Plitidepsin (Aplidin®), a new medicine for the treatment of relapsed and refractory myeloma, has received a second negative recommendation from the Committee for Medicinal Products for Human Use (CHMP). This decision means that plitidepsin is very unlikely to be made available to patients across Europe.

This upholds a previous negative recommendation from the CHMP, which was reviewed following an appeal by the pharmaceutical company Pharma Mar.

The CHMP is the scientific advisory committee of the European Medicines Agency (EMA), the European licensing body. It provides advice to the European Commission on new medicines going through the licensing process and whether they should be granted marketing authorisation across Europe. Their assessment is based on whether a drug is safe and effective enough to be used in patients.

Once the CHMP issues a negative opinion, the European Commission has 60 days to reach a final decision on a new medicine.

For a new medicine to be approved, members of the CHMP need to be convinced of the survival benefit of the medicine and that the drug is unlikely to impact negatively on quality of life.

The Phase III clinical trial looking at plitidepsin (known as the ADMYRE trial) found an overall survival benefit of plitidepsin and dexamethasone compared to dexamethasone alone. However, the CHMP committee did not think it represented a significant survival benefit for patients – particularly, as there were more severe side-effects reported by patients in the plitidepsin arm. Despite seeking evidence from the company, doctors and patients, the CHMP remained unconvinced that the medicine would add value to the myeloma pathway to patients.

Plitidepsin is an investigational drug for the treatment of relapse and refractory myeloma. It is a first-in-class drug specifically targeting eEF1A2 in myeloma cells and is of marine origin. The Phase III licensing trial, known as ADMYRE, looked at plitidepsin in combination with dexamethasone vs dexamethasone in relapsed and/or refractory myeloma. Data recently published at the 2017 American Society of Haematologists (ASH) Annual Meeting highlighted that plitidepsin improves progression free and overall survival in myeloma patients.

Ananda Plate, Myeloma Patients Europe (MPE) CEO, said: “This is a disappointing decision for myeloma patients. However, following an extensive review by the CHMP, they remain unconvinced that survival benefits of the medicine outweigh the risks. Whilst MPE considers there to be a place in the myeloma pathway for plitidepsin, we respect the decision of the CHMP and commend their involvement of patients in the appeal process.

“We hope PharmaMar continues to explore the benefits of plitidepsin in combination with other medicines and in other stages of the disease given the promising early results.”

What are the next steps for plitidepsin?

There are no other avenues open to PharmaMar to get approval of plitidepsin and dexamethasone in Europe. This is because it has received a negative opinion on appeal. There are also no ongoing trials looking at plitidepsin in combination with dexamethasone, so there is no further data to add to the case made to the EMA.

MPE said that plitidepsin has shown good affect in combination with other myeloma drugs. For example, an early phase trial highlighted a positive effect when given in combination with bortezomib (Velcade®) and dexamethasone. The charity added that now the EMA has issued a negative recommendation on plitidepsin, there is nothing stopping PharmaMar exploring the safety and efficacy of plitidepsin different combinations and stages of the disease. 

Myeloma Patients Europe sent a letter to the CHMP last December saying that: "Data from the Phase I-III clinical trial and the experience of haematologists show that patients respond well to plitidepsin in combination with dexamethasone. Plitidepsin has been shown to develop responses in patients who have been pre-treated with a range of existing treatments. The intravenous administration method is acceptable. We sincerely hope that the CHMP is willing to guarantee plitidepsin a positive recommendation, only by ensuring the approval of new and promising treatments for myeloma patients across Europe, we can maintain survival rates in myeloma on an upward trajectory."

Questions regarding the decision were recently raised in the European Parliament.