Date: 2015-12-07
Type of information: Results
phase: 3
Announcement: results
Company: AB Science (France)
Product: masitinib
Action
mechanism: 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.
Disease: systemic severe mastocytosis
Therapeutic area: Rare diseases - Immunological diseases
Country:
Trial
details: The phase 3 study was designed to evaluate masitinib efficacy and safety in severe systemic mastocytosis patients, with or without D816V mutation of c-Kit. The primary objective of the phase 3 study was to detect a statistically significant difference between masitinib (plus concomitant symptomatic treatments) and placebo (plus concomitant symptomatic treatments) in cumulative response on four severe symptoms, referred to also as handicaps.
Patients enrolled in the phase 3 study had between one and four of the following severe mastocytosisrelated symptoms at baseline:
Pruritus score ≥ 9
Number of flushes per week ≥ 8
Depression measured by the Hamilton rating scale (HAMD-17) score ≥ 19
Asthenia measured by the Fatigue Impact Scale total score ≥75.
The study enrolled 135 patients with severe systemic mastocytosis. Primary analysis (referred to as “4H75% response”) was based on the comparison between masitinib and placebo in the number of actual responses between week 8 and week 24 divided by the total number of possible responses over the same treatment period. At each patient evaluation between weeks 8 and 24, each of the above four severe symptoms was evaluated. An improvement ≥ 75% with respect to baseline in one symptom represented one positive treatment response.
Secondary analyses were based on the following endpoints:
Cumulative 75%-response rate for pruritus (1H75% response)
Cumulative 75% response rate on the handicaps of pruritus or flushes (2H75% response)
Cumulative 75% response rate on the handicaps of pruritus or flushes or depression (3H75% response)
Mean change in tryptase level relative to baseline at week 24, in patients with baseline level ≥20 µg/L.
Latest
news: * On December 7, 2015, AB Science announced results from phase 3 study of masitinib in the treatment of adult patient with severe systemic mastocytosis unresponsive to optimal symptomatic treatment. The results showed that masitinib 6 mg/kg/day was superior to optimal symptomatic treatment on the primary efficacy analysis as well as secondary efficacy analyses. No new safety signals for masitinib were observed in this phase 3 study. * On November 30, 2015, AB Science announced that a phase 3 study evaluating masitinib in the treatment of adult patient with severe systemic mastocytosis has met its primary objective well as all its secondary objectives. * On October 6, 2015, AB Science announced the communication of new phase 2 data in systemic severe mastocytosis aimed at simulating the targeted phase 3 study population and response criteria. Based on pooled data taken from the two phase 2 studies Pooled phase 2 studies simulation of phase 3 population and response criteria: Prior to conducting this phase 3 trial, AB Science completed two phase 2 studies, one study included systemic mastocytosis patients expressing the D816V mutation of c-Kit, and another study included systemic mastocytosis patients without the D816V mutation of c-Kit in at least one organ. These two studies comprised a total of 46 patients, including 28 diagnosed with a severe systemic mastocytosis which consists of the population of the phase 3 efficacy analysis. Placebo effect and expected difference with masitinib: The following conclusions can be drawn from this new data analysis aimed at simulating the targeted phase 3 study population and response criteria: * On November 12, 2013, AB Science announced that the read-out of the phase 3 study in mastosytosis is expected by end of 2014. Phase 3 study was accelerated and expanded recently outside of Europe and the USA, in Russia, India and Latin America. *On November 11, 2013, AB Science announced that the independent Data and Safety Monitoring Board (DSMB) created as part of the company pivotal clinical study evaluating masitinib in the treatment of mastocytosis has recommended continuation of the study, based upon completion of the futility analysis included in the study protocol. The analysis was performed with two-third of the target population to recruit. The futility analysis was performed by the independent Data and Safety Monitoring Board. It consisted in testing the possibility of masitinib to demonstrate superiority over placebo on the primary analysis set in the protocol, based on the EMA guideline on clinical trials in small populations (CHMP/EWP/83561/2005).
The 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=0.0100, Odd ratio=3.63) in the mITT population (primary analysis). Sensitivity analysis according to the per protocol (PP) population, i.e. the sets of patients who participated in the study as intended, gave a 4H75% response rate of 20.1 % versus 7.4%, respectively (p=0.0146, Odd ratio=3.88).
Success in the primary analysis was supported by positive outcomes in all secondary analyses. - The cumulative 75% response rate until week 24 on the handicaps of pruritus or flushes or depression (3H75% response) was 24.7% versus 9.8% for the masitinib and placebo treatment-arms, respectively, (p=0.0071, Odd ratio=3.06) in the mITT population. In the per protocol population this response ratewas 26.5 % versus 9.8%, respectively (p=0.0038, Odd ratio=3.33).
- The cumulative 75% response rate until week 24 on the handicaps of pruritus or flushes (2H75% response) was 27.2% versus 10.7% for the masitinib and placebo treatment-arms, respectively (p=0.0380, Odd ratio=2.63) in the mITT population. In the per protocol population this response rate was 29.5% versus 10.7%, respectively (p=0.0220, Odd ratio=2.89).
- The cumulative 75% response rate until week 24 on the handicap of pruritus was 22.0% versus 7.3% for the masitinib and placebo treatment-arms, respectively (p=0.0322, Odd ratio=3.13) in the mITT population. In the per protocol population this response rate was24.7 % versus 7.3%, respectively (p=0.0146, Odd ratio=3.69).
When looking at other individual handicaps of flush, Hamilton, and FIS (Fatigue Impact Scale), a consistent superiority was observed for all handicaps, showing that masitinib can reduce each of these symptoms.
- The cumulative 75% response rate until week 24 on the handicap of flush was 39.9% versus 19.0% for the masitinib and placebo treatment-arms, respectively, (Odd ratio=3.03) in the mITT population.
- The cumulative 75% response rate until week 24 on the handicap of depression was 18.6% versus 7.6% for the masitinib and placebo treatment-arms, respectively, (Odd ratio=2.71) in the mITT population.
- The cumulative 75% response rate until week 24 on the handicap of fatigue was 7.7% versus 3.2% for the masitinib and placebo treatment-arms, respectively, (Odd ratio=4.84) in the mITT population.
Although the percentage difference with placebo was lower on fatigue than other handicaps, the difference was still statistically significant (p<0.05). It is possible that this relatively small difference between masitinib and placebo on fatigue may be due to the choice of the measure using the Fatigue Impact Scale (FIS), as it was published after the start of the study that FIS not sensitive enough to detect change over time (meaning should be used with caution to assess a drug supposed to improve fatigue symptoms). This may also account for the superior response rate observed for the 3H75% criterion when compared with the 4H75% criterion.
The positive results on patient reported outcomes on the symptoms associated with the disease were also supported with a reduction in the tryptase, which is an objective biological marker of mast cell burden and activity. Indeed, the mean change in tryptase level relative to baseline was minus 18.0% with masitinib versus +2.2% (p=0.0001) in the mITT population and minus 20.0% with masitinib versus +2.2% (p<0.0001) in the per protocol population.
The effect of masitinib was further substantiated by an observed sustainability in clinical benefit, as evidence by the long-term follow-up data. After the 6-month protocol period, patients were authorized to enter into the study’s extension phase. Considering the week 0 to week 96 period (2 years):
- The 4H75% response was 17.2% versus 7.1% for the masitinib and placebo treatment-arms, respectively (p=0.0102, Odd ratio=3.37) in the mITT population and 18.7 % with masitinib versus 7.1% (p=0.0062, Odd ratio=3.66) in the per protocol population.
- The 3H75% response was 22.1% versus 8.6% for the masitinib and placebo treatment-arms, respectively (p=0.0030, Odd ratio=3.10) in the mITT population and 24.1% with masitinib versus 8.6% (p=0.0013, Odd ratio=3.42) in the per protocol population. There was no new safety finding with masitinib through this study.
A patent was filed before disclosure of the detailed results in order to claim a potential 20 year exclusivity period for masitinib in the label of patients with severe systemic mastocytosis.
in mastocytosis, results are indicative of the outcome expected for the on-going phase 3 study. Findings from this simulation are to be presented at the next congress of the European Competence Network on Mastocytosis (ECNM) (October 8-10 2015 in Munich, Germany) and also at the International European Mast Cell and Basophil Research Network (EMBRN) meeting (October 21-23 2015 in Marseille, France).
AB Science is near to complete the first phase 3 clinical trial ever in mastocytosis. The design is to evaluate masitinib efficacy in severe systemic mastocytosis patients, with or without D816V mutation of c-Kit. The objective (primary endpoint) of the phase 3 study is to detect a statistically significant difference between masitinib (plus concomitant symptomatic treatments) and placebo (plus concomitant symptomatic treatments) in cumulative response on four severe symptoms, named handicaps. Patients enrolled in the phase 3 study can have between one and four of the following severe mastocytosis related symptoms at baseline:
- Pruritus score ≥ 9
- Number of flushes per week ≥ 8
- Depression measured by Hamilton rating scale (HAMD-17) score ≥ 19
- Asthenia measured by Fatigue Impact Scale total score ≥ 75
At each patient evaluation between weeks 8 and 24, each of the above severe symptoms is evaluated. An improvement ≥ 75% with respect to baseline in one symptom is recorded as one positive treatment response.
The primary analysis is based on the comparison between masitinib and placebo in the number of actual responses between week 8 and week 24 divided by the total number of possible responses over the same treatment period. This endpoint is referred to below as the “4 Handicaps 75% Response or 4H75%-response”.
Key results from these pooled phase 2 data are as follows:
- The overall cumulative 75% response rate (4 Handicaps 75% Response) was 26.1% in the pooled population of systemic patients with severe symptoms at baseline. The 75% response rate (non cumulative) at week 24 was 23.5% in the same population.
- 52.8% and 28.6% of patients suffering respectively from the mastocytosis-related symptoms of severe flush and severe pruritus, responded to masitinib treatment (based on the cumulative 75% response rate), with a reduction of the symptom by at least 75% with respect to baseline.
- There was no significant difference in response to masitinib between mastocytosis patients with wild type c-Kit or D816V mutation of c-Kit.
- 78% of the overall pooled mastocytosis population completed the protocol period and participated to the extension phase after week 24. Furthermore, 24% of patients were still receiving masitinib treatment after 6 years, suggesting a lifetime benefit with masitinib may be possible.
a) For phase 3 to confirm phase 2, the expected 4 Handicaps 75% Response is expected to be around 20%.
b) Placebo effect is unknown since there has been no previous controlled study in indolent mastocytosis.
c) The phase 3 objective is to detect a statistical difference in the 4H75%-response criterion between masitinib and placebo with p-value < 0.05. A 10% difference would reach this objective.
d) A 4H75%-response of around 20% for the masitinib treatment-arm and a difference with placebo of around 10% is widely interpreted as representing a relevant clinical benefit, as evidenced by comparison with analogous response criterion reported for a recently registered drug in rheumatoid arthritis.
- The 4H75%-response criterion used in the phase 3 mastocytosis study signifies an almost complete disappearance of symptoms
- Rheumatoid arthritis studies use ACR20, ACR50, and ACR70 criteria, which measure respectively a reduction by 20%, 50%, and 70% of disease symptoms. ACR70 is a comparable endpoint to the 4H75%-response criterion
- The latest drug registered in rheumatoid arthritis generated an ACR70 ranging from 13.2 to 19.9 (mean 15.3) versus placebo ranging from 1.3 to 5.8 (mean 2.7)
Olivier Hermine is President of the scientific committee of AB Science and coordinator of the Reference Center for Mastocytosis in France (CeReMast), which is one of the largest centers worldwide in terms of mastocytosis patient’s population. He commented these findings: “A 75% reduction in severe symptoms at baseline is a relevant clinical benefit. The major response observed on flush and pruritus is interesting because it proves that masitinib has a strong biological activity against the activation of mast cells as these two symptoms are well recognized to be associated with mast cell activation in mastocytosis. Also, the longterm
follow-up data suggest that the observed treatment effect is maintained over time”. The phase 3 is currently closed to enrolment. The unblinding of phase 3 results is planned for November 2015 once all data have been collected and the database cleaned. Communication of results will be done soon after.
