[PIO] European Medicines Agency recommends not renewing the marketing authorisation of Translarna for Duchenne muscular dystrophy

The EMA's Committee for Medicinal Products for Human Use (CHMP) recommended not renewing the conditional marketing authorisation for Translarna (ataluren), a medicine for the treatment of patients with Duchenne muscular dystrophy. Translarna is used in patients whose disease is caused by a specific genetic abnormality called an 'uninterpretable mutation' in the dystrophin gene and who are ambulatory.

The CHMP issued an initial negative opinion on the renewal of the marketing authorization for Translarna in September 2023, which was confirmed in January 2024 following a review requested by the company marketing the drug. Both rounds of evaluation concluded that Translarna's effectiveness had not been confirmed, following a reassessment of the drug's benefits and risks.

In May 2024, the European Commission asked the CHMP to further consider whether the available data on Translarna were sufficiently comprehensive to reach a conclusion on the benefit-risk balance of the medicine, and whether additional real-world data brought before the Commission during the decision-making process (including three recent publications) might influence the CHMP's conclusion. In addition, following the appeal judgment of the Court of Justice of the European Union (CJEU) on 14 March 2024 in case C-291/22 P, the EMA decided to convene a new Scientific Advisory Group on Neurology (SAG) for Translarna. Consequently, the assessment was reopened at this stage of the original renewal process.

In relation to the European Commission's request, the CHMP reviewed recent publications, one of which analysed the combined data from three clinical trials with Translarna already evaluated by the CHMP (meta-analysis)1, a second, which assessed the level of consensus among 12 clinicians on the use of Translarna2, and a third, which described an initiative to collect data on rare neuromuscular disorders. The Committee also reviewed additional information received from parents or caregivers of boys with Duchenne muscular dystrophy, patient organizations, health professional organizations, and treating physicians, as well as reports from individual patients treated with Translarna.

The CHMP carefully reviewed this information and concluded that it did not provide sufficient evidence to confirm the efficacy of the drug. In particular, the Committee noted that the methods used to conduct the meta-analysis had several shortcomings and its results could not override the negative findings of the individual studies included in the meta-analysis. The other two publications did not provide new data on the efficacy of the drug. Therefore, the Committee concluded that these additional data do not affect its previous conclusion on the benefit-risk balance of Translarna.

For this opinion, the CHMP also considered the advice of the new Scientific Advisory Group on Neurology. This group was composed of experts, including neurologists and individuals with lived experience of Duchenne muscular dystrophy, who provided their views on specific questions raised by the CHMP. During the evaluation, individuals with lived experience of Duchenne muscular dystrophy also presented their views to the CHMP during its plenary meetings.

In reaching its opinion, the CHMP took into account all the above information, as well as all the data collected on the medicinal product since its authorisation in 2014. This data includes data from the main study that supported the licensing and from the two post-marketing studies requested by the CHMP to confirm the efficacy of the medicine.

The two studies conducted after the licensing of the medicine failed to confirm the benefits of the medicine, including its efficacy in patients with progressive decline in walking ability, who were expected to derive greater benefit from treatment with Translarna. The CHMP also reviewed data from a study comparing two patient registries. However, due to differences between these two registries, as well as uncertainty about their indirect comparison, it was not possible to draw a firm conclusion about the efficacy of the medicine in real world data, and the Committee considered that this study could not compensate for the findings of the failed post-clinical studies. After a thorough evaluation of all the data, the Committee concluded that the efficacy of Translarna has not been confirmed in patients with Duchenne muscular dystrophy, whose disease is caused by an "uninterpretable mutation."

The Committee acknowledged the high unmet medical need for an effective treatment for patients with this rare disease. It considered, however, that the data now available for Translarna are comprehensive and concluded that the benefit-risk ratio for the drug is negative. It therefore recommended not renewing the marketing authorisation for the medicine in the EU.

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

Information for patients and caregivers

1. At the request of the European Commission, the EMA's CHMP has reviewed the additional data in relation to the renewal of the marketing authorisation for Translarna, together with all available data on the medicine.
2. This additional data included the results of three (3) recent publications, information received from parents or carers, patient organisations, health professional organisations and treating physicians, as well as reports of individual patients treated with Translarna.1,2,3
3. In addition, the CHMP considered the views of a scientific advisory group on neurology, composed of experts, including neurologists and people with lived experience of Duchenne muscular dystrophy. This group provided answers to specific questions posed by the CHMP.
4. The CHMP carefully considered all this information, as well as the data collected on Translarna since its marketing authorisation in 2014. The Committee recognised the high unmet medical need for an effective treatment for this rare disease. However, taking into account the available data, the Commission concluded that the efficacy of Translarna has not been confirmed in patients with Duchenne muscular dystrophy, whose disease is caused by an "uninterpretable mutation".
5. Therefore, the Commission recommends not renewing the marketing authorisation of Translarna in the EU
6. This means that if this recommendation is confirmed by the European Commission, the medicine will no longer be authorised in the EU.
7. Until then the marketing authorisation for Translarna remains valid. If you have any questions, talk to your doctor or contact your national competent authority.

Information for healthcare professionals

1. At the request of the European Commission, the EMA CHMP has reviewed additional data in relation to the renewal of the marketing authorisation for Translarna, together with all available data on the medicine.
2. These additional data included:

-three recent publications: a meta-analysis of three (3) clinical trials with Translarna (Study 007, Study 020 and Study 041), an article on a newly established registry compiling data on rare neuromuscular disorders, and a study on the level of consensus among 12 clinicians on the use of Translarna.

- additional information from parents or caregivers, patient organisations, health professional organisations and treating physicians

- reports with subject level data on boys treated with Translarna

1. The CHMP carefully reviewed all this information and concluded that it did not provide sufficient evidence to confirm the efficacy of the medicine.
2. The Committee noted in particular that the meta-analysis, which had already been assessed and discussed by the CHMP, has several methodological shortcomings, therefore its results cannot override the negative findings of the individual studies. The publication on rare neuromuscular disorders did not discuss the efficacy of Translarna, while the publication on the level of consensus among neurologists did not provide new data on the efficacy of the drug
3. In addition, the CHMP took into account the views of a scientific advisory group on neurology composed of experts, including neurologists and individuals with lived experience of Duchenne muscular dystrophy. This group provided answers to specific questions posed by the CHMP.
4. In its opinion, the CHMP took into account all this information and the data collected on Translarna from its marketing authorisation.
5. The Committee recognised the high unmet medical need for effective treatment for patients with this rare disease. However, taking into account all available data, it concluded that the efficacy of Translarna has not been confirmed in patients with Duchenne muscular dystrophy, whose disease is caused by an 'uninterpretable mutation'.
6. Therefore, the Commission has recommended that Translarna's marketing authorisation in the EU should not be renewed
7. This means that if this recommendation is confirmed by the European Commission, the drug will no longer be authorised in the EU.
8. Until then, the marketing authorisation for Translarna remains valid in the EU. If you have any questions, you can contact the national competent authority.

More about the medicine

Translarna received conditional marketing authorisation in the EU on 31 July 2014 for the treatment of patients with Duchenne muscular dystrophy, whose disease is caused by an "untranslatable mutation" in the dystrophin gene.

Duchenne muscular dystrophy is a serious and rare disease for which no approved treatments other than Translarna are available. It is a genetic disease that causes progressively increasing 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, is expected to act by allowing the protein production mechanism in the cells to bypass the genetic mutation, resulting in the cells producing the functional dystrophin protein. More information about Translarna is available on the drug page on the EMA website.

More about the process

Translarna's marketing authorisation renewal application was 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 formulated 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, which was forwarded to the European Commission for a final, legally binding, decision.

On 24 May 2024, the European Commission asked the Commission to further consider whether the available data on Translarna were sufficiently comprehensive to reach a conclusion on the benefit-risk profile of the medicinal product and whether additional real world data, which were brought before the Commission during the decision-making process, could influence the CHMP's conclusion on the benefit/risk profile of Translarna.

In addition, following the appeal judgment of the Court of Justice of the European Union on 14 March 2024 in Case C-291/22 P, the EMA decided to convene a new Scientific Advisory Group on Neurology (SAG-N) for Translarna. Consequently, the assessment was reopened at this stage of the original renewal procedure.

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

The company marketing Translarna can request a review within 15 days of receiving the opinion.

(D/CG)
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