Type of information: Negative opinion for the granting of a Market Authorisation in the EU
Product name: Aplidin®
Therapeutic area: Cancer - Oncology
- depsipeptide derivative. Plitidepsin is an investigational anticancer agent of marine origin, originally obtained from the tunicate Aplidium albicans. It specifically binds to the eEF1A2 and targets the non-canonical role of this protein, resulting in tumor cell death via apoptosis (programmed death).
- Plitidepsin is currently in clinical development for hematological cancers, including a Phase III study in relapsed or refractory multiple myeloma, a Phase Ib trial in relapsed or refractory multiple myeloma as a triple combination of plitidepsin, bortezomib and dexamethasone, and a Phase II study in relapsed or refractory angioimmunoblastic T-cell lymphoma. A Phase III trial in relapsed or refractory multiple myeloma has been completed. Plitidepsin has received orphan drug designation by the EMA and the FDA.
Company: Pharmamar (Spain)
Disease: relapsed/refractory multiple myeloma
- • On March 22, 2018, the CHMP announced that it has re-examined the opinion, and confirmed the refusal of the marketing authorisation.
- • On January 3, 2018. PharmaMar has announced the initiation of the re-examination process by the European Medicines Agency (EMA) for Aplidin® (plitidepsin) for the indication of relapsed and refractory multiple myeloma. The re-examination procedure is handled by the EMA´s CHMP
and usually lasts around 4 months. After finalizing this process of re-examination, the European Commission will be in charge of emitting the final verdict on the Marketing Authorization Application (MAA) for Aplidin®, which could arrive around June or July, 2018.
- • On December 14, 2017, the Committee for Medicinal Products for Human Use (CHMP) adopted a negative opinion, recommending the refusal of the marketing authorisation for Aplidin®, intended for the treatment of multiple myeloma.
- The CHMP indicated that Pharma Mar 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.
- • On November 8, 2017, Pharma Mar announced that based on the preliminary feed-back from the Committee for Medicinal Products for Human Use (CHMP), the company expects an Opinion recommending against approval of the Marketing Authorization Application (MAA) for Aplidin® for the treatment of multiple myeloma submitted in October 2016. The company said that it is deeply surprised about this CHMP negative trend vote for the following reasons:
- - 1º The ADMYRE trial (pivotal Phase III), which was the basis of the MAA, obtained EMA Protocol Assistance.
- - 2º ADMYRE met its primary end-point (Progression Free Survival-PFS), being statistically significant (p=0.0054).
- - 3º Rapporteur Day 180 Joint CHMP and PRAC Response Assessment communicated on October 31st, 2017, after a one year assessment process, did not contain any major objection and it indicated that MAA could be approvable.
- - 4º Despite not having major objections in the referred Report, the company was required to participate in an oral explanation yesterday before the CHMP. The discussion was focused on certain statistical methodology applied to one of the secondary end-points of ADMYRE trial that had been previously accepted by the Rapporteurs.
- - 5º CHMP negative trend vote was verbally communicated to the company by the EMA.
- • On October 28, 2016, PharmaMar has announced that the European Medicines Agency (EMA) has accepted to assess the Marketing Authorization Application for Aplidin® (plitidepsin) in combination with dexamethasone for the treatment of relapsed/refractory multiple myeloma. PharmaMar submitted this application for the antitumor drug of marine origin, Aplidin®, in combination with dexamethasone given the positive results obtained from the ADMYRE study. This randomized, Phase III study has evaluated the efficacy and safety of Aplidin® with dexamethasone versus dexamethasone alone in patients with relapsed/refractory multiple myeloma after at least three, but no more than six, prior therapeutic regimens. The results of the ADMYRE study showed a statistically significant 35% reduction in the risk of progression or death over the comparator. The study met its primary endpoint.
Submission of marketing authorization application USA :
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
Favourable opinion UE:
Favourable opinion USA:
Orphan status USA: 2004-09-30
Orphan status UE: 2004-11-16
Pediatric exclusivit _USA:
Pediatric exclusivity UE: