dm+d

Unassigned

New Medicines

AlsitekAmyotrophic lateral sclerosis (motor neurone disease), familial or sporadic - add-on therapy in patients on a stable dose of riluzole

Information

Alsitek
New molecular entity
AB Science
AB Science

Development and Regulatory status

Phase III Clinical Trials
Pre-registration (Filed)
Phase III Clinical Trials
Yes
Yes
Aug 22AB Science announces it has filed masitinib for the treatment of ALS to the EMA based on the PII/III AB10015 trial [28]
Nov 21AB Science announces it has received authorisation from the FDA to resume patient enrolment in the confirmatory PIII study [26].
Sep 21AB Science announces it has received authorisation from the French National Agency for the Safety of Medicines and Health Products (ANSM) to resume patient enrollment in the confirmatory PIII study in ALS, and from Norway and other European countries [25].
Jun 21Company suspends all ongoing masitinib trials (in mastocytosis, ALS and COVID) while they investigate a possible risk of ischaemic heart disease [23].
Jun 20In 2020, AB Science will continue to allocate the bulk of its resources to the further development of masitinib, including initiating the confirmatory study in ALS [21].
Apr 20AB Science expects that the COVID-19 pandemic will have limited impact on development of masitinib. However, for the new PIII AB19001 confirmatory study, patient enrolment will start once post-pandemic conditions permit proper access to the sites, which may delay the enrolment date initially planned in March 2020 by up to 3 months [18].
Nov 19AB Science will make a decision on whether to re-file to the EMA in Q1 20, and if so a decision from the EMA would be expected by end Q4 20 [16].
Jun 19AB Science has new data to address the three major objections previously raised by EMA. However, no decision has been taken yet regarding a potential new submission for conditional marketing authorisation based on the final results from AB10015 study. If a new submission is made, it can only be under the normal assessment timeline because results for single pivotal study need to be exceptionally compelling in the context of an accelerated assessment [15].
Oct 18AB Science is continuing to evaluate the possibility to resubmit the application based on the final results from study AB10015. As part of the resubmission, AB Science intends to submit final safety data, new sensitivity analyses on the primary analysis of the ALSFRS-R score for patients who stopped the study prematurely, applying recommended methods as per EMA guidelines in order to corroborate the results based on the LOCF method (last observation carried forward), and new preclinical data reinforcing the mechanism of action of masitinib, which is an important consideration in the context of an application based on a single pivotal trial. Moreover, a second study is needed to confirm the results of this first pivotal study, even in case of positive opinion by the CHMP. AB Science will initiate this confirmatory study in the treatment of ALS once the scientific advice procedure regarding the design of the trial is completed and once the ANSM clinical hold is lifted [13].
May 18AB Science announces it will not pursue re-examination of its European marketing application for masitinib as a treatment for amyotrophic lateral sclerosis (ALS) after all, as it has concluded that the re-examination procedure would not be the most appropriate format to address all the pending concerns raised by the CHMP, largely because new data cannot be submitted as part of the process. Instead, it intends to discuss with the EMA the pathway forward to seek marketing authorisation, including submission of final safety data from study AB10015 and new preclinical data reinforcing the mechanisms of action of the drug [12].
Apr 18AB Science has requested re-examination of the CHMP written negative opinion: the Committee will therefore re-examine its opinion and issue a final recommendation. The Committee had originally concluded that the main study in patients with ALS did not show that the drug was effective in slowing disease progression; it considered that the patient classification used was arbitrary and that deficiencies in the way the study was performed in two sites cast doubt on the integrity of the data [11].
Apr 18CHMP has adopted a negative opinion for the marketing authorization of masitinib in the treatment of adult patients with Amyotrophic Lateral Sclerosis. Next opinion due July 18 [10].
Sep 16AB Science announces that the EMA has accepted the filing for masitinib in treatment of ALS, based on the results of preclinical data and pre-planned interim results of the PII/III trial (NCT02588677). The final EMA decision is expected in the second half of 2017 [7].
Aug 16EMA grants orphan drug status for masitinib for ALS [6].
Jun 16AB Science announces that Rapporteurs appointed by the EMA have recommended the filing of masitinib in combination with riluzole in the treatment of adult patients with ALS for conditional marketing authorisation. This request for filing was based on clinical data from the phase 2/3 study AB10015, which was successful on its pre-specified primary endpoint at the interim analysis, as well as preclinical data on masitinib mechanism of action in ALS, and manufacturing process. AB Science expects to file by end Q3 16 [5].
Mar 15Granted orphan drug status for ALS in the US [3].
Oct 14PIII for ALS [1].

Category

A potent and selective protein-tyrosine kinase inhibitor of the mutated and wild-type forms of the juxtamembrane region of the c-Kit receptor. It also inhibits the platelet-derived growth factor receptor and the mutated fibroblast growth factor receptor.
The incidence of ALS ranges from 1.8-2.2 per 100,000 population, with a prevalence of between 4.0-4.7 per 100,000 population in the UK. It is a form of motor neurone disease.
Amyotrophic lateral sclerosis (motor neurone disease), familial or sporadic - add-on therapy in patients on a stable dose of riluzole
Oral

Further information

Yes

Trial or other data

Mar 22PIII (AB19001; NCT03127267) trial is recruiting; collection of primary outcome data should complete in Dec 23 [27].
Jul 21AB Science publishes long-term survival analysis of masitinib in ALS which shows long-term OS (75 months average follow-up from diagnosis) with oral masitinib (4.5 mg/kg/day) could prolong survival by ~ 2 years vs. placebo (both added to riluzole), provided treatment starts prior to severe impairment of functionality.[24]
Nov 20PIII (AB19001; NCT03127267) trial is recruiting; collection of primary outcome data should complete in Dec 22 [22].
Apr 20PIII (AB19001; NCT03127267) trial is due to start recruiting in Jun 20, and complete collection of primary outcome data in Jun 22 [20].
Mar 20FDA allows AB Science to initiate its PIII (AB19001; NCT03127267) trial. Study AB19001 is intended to confirm the previously published results from the first PII/III study (AB10015) which demonstrated that masitinib at 4.5 mg/kg/day in combination with riluzole significantly slowed ALSFRS-R decline by 27% compared to riluzole alone at week 48 (p<0.05). Evidence of a dose-response was observed in the previous AB10015 study with maintenance doses of 3.0 and 4.5 mg/kg/day, with an acceptable safety profile. Therefore, this confirmatory trial will evaluate an even higher 6.0 mg/kg/day dose in one of the two active arms [19].
Jan 20Subgroup analysis of PII/III trial (AB10015; NCT02588677) confirmed that patients with less severe disease at the start of treatment are those likely to benefit most from masitinib. This subgroup has been selected for a new confirmatory PIII trial. The design of the PIII confirmatory study has been optimised to increase the probability of success and has been validated by EMA through protocol assistance. It is expected to start in Q1 20 and complete in Q1 22 [17].
May 19PIII study (NCT03127267) to compare the efficacy and safety of masitinib in combination with riluzole versus matched placebo in combination with riluzole for the treatment of ALS is due to start recruiting. 495 patients will be recruited. Primary outcome is change in Amyotrophic Lateral Sclerosis functional rating scale (ALSFRS)-Revised at 48 weeks; collection of these data is due to complete May 21 [14].
Aug 17Following suspension of all ongoing trials in France because of deviations from good clinical practice, external and independent audits of ALS studies have been completed and have not identified any under-reporting of safety data [9].
Aug 17PII/III study (NCT02588677) has met its pre-specified primary endpoint. Final analysis was performed based on 394 patients treated for 48-weeks and randomly allocated to three different treatment arms: masitinib at 4.5 mg/kg/day, versus masitinib at 3 mg/kg/day, versus placebo, each administered as an add-on to riluzole. Primary endpoint was based on the change from baseline to week 48 in ALSFRS-R. Also consistent with EMA guidance, Progression Free Survival (PFS) was included as a key secondary endpoint for registration, with progression being defined as ALSFRS-R deterioration of more than 9 points or death. A stepwise sequence of analysis was predefined to first test masitinib at 4.5 mg/kg/day versus placebo, and then masitinib at 3 mg/kg/day versus placebo. For masitinib at 4.5 mg/kg/day: - Primary analysis on the change in ALSFRS-R score at week 48 (mLOCF methodology) is statistically significant with a P-value of 0.014. - Sensitivity tests on the primary analysis consisted in two models to impute a value at week 48 for any patients who discontinued treatment before week 48. Those sensitivity analyses are also significant with a P-value of 0.020. - The key secondary analysis on PFS was statistically significant with a P-value of 0.016. - Quality-of-life measured by change in ALSAQ score was also statistically significant with a p-value<0.01. For masitinib at 3 mg/kg/day: - There was a trend in favor of masitinib versus placebo for change in ALSFRS score at week 48 (LOCF methodology) and likewise for the two imputation models (sensitivity analyses) and in PFS (secondary analysis). - The change in quality-of-life was statistically significant (p-value<0.01) in favor of masitinib. The adverse events observed for masitinib in study AB10015 were consistent with its known safety profile. There were no new safety events at final analysis as compared with interim analysis [9].
May 17A Science announces new data on masitinib showing that adding an daily dose to background therapy with riluzole slowed symptom progression by 27% compared to riluzole plus placebo [8].
Jan 16NCT02588677 is a PII/III placebo controlled RCT being conducted in the EU and US of masitinib in combination with riluzole in 381 patients with ALS. The study is due to complete Jun 17 [4].
Nov 14PII study to compare the efficacy and safety of masitinib versus placebo in the treatment of 45 patients suffering from ALS is underway. The primary endpoint is ALS functional rating scale (ALSFRS)-revised, at week 48 (EudraCT number 2010-024423-24) [2].

Evidence based evaluations

MasiproIndolent systemic or cutaneous mastocytosis

Information

Masipro
Licence extension / variation
AB Science
AB Science

Development and Regulatory status

None
Phase III Clinical Trials
Phase III Clinical Trials
Yes
Yes
Sep 21Patient enrollment has resumed in the confirmatory PIII study (AB19001) in ALS, the confirmatory PIII study (AB15003) in mastocytosis and the PII study (AB20001) in Covid-19 [18].
Jun 21Company suspends all ongoing masitinib trials (in mastocytosis, ALS and COVID) while they investigate a possible risk of ischaemic heart disease [17].
Nov 19AB Science note that a PIII (AB15003; EudraCT 2016-001447-39) confirmatory study is planned in order to request a MA. This PIII study is being initiated and enrolment of 140 patients from 30 specialised centres is anticipated to begin in Q1 2020[15].

Mar 19: Still listed as PIII in company pipeline [14].


Dec 18: An inspection has taken place, but AB Science has yet to announce whether the clinical hold has been lifted [13].


Oct 18: No longer listed in AB Science pipeline. In an update on activities in H1 18, AB Science note that launch of confirmatory studies in ALS and mastocytosis is subject to the lifting of the clinical hold in France [13].


Sep 17: AB Science intends to initiate a confirmatory study in patients with smouldering or indolent systemic severe mastocytosis unresponsive to optimal symptomatic treatment in order to confirm results from the first pivotal study [12].


Sep 17: Second EU negative opinion [12].


Jun 17: AB Science has requested a re-examination of the CHMP opinion. Upon receipt of the grounds of the request, the CHMP will re-examine its opinion and issue a final recommendation [11].


May 17: EU negative opinion. The CHMP was concerned about reliability of study results because a routine good clinical practice inspection at 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 safety 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 [10].


Jun 16: Filed in EU for mastocytosis [7,8].


Nov 14: Orphan drug status granted by FDA and EMA[5].

Category

Tyrosine kinase inhibitor (TKI) selectively inhibiting c-kit
In mastocytosis, mast cells invade various organs and can inhibit their functionality and eventually cause degeneration. Mastocytosis affects ~ 2.6 in 10,000 people in the EU, equivalent to a around 132,000 people [3].
Indolent systemic or cutaneous mastocytosis
Oral

Further information

Yes

Trial or other data

Nov 21PIII study (NCT04333108) is recruiting, with collection of primary outcome data still estimated to finish in Dec 22 [19].
Feb 21Recruitment to PIII NCT04333108 continues; primary completion date is Dec 22 [16].
Jan 17PIII NCT00814073 study is published in The Lancet [9].
Nov 15AB Science announced that a PIII study evaluating masitinib in the treatment of severe systemic mastocytosis has met its primary objective as well as secondary objectives (NCT00814073). The primary endpoints included pruritus score, number of flushes per week, depression measured by the Hamilton rating scale and asthenia measured by the fatigue impact scale. Masitinib was in the randomised, double-blind, placebo-controlled phase III trial in patients with smouldering systemic, indolent systemic, or cutaneous mastocytosis with handicap. The 24-week trial enrolled 135 patients in the the US, Austria, Bulgaria, Czech Republic, France, Germany, Italy, Slovakia, Bulgaria, Hungary, Greece, Spain, United Kingdom and Latvia. Enrolment was expanded to include Russia, India and Latin America. In November 2013, AB Science announced that the independent Data and Safety Monitoring Board had recommended continuation of the trial, based upon completion of a futility analysis included in the study protocol. The study was completed in December 2015. A PIII trial is expected to initiate in 2015, in paediatric patients with mastocytosis [6].
Mar 14No update available on progress of PIII NCT00814073 study [4].
Nov 13The independent Data and Safety Monitoring Board for the PIII study has recommended continuation of the study, based upon completion of the futility analysis performed on two-thirds of the target population [2].
Nov 13NCT00814073 is a a 24-week with possible extension, prospective, multicentre, randomized, double blind, PIII study of masitinib at 6 mg/kg/day vs placebo in treatment of 200 adults with smouldering systemic, indolent systemic or cutaneous mastocytosis with handicap. The primary outcome is responder rate at week 24. The study started in 2008 and was due to complete Jun 13 [1].

Evidence based evaluations

Mild to moderate Alzheimer's disease - adjunct

Information

Licence extension / variation
AB Science
AB Science

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials

Category

Tyrosine kinase inhibitor
Alzheimers disease is the most common form of dementia, accounting for 50%-60% of all cases. The prevalence of dementia is below 1% in individuals aged 60-64 years, but shows an almost exponential increase with age, so that in people aged 85 years or older the prevalence is between 24% and 33% in the Western world.
Mild to moderate Alzheimer's disease - adjunct
Oral

Severe persistent asthma, oral or high-dose inhaled corticosteroid-dependent +/- elevated eosinophil levels

Information

New molecular entity
AB Science
AB Science

Development and Regulatory status

None
Phase III Clinical Trials
Phase III Clinical Trials

Category

Tyrosine kinase inhibitor that targets mast cells
At least 1 in 10 children, and 1 in 20 adults, have asthma [3]. NICE estimates the prevalence of severe persistent asthma to be 47 per 100,000 population.
Severe persistent asthma, oral or high-dose inhaled corticosteroid-dependent +/- elevated eosinophil levels
Oral

Evidence based evaluations

Masiviera (EU), Kinaction (US)Advanced or metastatic, chemo naive pancreatic cancer - in combination with gemcitabine

Information

Masiviera (EU), Kinaction (US)
Licence extension / variation
AB Science
AB Science

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials
Yes

Category

Tyrosine kinase inhibitor which targets c-kit, platelet-derived growth factor receptors (PDGFR) & fibroblast growth factor receptor 3 (FGFR3)
The annual incidence rate of PC is ~ 12 per 100,000. In 2008, there were 7,179 new diagnoses in England and Wales (CancerResearchUK). The majority of patients present at an advanced stage and < 3% survive to 5 years. Around 10-15% of patients receive chemotherapy (NICE TA25 May 01).
Advanced or metastatic, chemo naive pancreatic cancer - in combination with gemcitabine
Oral

Further information

Yes

Evidence based evaluations

Metastatic, castrate resistant prostate cancer - first-line combination

Information

Licence extension / variation
AB Science
AB Science

Development and Regulatory status

None
Phase III Clinical Trials
None

Category

Tyrosine kinase inhibitor
Prostate cancer is the most common cancer in men and makes up 26% of all male cancer diagnoses in the UK. The age-standardised incidence of prostate cancer in the UK in 2010 was 104.5 per 100,000 population. [2]
Metastatic, castrate resistant prostate cancer - first-line combination
Oral

Multiple sclerosis (MS), primary progressive or relapse-free secondary progressive - first-line

Information

Licence extension / variation
AB Science
AB Science

Development and Regulatory status

None
Phase III Clinical Trials
Phase III Clinical Trials

Category

Protein tyrosine kinase inhibitor
About 1 in 1,000 population have MS. 10-15% of suffers have primary progressive subtype at onset and up to 80% have relapsing/remitting MS (RRMS). About 50% of patients with with RRMS develop secondary progressive MS during the first ten years of their illness [3].
Multiple sclerosis (MS), primary progressive or relapse-free secondary progressive - first-line
Oral

Evidence based evaluations