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Following re-examination, EMA’s human medicines committee (CHMP) has confirmed its initial reccomendation to not renew the conditional marketing authorisation for Translarna (ataluren). This medicine is used for treating patients with Duchenne muscular dystrophy whose disease is caused by a type of genetic defect called a ‘nonsense mutation’ in the dystrophin gene.

The initial recommendation followed the full re-evaluation of Translarna’s benefits and risks during the renewal of its marketing authorisation, which concluded that its effectiveness had not been confirmed.

As part of the re-examination requested by the company that markets Translarna, the CHMP re-assessed the data from a study carried out after authorisation as a specific obligation (study 041) and the results from a study comparing two patient registries.

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

In these patients, the distance they could walk in six minutes, after 18 months of treatment, decreased by about 82 metres in the Translarna group compared with 90 metres in the placebo (a dummy treatment) group; however, this difference was not statistically significant, meaning that it may be due to chance.

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

Patient registry data

An important part of the CHMP’s re-examination was the assessment of data from a study comparing the health outcomes of patients from two registries. In the study, patients from the STRIDE registry were treated with Translarna for an average of 5.5 years between 2015 and 2022, while patients from the CINRG DNHS registry were not treated with Translarna and were followed between 2006 and 2016.

Results indicated that patients in the STRIDE registry lost their ability to walk about 3.5 years later than those in the CINRG DNHS registry; however, due to several issues and uncertainties linked to the data from these registries, the CHMP could not conclude that the difference seen between the two registries was due to an effect from Translarna.

An important uncertainty relates to the fact that the STRIDE registry was set up more recently than the CINRG DNHS registry. This means that patients included in STRIDE were able to benefit from more recent advances in non-pharmacological treatments, for example physiotherapy, which would have provided them with additional benefits. There were also uncertainties about how differences in the use of steroids – the main standard of care 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 causing Duchenne muscular dystrophy, which could have biased the results in favour of those treated with Translarna. Because of all these limitations, the CHMP could not draw conclusions on the benefits of Translarna from the registry data.

During the re-examination, the CHMP consulted a group of experts in neurology as well as patient representatives. It also took into account several contributions received from families, individual physicians, patients and healthcare professional organisations.

The CHMP considered all the data available and the views of experts, patients and third parties in reaching its final decision. The committee also acknowledged the high unmet medical need for an effective treatment for patients with Duchenne muscular dystrophy. However, based on all the evidence accumulated since the medicine’s authorisation, the committee concluded that the effectiveness of Translarna has not been confirmed in patients with Duchenne muscular dystrophy caused by a nonsense mutation, including those who were expected to have a better response to treatment.

The CHMP considered that the data now available on the medicine are comprehensive and concluded that Translarna’s benefit-risk balance is negative. The committee therefore recommended not renewing the medicine’s marketing authorisation in the European Union (EU).

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

Information for patients and carers

A full review of all the data available on the benefits and risks of Translarna has concluded that the effectiveness of the medicine has not been confirmed in patients with nonsense mutation Duchenne muscular dystrophy.

The review considered results from studies, data from patient registries and the views of experts in neurology and patient representatives, as well as contributions from families, individual doctors, patients and healthcare professional organisations.

The review included the evaluation of a recent study involving patients with nonsense mutation Duchenne muscular dystrophy, which compared the effect of Translarna with that of placebo (a dummy treatment) after 18 months of treatment. The study failed to show that Translarna had a beneficial effect in those patients with a progressive decline in their ability to walk, although they were expected to benefit most from treatment with Translarna.

In addition, no conclusion on the benefits of Translarna could be drawn from a study based on information from patient registries due to several issues and uncertainties with the data.

Therefore, EMA concluded that the benefits of Translarna have not been confirmed and recommended that the marketing authorisation for Translarna should not be renewed. Once this recommendation is confirmed by the European Commission, the medicine will no longer be authorised in the EU.

If you or your child is receiving Translarna, you should speak to your doctor about this decision and what it means for you or your child’s treatment.

Information for healthcare professionals

A full review of all the data available on the benefits and risks of Translarna has concluded that the efficacy of the medicine has not been confirmed.

Consequently, EMA has recommended not renewing the marketing authorisation for Translarna. Once this recommendation is confirmed by the European Commission, the medicine will no longer be authorised in the EU.

Healthcare professionals should not start any new patients on Translarna.

For patients currently using Translarna, healthcare professionals should explain why there is a recommendation to not renew the medicine’s marketing authorisation and discuss their ongoing care.

Translarna received a conditional marketing authorisation in July 2014; the marketing authorisation was subject to annual renewals based on the results of additional studies imposed on the Marketing Authorisation Holder (MAH).

In 2016, the CHMP requested the MAH for Translarna to conduct a new study on the medicine’s efficacy, looking in particular at patients in the Ambulatory Decline 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, randomised (1:1), double-blind, placebo-controlled trial carried out in 360 patients aged 5 years or older with nonsense mutation Duchenne muscular dystrophy. A 72-week double-blind phase was followed by an open-label extension of another 72 weeks where patients who received placebo switched to Translarna.

• The primary endpoint was the change from baseline in the 6-minute walking distance (6MWD) at 72 weeks. In ADP patients (n=185), the mean change from baseline in 6MWD was ‑81.83 meters in the Translarna group versus -90.09 meters in the placebo group, a non-significant difference of 8.26 meters (95% confidence interval [CI]: -26.05; -9.53, p=0.36).
• The CHMP concluded that study 041 results failed to confirm Translarna’s efficacy. These results were considered particularly relevant since the study included a population of patients expected to be most sensitive to the medicine.
• The CHMP concluded that the two confirmatory phase 3 studies requested after Translarna’s authorisation (020 and 041) failed to confirm results of the initial phase 2 study (007) that supported the marketing authorisation of the medicine.
• One important focus of the CHMP review was the assessment of data from a study comparing the health outcomes of patients from two patient registries. In the study, patients from the STRIDE registry were treated with Translarna for an average of 5.5 years between 2015 and 2022, while patients from the CINRG DNHS registry were not treated with Translarna and were followed between 2006 and 2016.
• The CHMP noted that patients from the STRIDE registry lost their ability to walk about 3.5 years later than patients followed in the CINRG DNHS registry.
• However, the committee could not draw conclusions from these data due a number of methodological limitations, including a high risk of selection and confounding bias due to the use of historical controls, a lack of appropriate matching of populations, and limitations in the data analysis.

The different study periods between the registries could have introduced a calendar bias since general standard of care has improved over time.

Furthermore, there were uncertainties regarding the way the differences in the use of steroids – the main standard of care for these patients – were controlled in the analysis. The duration of steroid use was modelled in a stepwise manner, assuming that the effect remained the same beyond 12 months of use, and thus neglecting the long-term effect of steroids.

Additionally, the two registries included different patient populations in terms of genetic background. The STRIDE registry was restricted to patients with Duchenne muscular dystrophy caused by nonsense mutation whereas the CINRG DNHS registry included a broader population of patients with Duchenne muscular dystrophy. This may have caused bias in favour of Translarna. These factors challenge the conditional exchangeability of the two groups, a requisite for estimating causal treatment effects.

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

• Therefore, the CHMP could not conclude that the difference in terms of time to loss of ambulation seen between the 2 registries was an effect of Translarna treatment.
• Lastly, the CHMP considered that the expected mechanism of action of Translarna, which is the increased production of dystrophin via ribosomal readthrough of the stop codon, has not been confirmed in the various pharmacodynamic studies.

More about the medicine

Translarna was authorised in the EU on 31 July 2014 for the treatment of patients with Duchenne muscular dystrophy whose disease is caused by a ‘nonsense mutation’ in the dystrophin gene.

Duchenne muscular dystrophy is a serious and rare condition for which no authorised treatments are available. It is a genetic disease that causes a gradually 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 a nonsense mutation, production of a normal dystrophin protein is stopped prematurely, leading to a shortened dystrophin protein that does not function properly. The active substance in Translarna, ataluren, is expected to work by enabling the protein-making apparatus in cells to move past the genetic mutation, allowing the cells to produce a functional dystrophin protein.

More about the procedure

The results of study 041, which were submitted as part of a variation application requesting a switch to standard marketing authorisation, and the renewal of the marketing authorisation application for Translarna were assessed by EMA’s Committee for Medicinal Products for Human Use (CHMP), responsible for questions concerning medicines for human use, which adopted EMA’s initial opinion on 14 September 2023.

The company that markets Translarna asked for re-examination of the CHMP’s opinion on the renewal application on 4 October 2023. After conducting the re-examination, the CHMP issued its final opinion on 25 January 2024.

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

(DC/MS)