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- Ελληνικά
The EMA's Committee for Medicinal Products for Human Use (CHMP) has recommended not renewing the marketing authorisation for Translarna (ataluren), a medicine for the treatment of patients with Duchenne muscular dystrophy. The disease is caused by a specific genetic abnormality called an "uninterpretable mutation" in the dystrophin gene and who are ambulatory.
The recommendation follows a full reassessment of the benefits and risks of the drug at the time of its marketing authorisation renewal, including the results of a new study that failed to confirm the efficacy of Translarna.
Because Translarna was intended to address an unmet medical need for a serious disease, the drug received a conditional marketing authorisation in July 2014. This type of marketing authorisation allows a drug to be authorised on the basis of less complete (full) data than is normally required, and where the benefits of its earlier availability outweigh the risks associated with its use pending further data. Conditionally authorised medicines are subject to specific post-marketing obligations aimed at generating complete data.
In 2016, at the time of the renewal of Translarna's marketing authorisation, the CHMP assessed new data from a study requested as part of the specific obligations, and considered that there were still uncertainties about the beneficial effects of the medicine. Therefore, the Committee asked the company to conduct a further study to assess efficacy primarily in a subgroup of patients with a progressive decline in walking ability, as these were expected to benefit more from Translarna treatment than the wider patient population.
In this subpopulation of patients, the study showed no statistically significant difference between Translarna and placebo (placebo) in terms of the distance patients could walk in 6 minutes after This means that the observed difference may be due to chance. The results in the wider patient population failed to confirm the effect observed in the original study supporting the marketing authorisation.
In addition, as part of the current marketing authorisation renewal, the CHMP re-evaluated all available data on the benefits and risks of Translarna. This included a patient registry data analysis that compared the health outcomes of patients treated with Translarna for an average of 5.5 years with those of patients who had not received Translarna. The CHMP noted the results with Translarna in terms of delayed loss of walking ability, however, the Committee was unable to draw conclusions from these data due to methodological issues and uncertainty associated with the indirect comparison. In addition, there was no clear benefit of Translarna for other endpoints evaluated by the CHMP. In re-evaluating all available data, the Committee considered that the results of the two post-licensing studies, which were more reliable than the patient registry data, did not confirm the beneficial effect of Translarna.
During this re-evaluation, the CHMP consulted a group of experts in neurology as well as patient representatives and took their views into account in its final recommendation.
The CHMP considered that the data now available for Translarna are complete. Based on the totality of the evidence, the Committee concluded that the efficacy of Translarna has not been confirmed in patients with Duchenne muscular dystrophy with an uninterpretable mutation , including those who were expected to have a better response to treatment. The Commission concluded that the benefit-risk balance of Translarna is negative and therefore recommended not to renew its marketing authorisation in the EU.
The CHMP opinion will now be forwarded to the European Commission, which will adopt a final legally binding decision applicable in all EU Member States.
Information for patients and caregivers
- A recent study failed to confirm that Translarna has a benefit in patients with Duchenne muscular dystrophy with an uninterpretable mutation, including patients with progressive decline in walking ability who were expected to benefit most from Translarna treatment.
- These results have been confirmed by a full evaluation of all the data now available on the benefits and risks of the drug. The assessment took into account the results of studies, data from a patient registry and the views of expert neurologists and patient representatives.
- As a result, the EMA has recommended that the marketing authorisation for Translarna should not be renewed. This means that the medicine will no longer be available in the EU.
- If you or your child is taking Translarna, you should talk to your doctor about how to stop treatment.
Information for healthcare professionals
- A comprehensive review of all the data now available on the benefits and risks of Translarna concluded that the effectiveness of the medicine has not been confirmed. Therefore, the conditional marketing authorisation for Translarna will not be renewed and the medicine will no longer be available in the EU.
- Healthcare professionals should not initiate treatment with Translarna in new patients.
- In patients currently using Translarna, healthcare professionals should explain why the medicine is being withdrawn from the market and discuss appropriate supportive therapies.
- Translarna received 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).
- In 2016, the CHMP requested the Translarna CRA to conduct a new study on the efficacy of the drug, looking specifically at patients in ambulatory declining 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 7 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 switched to Translarna.
- 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).
- For the whole population (n=359), the mean change in 6MWD was -53.01 meters in the Translarna group versus -67.43 meters in the placebo group (95% CI: 1.83, 27.01, pnominal=0.025).
- Key secondary endpoints were the mean change in the composite timed functional tests (TFT) (time to traverse 10 meters by running/walking + time to climb 4 stairs + time to descend 4 stairs) and the change in the North Star ambulatory assessment (NSAA). In the ADP subgroup, the difference for the composite TFT score was -1.04 seconds (95% CI -0.204; 5.204, pnominal=0.09) and the difference for the total NSAA score was 0.9 points (95% CI -0.22, 2.02, pnominal=0.13).
- 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.
- The CHMP also conducted a full reassessment of the benefits and risks of Translarna as part of the application for the renewal of the marketing authorisation of the medicinal product. This review included data from studies 007, 020 and 041, as well as data from the STRIDE registry study (025o).
- CHMP reviewed registry-based study data that compared the outcomes of patients treated with Translarna in the STRIDE registry with natural history data. The CHMP noted results with Translarna in terms of delay in gait loss, however, the Committee was unable to draw conclusions from these data due to methodological issues and uncertainty associated with the indirect comparison. In addition, there was no clear benefit of Translarna for other endpoints evaluated by the CHMP.
- The CHMP concluded that the two confirmatory Phase 3 studies (020 and 041) that were requested following the licensure of Translarna failed to confirm the results of the initial Phase 2 study (007) that supported the marketing authorization of the drug.
More about the medicine
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 "untranslatable mutation" in the dystrophin gene.
Duchenne muscular dystrophy is a serious and rare disease for which no approved treatments are available. It is a genetic disease that gradually causes weakness and loss of muscle function. 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 procedures
The results of study 041, which were submitted as part of a variation application requesting a transition to a standard marketing authorisation, and the renewal of the marketing authorisation application for Translarna were assessed by the EMA's Committee for Medicinal Products for Human Use (CHMP), which is the committee responsible for questions about medicines for human use.
The EMA will now send the CHMP's opinions on the variation and renewal application to the European Commission, which will issue a final legally binding decision applicable in all EU Member States.
The company marketing Translarna may request a review within 15 days of receiving the opinions.
Contents of this article including associated images are owned by PIO
Views & opinions expressed are those of the author and/or PIO
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