-16 years with at least 300 m on 6MWD and at least 5s stand from supine (primary) and boys with 300-400 m on 6MWD.3

All told, in comparison with placebo, there were significant differences in mean 6MWD in both the intent-to-treat (ITT) population (ataluren, n = 183; placebo, n = 176) and the subgroup of boys with 300 m to 400 m 6MWD (ataluren, n = 86; placebo, n = 83).The change from baseline and rate of change favored ataluren in the ITT population (14.4 m; 0.20 m per week; = .0248) and 300 m to 400 m 6MWD subgroup (24.2 m; 0.34 m per week; = .0310). These findings, the authors noted, represented a 21% and 30% slowing of the decline rate in 6MWD in these groups, respectively.4

In the primary analysis subgroup (ataluren, n = 92; placebo, n = 93) the change from baseline in 6MWD was –81.8 m and –90.1 m in the ataluren and placebo groups, respectively, for a difference of 8.3 m (P = .3626). This represented a 9% slowing of rate of decline. Of note, the 300 m to 400 m 6MWD subgroup experienced significant benefits on North Star Ambulatory Assessment (NSAA) scores and timed function test (TFT) scores. Specifically, data reported at the 2023 American Academy of Neurology annual meeting that the NSAA liner score between-group difference was 3.3 points (ataluren, –10; placebo, –13.3; P = .0419), while total score between-group difference was 1.1 points (ataluren, –4.4; placebo, –5.5; P = .0837).

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.5

1. CHMP issues negative opinion for renewal of conditional marketing authorization for Translarne (ataluren) following re-examination procedure. News release. PTC Therapeutics. January 25, 2024. Accessed January 30, 2024.
2. Bushby K, Finkel R, Wong B, et al. Ataluren treatment of patients with nonsense mutation dystrophinopathy. Muscle & nerve. 2014;50(4):477-487. doi:10.1002/mus.24332
3. McDonald CM, Wu S, Gulati S, et al. Safety and efficacy of ataluren in nmDMD patients from study 041, a phase 3, randomized, double-blind, placebo-controlled trial. Neurology. 2023;100(17). doi:10.1212/WNL.00000000000020250
4. 8 McDonald CM, Wu S, Gulati S, et al. Safety and Efficacy of Ataluren in nmDMD Patients from Study 041, a Phase 3, Randomized, Double-Blind, Placebo-Controlled Trial. Presented at: AAN Annual Meeting; April 22-27, 2023; Boston, MA and Virtual. Neurology. doi:10.1212/WNL.00000000002025052
5. United States Securities and Exchange Commission. PTC Therapeutics. June 30, 2023. Accessed January 30, 2024.
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