UK Recommends Routine Funding of TRANSLARNA (Ataluren) for Duchenne Muscular Dystrophy Based on RWE, Contrasting with EMA’s Decision

TRANSLARNA, manufactured by PTC Therapeutics, was approved for reimbursement in the UK as an option for treating DMD resulting from a nonsense mutation in the dystrophin gene in people two years and over who can walk in February 2023. RWE constituted the main evidence used to estimate the treatment benefits of TRANSLARNA compared with best supportive care, which influenced the reimbursement decision. TRANSLARNA is recommended, within its marketing authorization, as an option for treating DMD if the manufacturer provides TRANSLARNA according to the commercial arrangement.

DMD is a severe, rare, progressive, muscle-wasting genetic condition caused by the lack of the dystrophin protein. DMD is recessive and X-linked, mainly affecting males, with symptoms appearing in children as early as three years old. The main symptom of DMD is motor dysfunction but, as the disease progresses, the gastrointestinal tract and vital organs such as the heart are affected.

The original submission in 2015, resulting in a managed access agreement for TRANSLARNA, was based on two randomized controlled trials. For the current reimbursement decision, however, the main evidence sources used by the manufacturer came from two RWE studies: the STRIDE and the CINRG studies2. NICE preferred the RWE over the clinical trials because they considered the endpoint outcome inappropriate. The primary outcome of the two trials was the six-minute walk distance (6MWD), which is not routinely performed in the UK. The patient experts expressed that this test matters less to them than other outcomes such as stamina in undertaking certain tasks. Data collected from the managed access agreement was also of limited use.

The RWE allowed the manufacturers to assess the impact of TRANSLARNA on outcomes such as the loss of ability to walk and disease progression at meaningful time points. These outcomes were considered by both patients and experts to be more meaningful. 

RWE Studies

The STRIDE is an ongoing, international, multicenter post-approval safety study of real-world TRANSLARNA use in individuals, aged two years and older, with nonsense mutation DMD in clinical practice, mainly in Europe. With a sample size of 360 patients, the STRIDE Registry was initiated to fulfill a post-marketing commitment to the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency, and to evaluate the long-term safety and effectiveness of TRANSLARNA in individuals with DMD in real-world routine clinical practice. The Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS) was a prospective, longitudinal, observational study of over 400 participants with DMD which enrolled patients between 2006 and 2016. It was designed to capture the natural history of the disease in people with DMD receiving the best supportive care and was mainly carried out in North America.

The manufacturer used propensity score matching to indirectly compare the clinical effectiveness of TRANSLARNA from STRIDE with best supportive care from CINRG. This involved matching patients in STRIDE to those in CINRG based on prognostic factors. The manufacturer used four prognostic factors in its matching (age at first symptoms, age at first corticosteroid use, duration of deflazacort, and other steroid use). Time-to-event data from the propensity-matched STRIDE and CINRG data was used to estimate parametric survival curves representing the rate of disease progression by transition through the health states.

The manufacturer’s indirect comparison of STRIDE and CINRG showed that TRANSLARNA delayed the median time to the loss of the ability to walk by a median of 5.4 years compared with best supportive care (17.9 years compared with 12.5 years, p<0.0001). The manufacturer provided two additional indirect comparisons of TRANSLARNA and best supportive care, including one matching people from the managed access agreement data to the NorthStar registry (a natural history study of people with DMD receiving best supportive care in the UK), and between Study 019 (a long-term follow up study of people receiving TRANSLARNA) and CINRG, however, there were difficulties in matching. The NICE committee acknowledged that TRANSLARNA is likely to slow down the progression of the disease, based on the results from the manufacturer’s indirect treatment comparison. The committee concluded that the STRIDE and CINRG indirect comparison was the most appropriate to use in decision-making, although its results had some degree of uncertainty due to some imbalances between the groups and the fact that the studies were performed in different locations.

As part of NICE’s appraisal process, the manufacturer submitted a new economic model based on data from the STRIDE and CINRG RWE studies as it better reflected the disease course, versus the model used in the original 2015 guidance which was based on clinical trial data.

Contrasting with NICE’s decision, the Committee for Medicinal Products for Human Use (CHMP) re-evaluated all the available data on the benefits and risks of ataluren, which included an analysis of patient registry data comparing health outcomes of patients who had been treated with ataluren for an average of 5.5 years with those of patients who had not received ataluren. Although the CHMP acknowledged the benefit of delaying the loss of the ability to walk, it raised methodological concerns and uncertainty linked with the indirect treatment comparison. The CHMP considered that the clinical trials conducted post-marketing approval, did not confirm the beneficial effect of ataluren.

Conclusions

The NICE committee noted that the cost-effectiveness estimates were uncertain because of the limitations in the clinical effectiveness data. However, considering the commercial agreement implemented, the committee determined that the most plausible incremental cost-effectiveness ratio (ICER) for TRANSLARNA was below the threshold acceptable for highly specialized technologies (£100,000). Therefore, it recommended TRANSLARNA for routine use in the NHS for treating DMD. On the other hand, EMA based its decision mostly on the post-marketing clinical trials and decided not to renew ataluren’s authorization. This is an interesting example of two major healthcare bodies drawing opposite conclusions based on valuing different sources of evidence.