Confirmatory long-term efficacy and safety results of ataluren in patients with nmDMD from Study 041, an international, randomized, double-blind, placebo-controlled, Phase III trial

Study 041 included a large, broad ITT population of 359 boys aged 5 years or older with nmDMD (Table 1). In this heterogeneous patient group, ataluren demonstrated slowing of muscle function decline across the primary and key secondary end points of slope of change in 6MWD, NSAA score and TFTs over 72 weeks. In the ITT population, ataluren-treated patients had a 21% slower rate of decline in 6MWD and a difference in 6MWD of 14.42 m compared with placebo-treated patients (Table 3).

Furthermore, in this study, ataluren was associated with reductions in the risk of 10% (Table 4 & Figure 2) and 5% persistent worsening in 6MWD of 31% and 30%, respectively, and a reduced risk of 30 m decline by 31%, compared with placebo (Supplementary Table 6 & Supplementary Figure 3). It has previously been demonstrated that 10% persistent worsening in 6MWD is predictive of LoA, with patients who have 10% persistent worsening in 6MWD in a 12-month period being significantly more likely to lose ambulation in 4 years [18]. It has also been shown that patients who experience a loss of approximately 30 m in 6MWD are more likely to experience a steep decline in 6MWD, leading to LoA [19]. Therefore, a decline of 30 m in 6MWD is considered clinically meaningful and has been shown to have real-world significance for patients, for example in terms of keeping up with their peers, traveling to a bus stop or making it to a restroom [15]. In Study 041, ataluren-treated patients experienced a decline of 30 m at a median time of 49.1 weeks, compared with 36.0 weeks for placebo-treated patients, giving a median delay of 13 weeks (Supplementary Table 6 & Supplementary Figure 3). This represents a 31% reduction in the risk of reaching this important threshold with ataluren compared with placebo. An approximately 5% persistent worsening in 6MWD has also been established as a threshold for clinically meaningful progression for a range of similar diseases with compromised neuromuscular and pulmonary function [6,16,20].

In the sensitive 6MWD 300–400 m subgroup (previously used in ACT DMD) [8], ataluren-treated patients had a 30% slower rate of decline in 6MWD and a difference in 6MWD of 24.21 m compared with placebo-treated patients (Table 3). Ataluren also reduced the risk of 30 m decline by 47% and reduced the risks of 10% and 5% persistent worsening in 6MWD by 47% and 42%, respectively (Table 4 & Supplementary Table 6). These results may suggest that treatment differences observed in 6MWD are indicative of a clinically meaningful delay in progressing to milestones that are prognostic for LoA in this patient subgroup. In this subgroup, ataluren-treated patients experienced a decline of 30 m at a median of 61.1 weeks, compared with 25.0 weeks for placebo-treated patients, representing a median delay of 36 weeks (Supplementary Table 6 & Supplementary Figure 3). This further highlights the sensitivity of this patient subgroup and the delayed LoA experienced by patients treated with ataluren compared with placebo. In the 6MWD ≥300 m and time to stand from supine ≥5 s subgroup, there was no difference observed for slope of change in 6MWD or in 10% persistent worsening in 6MWD between ataluren and placebo.

The NSAA provides complementary information to the 6MWT on different aspects of motor function relating to everyday functional abilities that are not captured by either the 6MWT or the NSAA alone [21]. Results of the NSAA demonstrated that the declines in both total and linear NSAA scores were statistically steeper in placebo-treated patients than in ataluren-treated patients in the ITT population, and in linear score for the 6MWD 300–400 m subgroup (Table 5). In the ITT population of this study, ataluren-treated patients gained a 2.3-point advantage in NSAA linear score compared with placebo. In ACT DMD, ataluren-treated patients gained a 1.5-point advantage compared with placebo, highlighting that a longer treatment duration with ataluren may lead to a greater benefit with a more pronounced separation in NSAA scores compared with placebo [8]. This may indicate a slower long-term decline of muscle function with ataluren treatment compared with placebo; the numerically moderate treatment differences in the 72 weeks of this study translate to clinically meaningful slowing of disease progression [22]. Modest changes in NSAA scores were also seen in other DMD studies. Vamorolone, a corticosteroid alternative for patients with DMD, led to an increase in NSAA score of 0.49 at week 48 when taken at 6 mg/kg/day compared with 2 mg/kg/day [23]. Unlike vamorolone, ataluren use is indicated for boys with nmDMD in addition to corticosteroids (part of SoC). Significant differences were not observed in the 6MWD ≥300 m and time to stand from supine ≥5 s subgroup for total or linear NSAA scores, or in the 6MWD 300–400 m subgroup for total NSAA score.

TFTs, which measure functional ability and evaluate response to therapy, have also been shown to be valuable outcome measures for patients with DMD [15,24]. Nominally significant differences between ataluren- and placebo-treated patients were observed for 10 m walk/run time in the ITT population and 6MWD 300–400 m subgroup and for time to climb four stairs in all three patient populations (Table 6). The differences in time to climb four stairs between ataluren and placebo for the ITT population, the 6MWD 300–400 m subgroup and the 6MWD ≥300 m and time to stand from supine ≥5 s subgroup were -1.06, -2.29, and -1.73 s, respectively. A difference of approximately 1.5–2.2 s is considered clinically meaningful [6,15], demonstrating the benefit of ataluren in the 6MWD 300–400 m subgroup and in the 6MWD ≥300 m and time to stand from supine ≥5 s subgroup. It has been shown previously that functional abilities in DMD are lost sequentially, with the ability to stand from supine being lost first, followed by the loss of ability to climb four stairs, and finally the loss of ability to walk/run 10 m [13]. This suggests that patients in the 6MWD ≥300 m and time to stand from supine ≥5 s subgroup may be more stable than expected, which may explain why no differences were seen in the ability to walk/run 10 m between ataluren- and placebo-treated patients.

Results from Study 041 build upon the body of evidence demonstrating that ataluren slows motor function decline and is associated with a favorable benefit–risk profile (a consistent adverse event profile) in patients with nmDMD [7]. To add to the totality of evidence, pooled analyses of a large, heterogeneous population of 701 patients from the ITT populations of Study 041, ACT DMD and Study 007 were performed; these results show that ataluren treatment resulted in a reduced decline in motor function across multiple clinically meaningful end points compared with placebo (Supplementary Figure 5). Pooled analyses can also be useful when assessing subgroup effects as they can increase the sample size [25]; the pooled analysis of the 6MWD 300–400 m subgroups from these studies also showed an even greater reduction in decline in 6MWD with ataluren compared with placebo, highlighting the consistent effect of ataluren treatment on slowing motor function decline.

As DMD progresses, all patients will eventually lose ambulation [26]. Although ataluren slows disease progression, it does not halt it, meaning that patients receiving ataluren will still lose ambulation but the time to LoA will likely be delayed, as demonstrated by data from Study 019 [27]. This was a phase III trial assessing ataluren safety in patients with nmDMD who received ataluren plus SoC. In this study, ataluren plus SoC was associated with a 2.2-year delay in LoA (p = 0.0006) compared with SoC alone in propensity score-matched patients from the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS) [27]. In the STRIDE Registry, as of January 2023, ataluren plus SoC significantly delayed age at LoA by 3.5 years compared with SoC alone in CINRG DNHS patients (data not published) [11]. In the first 48 weeks of Study 041, 4/183 ataluren-treated patients (2.2%) and 8/176 patients who received placebo (4.5%) lost ambulation in the ITT population. These findings are consistent with those from previous 48-week trials: in Study 007, 4/57 ataluren-treated patients (7%) and 6/57 patients who received placebo (11%) lost ambulation; and in ACT DMD, 9/114 ataluren-treated patients (8%) and 14/114 patients who received placebo (12%) lost ambulation (Supplementary Table 5) [6,8]. By week 72 of Study 041, as expected with further disease progression, 12/183 ataluren-treated patients (6.6%) and 20/176 patients who received placebo (11.4%) lost ambulation. Similar LoA results were observed in the 6MWD 300–400 m subgroup both at 48 and 72 weeks. Interestingly, 12/12 ataluren-treated patients (100%) and 19/20 placebo-treated patients (95.0%) who lost ambulation had a baseline time to stand from supine of <5 s, which is a prognostic indicator of functional decline and subsequent LoA (Supplementary Table 4) [28].

In addition to delaying time to LoA, ataluren plus SoC significantly delayed age at decline to percent-predicted forced vital capacity of <60% and <50% by 1.8 and 2.3 years, respectively [10], demonstrating the benefits of ataluren after LoA. Furthermore, in a study looking at off-label ataluren use in nonambulatory patients, serial echocardiography, pulmonary lung function tests and assessment of muscle strength indicated mild attenuation of disease progression 18–26 months after the initiation of ataluren treatment [29]. Study 041 was the first trial of ataluren to investigate changes in upper limb function. Although there were no differences in any of the PUL assessments in the ITT population, probably owing to the relatively young patients in this population (Table 1), differences from baseline to week 72 were seen between ataluren- and placebo-treated patients in high-level shoulder scores and in mid-level elbow scores in the sensitive 6MWD 300–400 m subgroup. This further demonstrates the beneficial effect of ataluren treatment on milestones beyond those relating to ambulation (Supplementary Table 7).

Safety results for ataluren were similar to those for placebo, indicating that TEAEs were largely attributable to underlying disease and current SoC, including concomitant corticosteroid treatment. Overall, the safety profile of ataluren was favorable (Table 2) and consistent with previous clinical trials and the STRIDE Registry [6,8–10,27,30]. In fact, in a study of ataluren use in nonambulatory patients, a reduction in body mass index was observed [29]. There were no adverse clinical effects or relevant abnormalities in routine laboratory values [29]. In ACT DMD, ataluren was generally well tolerated and no new safety signals were identified. The data showing clinical benefit are particularly important when considering the fatal nature of nmDMD [8].

Concerns have been raised about the safety profile of givinostat, a histone deacetylase inhibitor for treating DMD [31]. Givinostat has been reported to cause thrombocytopenia and hypertriglyceridemia [32]. Therefore, platelet count and triglyceride level monitoring are necessary, and dose adjustments, treatment suspension or treatment discontinuation may be required [32]. These safety concerns have not been reported with ataluren use.

Treatment effects are likely to vary owing to the heterogeneity of DMD [33], making subgroup analyses necessary [25]. Historically in DMD clinical trials, subgroups have been defined by baseline levels of function to enrich for predictable disease progression to show a more robust short-term effect, particularly when there is a concern that the broader ITT population is not sufficiently powered to demonstrate a short-term treatment benefit [6,8]. This was the largest phase III study ever conducted in DMD; therefore, it was adequately powered to demonstrate a significant treatment effect in the broad ITT population. The prespecified subgroups in this study (6MWD 300–400 m, and 6MWD ≥300 m and time to stand from supine ≥5 s) were selected to include patients who were likely to experience functional decline during the study period and in whom a treatment effect could be better captured. Both subgroups included the ≥300 m threshold in 6MWD. The use of time to stand from supine ≥5 s as an inclusion criterion for the 6MWD ≥300 m and time to stand from supine ≥5 s subgroup was unsuccessful in enriching for patients who experienced a treatment effect, and no differences between ataluren and placebo were observed for 6MWD, time to 10% persistent worsening in 6MWD, NSAA, 10 m walk/run time and time to descend four stairs in this subgroup. This is likely because this group includes patients who have a 6MWD of >350–400 m. Findings from natural history studies show that patients with a baseline 6MWD of >400 m have fewer declines across multiple measures of physical function compared with patients with a baseline 6MWD of <400 m [8,15]. This may explain why the 6MWD ≥300 m and time to stand from supine ≥5 s subgroup was less sensitive than the ITT population and why the 6MWD 300–400 m subgroup was the most sensitive in showing a treatment benefit for the selected end points in this study. Of the 185 patients in the 6MWD ≥300 m and time to stand from supine ≥5 s subgroup, 60 (32.4%) had a 6MWD ≥400 m; motor function remained more stable in these patients throughout the study than in the other patients in this subgroup, regardless of whether they received ataluren or placebo. This may also explain why results for the primary end point and several secondary end points in this subgroup numerically favored ataluren but did not reach statistical significance.

Considering the complexity and heterogeneity of DMD in terms of disease severity and progression, observing statistically significant treatment effects on disease progression in the short term duration of a clinical trial is challenging; a longer follow-up time is required to observe a true treatment effect [33]. The 18-month, placebo-controlled period of Study 041 enabled a statistically significant treatment effect of ataluren to be attained in a broad ITT population. This study is the first to demonstrate statistically significant delays in motor function decline among multiple clinically meaningful outcomes with ataluren treatment compared with placebo in the ITT population, which includes patients from 69 international sites receiving SoC, including corticosteroids. Nominally significant differences in time to 10% persistent worsening, 5% persistent worsening and 30 m decline in 6MWD were seen in the ITT population and the 6MWD 300–400 m subgroup. Furthermore, ataluren-treated patients had a 36-week median delay in 30 m decline in 6MWD compared with placebo-treated patients, which may be meaningful for patients’ quality of life. A robust treatment effect in 6MWD, TFTs and NSAA was also seen in the sensitive 6MWD 300–400 m subgroup at a magnitude previously demonstrated in ACT DMD [8].

Factors that could be investigated further to help to contextualize the Study 041 data include the potential variability in adherence to DMD SoC guidelines in different participating countries and the impact of the COVID-19 pandemic, which overlapped with Study 041. The results from the open-label period of Study 041 will help to consolidate findings from the 72-week double-blind period [34].

D Vlodavets, S Wu, A Kostera-Pruszczyk, J-H Chae, S Gulati, J-H Shin, Michelle Lorentzos, Anita Cairns, Yuh-Jyh Jong, H Komaki¹, J Statland¹, A Prufer de Queiroz Campos Araujo, J Gurgel-Giannetti, Y Takeshima, RE Escobar Cedillo, P Karachunski, K Haginoya and V Penematsa contributed to data curation, writing – reviewed and edited the manuscript draft, and approved the final version that was submitted. C Chou contributed to the formal analysis and interpretation of data, writing – reviewed and edited the manuscript draft, and approved the final version that was submitted. P Williams and C Werner contributed to the interpretation of data, writing – reviewed and edited the manuscript draft, and approved the final version that was submitted.¹⁹, CM McDonald contributed to conceptualization, data curation, writing – reviewed and edited the manuscript draft, and approved the final version that was submitted.

The authors thank the patients and their families for their participation in the Study 041 clinical trial, and the individuals involved in the conduct of this study. The authors also thank the Study 041 investigators: Hoda Abdel-Hamid, Russell Butterfield, Saunder Bernes, Craig Campbell, Sophelia Chan Hoi Shan, Arijit Chattopadhyay, John Day, Darryl De Vivo, Micaela del Rosari Avila Cobo, Hacer Durmus, Maria Bernadete Dutra de Resende, Erika Finanger, Velina Guergueltcheva, Maina Kava, Jeehun Lee, Wang-Tso Lee, Hanns Lochmuller, Tim Lotze, Xinguo Lu, Neeharika Lakshmi Mathukumalli, Yoshihiro Maegaki, Weldon Mauney III, Tsuyoshi Matsumura, Ryan Monique, Sumitha Murugesu, Aditya Nair, Atchayaram Nalini, Erin Neil Knierbein, Katsuhisa Ogata, Shiro Ozasa, Seth Perlman, Leigh Ramos-Platt, Matilde Ruiz-Garcia, Crystal Proud, Dimitry Rudenko, Shinji Saitoh, Naveen Sankhyan, Oranee Sanmaneechai, Siddharth Shah, Jonathan Strober, Cuixia Tian, Meow Keong Thong, Vrajesh Udani, Venkataraman Viswanathan, Ning Wang, Fei Yin, Takeshi Yoshida and Shuizhen Zhou. The authors also thank Greg Gordon, Panayiota Trifillis and Shu-Jui Liang for their contributions to the study. Finally, the authors thank Jill Castle, a parent of a patient with nmDMD, who has helped with the development of the Plain Language Summary abstract.

This work was funded by PTC Therapeutics.

S Wu, J-H Chae, S Gulati, Y Takeshima, P Karachunski and K Haginoya have no conflicts of interest. D Vlodavets has acted as a principal investigator of clinical trials for BIOCAD, Biogen, Modis Therapeutics, Novartis, NS Pharma, Pfizer, PTC Therapeutics, Roche and Sarepta Therapeutics. A Kostera-Pruszczyk has received advisory board fees from Pfizer, PTC Therapeutics, Roche and Sarepta Therapeutics; has received lecture fees and travel support from PTC Therapeutics and Roche; and has acted as a pricipal investigator for DMD clinical trials sponsored by GlaxoSmithKline, Pfizer, PTC Therapeutics and Sarepta Therapeutics. J-H Shin has acted as a principal investigator on DMD clinical trials sponsored by PTC Therapeutics, Pfizer, Sarepta Therapeutics and Nippon Shinyaku. M Lorentzos has acted as a principal investigator on clinical trials for PTC Therapeutics, Sarepta Therapeutics, Pfizer, and NS Pharma and has consulted on advisory boards for Roche, Sarepta Therapeutics and Biogen. A Cairns has acted as a principal investigator of clinical trials for Biogen, NS Pharma, Pfizer, PTC Therapeutics and Sarepta Therapeutics; and has received fees for participation in advisory boards from Biogen, Novartis and Roche. YJ Jong has acted as a principal investigator of clinical trials for Biogen, Novartis, NS Pharma, Pfizer, PTC Therapeutics, Roche and Sarepta Therapeutics. H Komaki has acted as a consultant on clinical trials for Kaneka, Taiho Pharmaceutical and Takeda; and has received research support for clinical trials from Nippon Shinyaku, Pfizer, PTC Therapeutics, Sarepta Therapeutics and Taiho Pharmaceutical. J Statland has received grant funding from the Friends of FSH Research, FSHD Canada, FSHD Society, MDA and NIH; and is a consultant or has served on advisory boards for Avidity Biosciences, Dyne Therapeutics, Fulcrum Therapeutics, ML Bio, Roche and Sarepta Therapeutics. A Prufer de Queiroz Campos Araujo has acted as a principal investigator of clinical trials for GlaxoSmithKline, PTC Therapeutics, Roche and Sarepta Therapeutics. J Gurgel-Giannetti has acted as a principal investigator of clinical trials for PTC Therapeutics, Biogen, Novartis and Roche, and has served on advisory boards for Roche, Biogen and Novartis. RE Escobar Cedillo has acted as a principal investigator of clinical trials for PTC Therapeutics. V Penematsa, C Chou, P Williams and C Werner are employees of PTC Therapeutics. CM McDonald has acted as a consultant for DMD clinical trials for Astellas, Capricor Therapeutics, Catabasis Pharmaceuticals, Catalyst Pharmaceuticals, Edgewise Therapeutics, Epirium Bio (formerly Cardero Therapeutics), FibroGen, Italfarmaco, Pfizer, PTC Therapeutics, Santhera Pharmaceuticals, Sarepta Therapeutics and Solid Biosciences; and has received research support for clinical trials from Capricor Therapeutics, Catabasis, Catalyst Pharmaceuticals, Edgewise Therapeutics, Italfarmaco, Pfizer, PTC Therapeutics, Santhera Pharmaceuticals, Sarepta Therapeutics and Solid Biosciences. The authors have no other competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript apart from those disclosed.

Medical writing support was provided by Dina Dakkak and Tim Ellison of PharmaGenesis London, London, UK and was funded by PTC Therapeutics.

The authors certify that this manuscript reports clinical trial data (NCT03179631). The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available owing to privacy or ethical restrictions.

This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit https://creativecommons.org/licenses/by-nc-nd/4.0/