EMA Recommends Refusal of the Marketing Authorisation for Plitidepsin

It was intended for the treatment of multiple myeloma in combination with dexamethasone

On 14 December 2017, the European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) adopted a negative opinion, recommending the refusal of the marketing authorisation for the medicinal product plitidepsin (Aplidin), intended for the treatment of multiple myeloma. 

The company that applied for authorisation is PharmaMar. It may request a re-examination of the opinion within 15 days of receipt of notification of this negative opinion. 

Aplidin is a cancer medicine that contains the active substance plitidepsin. It was to be available as powder and solvent to be made up into a solution for infusion into a vein. 

Aplidin was expected to be used to treat adults with multiple myeloma who have received at least three prior cancer treatments (including bortezomib, and either lenalidomide or thalidomide). Aplidin was to be used in combination with dexamethasone. 

Aplidin was designated an ‘orphan medicine’ (a medicine to be used in rare diseases) on 16 November 2004 for the treatment of multiple myeloma. 

The active substance in Aplidin, plitidepsin, blocks a protein called eEF1A2. eEF1A2 is involved in breaking down wrongly folded proteins, which are toxic to myeloma cells. By blocking eEF1A2, plitidepsin causes the accumulation of these proteins in multiple myeloma cells, damaging them and ultimately leading to their death. 

The company presented the results of one main study involving 255 patients with multiple myeloma who had been treated with at least 3 other cancer medicines. In this study, Aplidin plus dexamethasone was compared with dexamethasone on its own, and the main measure of effectiveness was progression-free survival. 

The CHMP was concerned that the data from the main study showed only a modest increase of around one month in the time patients given Aplidin lived without their disease getting worse, compared with those treated with dexamethasone alone. 

In addition, improvement in overall survival was not sufficiently demonstrated. 

Regarding safety, severe side effects were reported more frequently with the combination of Aplidin and dexamethasone than with dexamethasone alone. 

Based on the above, the CHMP was of the opinion that the benefits of Aplidin did not outweigh its risks and recommended that it be refused marketing authorisation.