[PIO] EMA confirms its recommendation not to renew the marketing authorisation of Translarna for Duchenne muscular dystrophy

Following a review, the EMA's Committee for Medicinal Products for Human Use (CHMP) has confirmed its original recommendation not to renew the conditional marketing authorisation for Translarna (ataluren), a medicine used to treat patients with Duchenne muscular dystrophy. The disease is caused by a specific genetic abnormality called an "untranslatable mutation" in the dystrophin gene.

The original recommendation was the result of a full re-evaluation of the benefits and risks of Translarna when the marketing authorisation was renewed, and concluded that the efficacy of the medicine had not been confirmed.

As part of the review requested by the company marketing Translarna, the CHMP reassessed data from a study conducted after licensure as a special requirement (Study 041) and the results of a study comparing two patient registries.

The CHMP concluded that the results of Study 041 failed to show that the drug was effective in patients with a progressive decline in walking ability, who were expected to have a greater benefit from treatment with Translarna compared to other patients included in the study.

In these patients, the distance they could walk in 6 minutes after 18 months of treatment was reduced by about 82 metres in the Translarna group compared with a reduction of 90 metres in the placebo (placebo) group. However, the difference between these two groups was not statistically significant, suggesting that it may be due to chance.

In addition, the Committee noted that the mechanism of action of Translarna has not been confirmed in additional studies, which showed only a very small effect of Translarna on the production of the protein dystrophin.

Patient registry data

An important part of the CHMP review was the evaluation of data from a study comparing patient health outcomes from two registries. In this study, patients from the STRIDE registry were treated with Translarna for an average of 5.5 years in 2015 and 2022, while patients from the CINRG DNHS registry were not treated with Translarna and were followed between 2006 and 2016.

The results indicated that patients from the STRIDE registry lost walking ability approximately 3.5 years later than patients from the CINRG DNHS registry. However, due to several issues and uncertainties associated with the data from these registries, the CHMP could not conclude that the difference observed between the two registries was due to an effect of Translarna.

A major uncertainty relates to the fact that the STRIDE registry was created more recently than the CINRG DNHS registry. This means that patients included in STRIDE were able to take advantage of more recent developments in non-drug therapies, such as physiotherapy, that would have provided additional benefits. There were also uncertainties about how differences in steroid use - the main established treatment for these patients - were taken into account in the analysis. In addition, the Committee noted that the patient populations in the two registries were different in terms of the genetic mutations that caused Duchenne muscular dystrophy, which could have influenced the results in favour of those treated with Translarna. Because of all these limitations, the CHMP was unable to draw conclusions about the benefits of Translarna from the registry data.

During the review, the CHMP consulted a panel of experts in neurology as well as patient representatives. It also took into account several contributions received from families, individual physicians, patients and health professional organisations.

The CHMP assessed all available data and the views of experts, patients and third parties in order to reach its final decision. The Committee also recognised the high unmet medical need for an effective treatment for patients with Duchenne muscular dystrophy. However, the Committee, based on all the data collected since the authorisation of the medicine, concluded that the efficacy of Translarna has not been confirmed in patients with Duchenne muscular dystrophy whose disease is caused by an "uninterpretable mutation", including those who were expected to have a better response to treatment.

The CHMP considered that the data now available for the drug are comprehensive and concluded that the benefit-risk ratio for Translarna is negative. The Commission therefore recommended not to renew the marketing authorisation of the medicine in the EU.

The EMA will now forward the opinion of the CHMP to the European Commission, which will adopt a final legally binding decision applicable in all EU Member States.

Information for patients and caregivers

1. A comprehensive review of all available data on the benefits and risks of Translarna concluded that the efficacy of the drug has not been confirmed in patients with Duchenne muscular dystrophy due to an "uninterpretable mutation".
2. The review took into account results from studies, data from patient registries and opinions of neurology experts and patient representatives, as well as contributions from families, individual physicians, patients and health professional organizations.
3. The review included an evaluation of a recent study involving patients with Duchenne muscular dystrophy due to an "uninterpretable mutation", which compared the effect of Translarna with placebo (placebo) after 18 months of treatment. The study failed to show that Translarna had a beneficial effect in patients with a progressive decline in walking ability, who were expected to have a greater benefit from Translarna treatment.
4. In addition, it was not possible to draw a conclusion about the benefits of Translarna from a study based on information from patient registries because of many issues and uncertainties about the data.
5. Therefore, the EMA concluded that the benefits of Translarna have not been confirmed and recommended that its marketing authorisation should not be renewed. When this recommendation is confirmed by the European Commission, the medicine will no longer have a marketing authorisation in the EU.
6. If you or your child is taking Translarna, you should talk to your doctor about this decision and what it means for you or your child's treatment.

Information for healthcare professionals

1. A comprehensive review of all available data on the benefits and risks of Translarna concluded that the effectiveness of the medicine has not been confirmed.
2. The EMA has therefore recommended that the marketing authorisation for Translarna should not be renewed. When this recommendation is confirmed by the European Commission, the medicinal product will no longer be authorised in the EU.
3. Healthcare professionals should not initiate treatment with Translarna in new patients.
4. In patients currently using Translarna, healthcare professionals should explain why there is a recommendation not to renew the marketing authorisation of the medicine and discuss the continuation of their care.
5. Translarna received a conditional marketing authorisation in July 2014. Its marketing authorisation was subject to annual renewals based on the results of additional studies imposed on the marketing authorisation holder (MAH).
6. In 2016, the CHMP requested that Translarna's MAH conduct a new study on the efficacy of the drug, specifically looking at patients in ambulatory descending phase (ADP) of their disease, as they were expected to have a better response to treatment based on previous post-hoc analyses.

Study 041 was a phase 3, randomized (1:1), double-blind, placebo-controlled study conducted in 360 patients aged 5 years and older with Duchenne muscular dystrophy with an uninterpretable mutation. A 72-week double-blind phase was followed by an open-label extension study for an additional 72 weeks where patients receiving placebo were switched to Translarna treatment.

The primary endpoint was change in 6-minute walking distance (6MWD) at 72 weeks. In the ADP subgroup (n=185), the mean change in 6MWD from baseline was -81.83 meters in the Translarna group versus -90.09 meters in the placebo group, with a non-significant difference of 8.26 meters (95% confidence interval [CI]] : -26.05, -9.53, p=0.36).

1. The CHMP concluded that the results of Study 041 failed to confirm the efficacy of Translarna. These results were considered particularly important as the study included a patient population that was expected to be more sensitive to the drug.
2. The CHMP concluded that the two confirmatory phase 3 studies requested following the licensing of Translarna (020 and 041) failed to confirm the results of the original phase 2 study (007) that supported the marketing authorisation of the drug.
3. An important point of the CHMP review was the evaluation of data from a study comparing patient health outcomes from two patient registries. In this study, patients from the STRIDE registry were treated with Translarna for an average of 5.5 years in 2015 and 2022, while patients from the CINRG DNHS registry were not treated with Translarna and were followed between 2006 and 2016.
4. The CHMP noted that patients from the STRIDE registry lost their walking ability approximately 3.5 years later than patients from the CINRG DNHS registry.
5. However, the Committee was unable to draw conclusions from these data due to certain limitations in the methodology, including a high risk of bias in selection parameters and confounding due to the use of historical comparative data, lack of appropriate population matching, and limitations in data analysis.

The different study periods of the two registries could have introduced a calendar bias, as the overall standard of care has improved over time.

There were uncertainties about how differences in steroid use - the main standard of care for these patients - were accounted for in the analysis. The duration of steroid use was modelled in a stepwise manner, assuming that the effect remained the same after 12 months of use, thus not taking into account the long-term effect of steroids.

In addition, the two registries included different patient populations in terms of genetic background. The STRIDE registry was limited to patients with Duchenne muscular dystrophy caused by an uninterpretable mutation, whereas the CINRG DNHS registry included a broader population of patients with Duchenne muscular dystrophy. This may have caused a bias in favour of Translarna. These factors call into question the conditional exchangeability of the two groups, a prerequisite for assessing the correlated treatment effects.

Finally, there were methodological issues with the way the analyses were conducted by the company, including a non-negligible drop-out rate in STRIDE and an unknown drop-out rate in the CINRG DNHS cohort study.

Therefore, the CHMP could not conclude that the difference in time to loss of mobility observed between the two registries was a result of Translarna treatment.

In conclusion, the CHMP considered that the expected mechanism of action of Translarna involving increased dystrophin production via ribosomal readout of the termination codon has not been confirmed in the various pharmacodynamic studies.

More about the drug

Translarna was approved in the EU on 31 July 2014 for the treatment of patients with Duchenne muscular dystrophy whose disease is caused by an "uninterpretable mutation" in the dystrophin gene.

Duchenne muscular dystrophy is a severe and rare disease for which no approved treatments are available. It is a genetic disease that gradually causes weakness and loss of muscle function, leading to death due to respiratory muscle weakness or cardiomyopathy. Patients with this disease lack normal dystrophin, a protein found in muscles that helps protect muscles from injury as they contract and relax.

In patients with Duchenne muscular dystrophy caused by an untranslatable mutation, the production of normal dystrophin protein is prematurely disrupted, leading to a shorter dystrophin protein that does not function properly. The active substance in Translarna, ataluren, acts by allowing the protein production mechanism in the cells to bypass the genetic mutation, resulting in the cells producing the functional dystrophin protein.

More about the process

The results of study 041, which were submitted as part of a variation application involving a transition to a standard marketing authorisation, and the marketing authorisation renewal application for Translarna were assessed by the EMA's Committee for Medicinal Products for Human Use (CHMP), which is the committee responsible for questions on medicinal products for human use, and which adopted the initial opinion of the EMA on 14 September 2023.

The company marketing Translarna requested a review of the CHMP's opinion on the renewal application on 4 October 2023. Following the review, the CHMP issued its final opinion on 25 January 2024.

The EMA will now send the CHMP's final opinion on the renewal application to the European Commission, which will issue a final legally binding decision applicable in all EU Member States.

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