Type of information: Negative opinion for the granting of a Market Authorisation in the EU
Product name: Masipro®
Therapeutic area: Rare diseases - Hematological diseases
- kinase inhibitor/tyrosine kinase inhibitor. Masitinib is a tyrosine kinase inhibitor that targets mast cells, important cells for immunity, as well as a limited number of kinases that play key roles in various cancers.
Company: AB Science (France)
Disease: severe systemic mastocytosis unresponsive to optimal symptomatic treatment
- • On September 14, 2017, the Committee for Medicinal Products for Human Use (CHMP) confirmed the refusal of the marketing authorisation.The CHMP was concerned about the reliability of the study results because a routine GCP (good clinical practice) inspection at the study sites revealed serious failings in the way the study had been conducted. In addition, major changes were made to the study design while the study was ongoing, which made the results difficult to interpret. Finally, data on the safety of the medicine were limited and there were concerns regarding the medicine’s side effects, including neutropenia and harmful effects on the skin and liver, which were of relevance particularly because the medicine was to be used long term. Therefore, the CHMP was of the opinion that the benefits of Masipro® did not outweigh its risks and recommended that it be refused marketing authorisation. The CHMP refusal was confirmed after re-examination.
.• On June 23, 2017, the Committee for Medicinal Products for Human Use (CHMP) announced that AB Science has requested a re-examination of the CHMP’s May 2017 opinion. Upon receipt of the grounds of the request, the CHMP will re-examine its opinion and issue a final recommendation.
- • On 18 May 2017, the Committee for Medicinal Products for Human Use (CHMP) adopted a negative opinion, recommending the refusal of the marketing authorisation for Masipro® intended for the treatment of systemic mastocytosis. AB Science presented data from a main study involving 135 patients with systemic mastocytosis who
had severe symptoms including at least one of the following: itching, hot flushes, depression and weakness. In the study, Masipro® was compared with placebo. The main measure
of effectiveness was based on improvements in any of the four symptoms mentioned above after 24 weeks of treatment.
The CHMP was concerned about the reliability of the study results because a routine GCP inspection at the study sites revealed serious failings in the way the study had been
conducted. In addition, major changes were made to the study design while the study was ongoing, which made the results difficult to interpret. Finally, data on the safety of the medicine were limited and there were concerns regarding the medicine’s side effects, including neutropenia (low levels of
white blood cells) and harmful effects on the skin and liver, which were of relevance particularly because the medicine was to be used long term. Therefore, at that point in time, the CHMP was of the opinion that the benefits of Masipro® did not outweigh its risks and recommended that it be refused marketing authorisation. AB Science will ask for a re-examination based on the following grounds.
GCP Findings: The deficiencies concerning inspection findings have been corrected by AB Science and do not modify the
study conclusions, both in terms of efficacy and safety assessment. In the re-examination procedure, an independent audit of such corrective actions will be provided.
Changes in the Study Design: As it was detailed on the publication of the phase 3 results in The Lancet, protocol amendments were implemented between 3.5 years and 2 years prior to database unmasking, in order to increase benefit risk balance of the study. The main changes were the following:
1) Restrict the study to the patient population with greatest medical need, i.e. only patients with smouldering or indolent systemic mastocytosis with severe baseline symptoms of mast cell mediator release;
2) The threshold for positive treatment response was increased from 50% to 75%, thereby enhancing the clinical relevance of improvement;
3) Change in statistical methodology for the study primary analysis, from patient response at week 24 to overall response during week 8 to week 24 based on patient x handicap.
The first two changes were reviewed by the CHMP during a scientific advice procedure and were deemed acceptable and in principle desirable.
The third change was not discussed through scientific advice but was in line with EMA guideline on clinical trials in small populations (CHMP/EWP/83561/2005). In the re-examination procedure, AB Science will highlight that the original analysis on 75% patient response at week 24 remained positive considering the original sample size (25.8% % with masitinib versus 13.1% with placebo, p-value=0.0238), proving that this third modification did not modify the study conclusion.
Benefit-risk assessment and SAG: The size of the safety database is acceptable for orphan disease. In the re-examination procedure, AB Science will provide the CHMP with updated 2017 data from other studies, demonstrating that the longterm safety profile is acceptable.
The risk of masitinib has to be reassessed in light of the benefit, after correction of the GCP findings.
The benefit risk balance has been assessed as positive by many key opinion leaders of the scientific community based on results from this single pivotal study.
- A recent publication in The Lancet of the result of the phase 3 of masitinib in mastocytosis concluded that masitinib is an effective and well tolerated agent for the treatment of severely symptomatic indolent or smouldering systemic mastocytosis.
No Scientific Advisory Group (SAG) was convened during the initial assessment phase. In the reexamination procedure, AB Science will ask for SAG in order to provide an additional opinion on the assessment of the benefit-risk balance and on the urgency for a treatment for patients with smouldering or
indolent systemic severe mastocytosis unresponsive to optimal symptomatic treatments.
Of note, the CHMP did not raise any objection, major or minor, concerning the manufacturing of masitinib, meaning that all objections previously raised by the CHMP in its previous assessments were successfully resolved by AB Science.
The re-examination should lead the CHMP to deliver a second opinion in Q4 2017.
- • On May 2, 2016, AB Science announced the filing for registration to European Medicines Agency (EMA) for masitinib in the treatment of adult patient with severe systemic mastocytosis unresponsive to optimal symptomatic treatment, with date of review process starting on 26 April 2016. Masitinib is the first treatment to be evaluated in this indication. Top-line results from this phase 3 were previously announced on 30 November 2015. Filing to EMA for the Marketing Authorization of masitinib in severe systemic mastocytosis was done on the basis of results from a phase III study showing that masitinib was superior to optimal symptomatic treatment on the primary efficacy analysis as well as secondary efficacy analyses.
This phase 3 randomized study compared masitinib plus optimal symptomatic treatment versus placebo plus optimal symptomatic treatment in adult patients with severe systemic mastocytosis, with or without D816V mutation of c-Kit. Study results showed that masitinib administered at 6 mg/kg/day was superior to the comparator, as measured by the cumulative 75% response rate until week 24 on the handicaps of pruritus or flushes or depression or fatigue (4H75% response). The 4H75% response was 18.7% for the masitinib treatment-arm versus 7.4% for the placebo treatment-arm (p=0.0076, Odd ratio=3.63) in the mITT population (primary analysis). According to protocol, the primary efficacy analysis was performed in the modified intent-to-treat population (mITT), yet the study was also successful on the sensitivity analysis performed in the intent-to-treat population (18.7% versus 7.6%, respectively, 0.0102, Odd ratio= 3.28).
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:
Orphan status UE: 2004-11-16
Pediatric exclusivit _USA:
Pediatric exclusivity UE: