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International Alliance of ALS/MND Associations

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AB Science – Masitinib

Background

Masitinib is an oral tyrosine kinase inhibitor that can inhibit macrophage and mast cell proliferation, while also stimulating their apoptosis, thereby reducing neuroinflammatory response. In preclinical SOD1 rat models of ALS/MND, treatment with masitinib seven days after the onset of paralysis resulted in slowed disease progression, decreased microgliosis and extended survival by 40%.

Trial Design & Results

A phase 2/3 clinical trial published in 2019 assessed the potential efficacy of mastinib in ALS/MND. The study was a double-blind, placebo-controlled trial in 394 participants that evaluated two doses of masitinib, 3.0 mg/kg/day and 4.5 mg/kg/day, in combination with riluzole over 48 weeks. A primary efficacy population of participants declared as normal progressors (<1.1 pts/month decline on ALSFRS-R) at the 4.5 mg/kg/day dose were declared to experience benefit vs. placebo, with a statistically significant 27% slowing of decline on the ALSFRS-r. Statistical significance was not achieved in the secondary analysis population consisting of combined normal and fast progressors. A survival analysis from the same trial, published in 2021, demonstrated a significant survival benefit of 25 months versus placebo in a subgroup receiving 4.5 mg/kg/day, having a baseline ALSFRS-R progression rate <1.1pts/month and a score of 2 or more at baseline for each ALSFRS-R component. The preliminary data from this study underpinned the decision to proceed with a phase 3 clinical trial. This is currently recruiting at more than 40 sites in 13 countries, with a goal of 495 participants across three arms; placebo, 4.5 mg/kg/day and 6.0 mg/kg/day. The trial will measure ALSFRS-R over 48 weeks as the primary outcome, with a quality of life measure, progression free survival, SVC, HHD and a combined assessment of function and survival (CAFS) as secondary outcomes. Based on the data obtained from the previous trial, eligibility will require a certain rate of progression and particular total and subscores on each of the items of the ALSFRS-R at screening.

It should also be noted that while masitinib demonstrated reasonable safety and tolerability in the phase 2/3 trial, there is a history of severe adverse events across several trials testing masitinib in various conditions including ischemic heart disease, autoimmune-like hepatitis and Stevens-Johnson Syndrome. There was a higher proportion of severe adverse events in the treatment arms of the trial and one third of the individuals on the 4.5 mg/kg/day dose had adverse events requiring dose reduction. In June 2021, a voluntary hold on worldwide clinical studies of masitinib was announced to investigate the potential risk of ischemic heart disease, which has since been lifted. This information should not discount evaluation of a potential effect in ALS/MND, but is important for treating physicians to be aware of.

The sponsor, AB Science, applied for Marketing Authorisation of masitinib (Alsitek) through the European Medicines Agency (EMA) based on the results of their phase 2/3 trial.  In 2018 the Committee for Medicinal Products for Human Use (CHMP) recommended a refusal of Marketing Authorisation for that application. Following additional analyses conducted on the phase 2/3 trial, the  EMA is currently reviewing masitinib for  conditional Marketing Authorization. Health Canada is also currently reviewing a New Drug Submission for masitinib in the treatment of ALS/MND under the Notice of Compliance with Conditions (NOC/C) policy. Both mechanisms support marketing of a treatment while confirmatory studies are ongoing, with the capacity for the regulators to revoke approval if efficacy is not demonstrated. 

If conditionally approved, the academic and clinical community need to consider whether the existing data from the phase 2/3 study is sufficient to warrant treatment of people with ALS/MND until the phase 3 trial readout occurs. The results of the first study, while intriguing, represent strong preliminary data to inform the ongoing phase 3 trial, but have a number of aspects that make it difficult to determine if the reported effects are due to chance. It should be noted that data from non-pivotal phase 2 or 2/3 studies are expected to provide the required information for designing the optimal phase 3 efficacy trials and questions around the reliability of results at this stage are not unique to this situation.

Summary

Given the available evidence, it is the opinion of the Scientific Advisory Council (SAC) that masitinib is a compound with preliminary results suggestive of a potential effect on ALS/MND progression and survival, but that the clinical and academic community has reservations as to whether the existing data is sufficient to warrant confidence in these effects. The ongoing phase 3 clinical trial is necessary to determine if there is any effect of masitinib in ALS/MND. Should regulatory bodies provide conditional approval of masitinib based on the existing data, further communication will be developed, but until then, there is as-yet no reason to recommend use of masitinib for the treatment of people living with ALS/MND.

International Alliance of ALS/MND Associations
May 2023


The original language of communication is English and any translation cannot be guaranteed for accuracy of messaging.

Primary Sidebar

Drugs in Development

  • AB Science – Masitinib
  • BrainStorm Cell Therapeutics – NurOwn
  • Clene Nanomedicine – CNM-Au8
  • Collaborative Medicinal Development – CuATSM
  • ILB – Tikomed
  • Kadimastem – AstroRx
  • Methylcobalamin
  • Mitsubishi Tanabe Pharma America – Oral Edaravone
  • Neuronata-R/Lenzumestrocel
  • NeuroSense – PrimeC
  • Neuvivo – NP001
  • T Regulatory Cell Therapies
  • Prilenia Therapeutics – Pridopidine
  • SOD1 Therapies & Trials

  • Graham Johnson, MND Australia

    Graham Johnson, MND Australia

  • Antonio Ventriglia,  ALS Liga Belgium,  Diagnosed 2013

    Antonio Ventriglia, ALS Liga Belgium, Diagnosed 2013

  • Fabio Carvalho

    Fabio Carvalho

  • Leon Ryba, Argentina

    Leon Ryba, Argentina

  • Josée Kolijn-de Man, Diagnosed 2015 , ALS Patients Connected, The Netherlands

    Josée Kolijn-de Man, Diagnosed 2015 , ALS Patients Connected, The Netherlands

  • David Bishop

    David Bishop

  • Animesh Kumar, Diagnosed 2013 , Asha Ek Hope Foundation, India

    Animesh Kumar, Diagnosed 2013 , Asha Ek Hope Foundation, India

  • Joanne Pratt, Diagnosed 2011 , MND Australia

    Joanne Pratt, Diagnosed 2011 , MND Australia

  • Shay Rishoni

    Shay Rishoni

  • Debbie Craghill, USA

    Debbie Craghill, USA

  • Valdomiro Xavier Honório, Brazil

    Valdomiro Xavier Honório, Brazil

  • Ali Var, Turkey

    Ali Var, Turkey

  • Conny van der Meijden, Diagnosed 2001,  ALS Netherlands

    Conny van der Meijden, Diagnosed 2001, ALS Netherlands

  • Claudette Sturk, ALS Society of Canada

    Claudette Sturk, ALS Society of Canada
    Picture2

  • Oliver Juenke, Germany

    Oliver Juenke, Germany

  • John Dinon, MND Australia

    John Dinon, MND Australia

  • Greg Heydet, ALS Hope Foundation, USA

    Greg Heydet, ALS Hope Foundation, USA

  • Sam Hayden-Harler, Motor Neurone Disease (MND) Association, UK

    Sam Hayden-Harler, Motor Neurone Disease (MND) Association, UK

  • Claudia Cominetti, Associazione conSLAncio Onlus,  Italy

    Claudia Cominetti, Associazione conSLAncio Onlus, Italy

  • IMG_2658

    IMG_2658

  • Jon Newsome, USA

    Jon Newsome, USA

  • Alejandro Aquino, Diagnosed 2011 , Asociación ELA Argentina

    Alejandro Aquino, Diagnosed 2011 , Asociación ELA Argentina

  • Calum Ferguson, Diagnosed 2010 , MND Scotland, UK

    Calum Ferguson, Diagnosed 2010 , MND Scotland, UK

  • MNDaSG Group PALS & CALS, Motor Neurone Disease Association, Singapore (MNDaSG)

    MNDaSG Group PALS & CALS, Motor Neurone Disease Association, Singapore (MNDaSG)

  • Steve

    Steve

  • Alfredo Santos, Diagnosed 2013 , ACELA, Colombia

    Alfredo Santos, Diagnosed 2013 , ACELA, Colombia

  • Xian-Zhang Niu, Diagnosed 2006 , Shaanxi ALS Association, China

    Xian-Zhang Niu, Diagnosed 2006 , Shaanxi ALS Association, China

  • Michael Lee, Australia

    Michael Lee, Australia

  • Joy Blakeley, Diagnosed 2017 , MND Australia

    Joy Blakeley, Diagnosed 2017 , MND Australia

  • Marcel R. Wernard, Diagnosed 2016,  ALS Patients Connected,  The Netherlands

    Marcel R. Wernard, Diagnosed 2016, ALS Patients Connected, The Netherlands

  • Andrea Zicchieri, Associazione conSLAncio Onlus, Italy

    Andrea Zicchieri, Associazione conSLAncio Onlus, Italy
    AndreaZicchieri_conSLAncioItaly

  • David Solomon, Diagnosed 2015, MND Association of England, Wales and N Ireland

    David Solomon, Diagnosed 2015, MND Association of England, Wales and N Ireland

  • Yolanda Armendariz, Diagnosed 2017 , FYADENMAC, Mexico

    Yolanda Armendariz, Diagnosed 2017 , FYADENMAC, Mexico

  • Elisabeth Zahnd, Switzerland

    Elisabeth Zahnd, Switzerland

  • Roy

    Roy
    roy

  • Mark Miller

    Mark Miller

  • Ismail Gokcek, Turkey

    Ismail Gokcek, Turkey
    ismail_gokcek_alsmnd_tr

  • Joyce Rusinak, Forbes Norris ALS Center, USA

    Joyce Rusinak, Forbes Norris ALS Center, USA

  • João Marcos Andrietta, Diagnosed 2008 , ABrELA, Brazil

    João Marcos Andrietta, Diagnosed 2008 , ABrELA, Brazil

  • Ian Roberts

    Ian Roberts

  • Aida Trzmiel de Guterman, Asociacion ELA Argentina, Diagnosed 2007, Argentina

    Aida Trzmiel de Guterman, Asociacion ELA Argentina, Diagnosed 2007, Argentina

  • Jette Odgaard Villemoes, Muskelsvindfonden, Denmark

    Jette Odgaard Villemoes, Muskelsvindfonden, Denmark

  • Bruno Leanza Mantegna, Diagnosed 1999 , AISLA Onlus, Italy

    Bruno Leanza Mantegna, Diagnosed 1999 , AISLA Onlus, Italy

  • March of Faces Photo Submission_OLGA_ELA ARGENTINA

    March of Faces Photo Submission_OLGA_ELA ARGENTINA

  • Ann Nicol

    Ann Nicol

  • 393647_2252248542053_984912751_n

    393647_2252248542053_984912751_n

  • Colm Francis Davis, Ireland

    Colm Francis Davis, Ireland

  • Angela Jansen, Deutsche Gesellschaft für Muskelkranke e.V.-DGM, Diagnosed 1995, Germany

    Angela Jansen, Deutsche Gesellschaft für Muskelkranke e.V.-DGM, Diagnosed 1995, Germany

  • IMG_1211

    IMG_1211

  • Malcolm Buck, Australia

    Malcolm Buck, Australia

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