Inhibitiory Effect on non-active progressive MS.

I

Masitinib is a tyrosine-kinase inhibitor used in the treatment of mast cell tumours in animals, specifically dogs. Masitinib has been studied for several human conditions including melanomamultiple myelomagastrointestinal cancerpancreatic cancerAlzheimer diseasemultiple sclerosisrheumatoid arthritismastocytosisamyotrophic lateral sclerosis and COVID-19

Masitinib is a tyrosine kinase inhibitor which inhibits tyrosine kinasesenzymes responsible for the activation of many proteins by signal transduction cascades. Specifically, masitinib targets the receptor tyrosine kinase c-Kit. Masitinib is also additional targets, it also inhibits the platelet derived growth factor receptor (PDGFR), lymphocyte-specific protein tyrosine kinase (Lck), focal adhesion kinase (FAK) and fibroblast growth factor receptor 3 (FGFR3) as well as CSF1R.

So it is evident that Mastinib is a dirty drug, meaning it has many potential activities…which can sometimes mean side-effects. There are a few with mastinib and a common one seems to be weakness

However one interesting target is CSF1R. Colony stimulating factor 1 receptor (CSF1R), also known as macrophage colony-stimulating factor receptor (M-CSFR), and means that it may affect microglia and macrophages.

Gushchina S, Pryce G, Yip PK, Wu D, Pallier P, Giovannoni G, Baker D, Bo X. Increased expression of colony-stimulating factor-1 in mouse spinal cord with experimental autoimmune encephalomyelitis correlates with microglial activation and neuronal loss. Glia. 2018;66:2108-2125.

Marzan DE, Brügger-Verdon V, West BL, Liddelow S, Samanta J, Salzer JL. Activated microglia drive demyelination via CSF1R signaling. Glia. 2021;69(6):1583-1604.

Another is PDGFR and this affects myelination. However the question is what does mastinib do to progressive MS. In this study they looked at primary progressive MS and non-active secondary progressive MS and it is claimed that there was a positive effect on walking in this two year trial. This is compared to placebo.

This agent is being developed in many different conditions which are sort of diverse in nature, suggesting there is no really clear understanding how it is working. But if it is working in prorgoressive MS

This is good news because it indicates that non-active progressive MS can be controlled to some extent.

Now the nagging feeling in this study they found an effect with 4.5mg/kg but it was inconclusive at 6mg/kg and in other studies they used 6mg/kg.. I don’t like these inverse dose drug effects…meaning as you drop the dose the effect appaers.

Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis: A Randomized, Phase 3, Clinical Trial.Vermersch P, Brieva-Ruiz L, Fox RJ, Paul F, Ramio-Torrenta L, Schwab M, Moussy A, Mansfield C, Hermine O, Maciejowski M; AB07002 Study Group.Neurol Neuroimmunol Neuroinflamm. 2022 Feb 21;9(3):e1148. doi: 10.1212/NXI.0000000000001148. Print 2022 May.

Background and objectives: Masitinib is a selective tyrosine kinase inhibitor, targeting innate immune cells (mast cells and microglia) that are involved in the pathophysiology of progressive multiple sclerosis (MS). Study AB07002 assessed oral masitinib in patients with progressive MS who were progressing but not clinically active.

Methods: This randomized, double-blind, 2 parallel-group, placebo-controlled trial assessing 2 dose levels of masitinib vs equivalent placebo was conducted at 116 hospital clinics and specialized MS centers in 20 countries. Randomization (2:1) with minimization was performed centrally using an automated system. Patients, physicians, and outcome assessors remained masked to treatment group allocation. Patients with primary progressive MS (PPMS) or nonactive secondary progressive MS (nSPMS) without relapse for ≥2 years, aged 18-75 years, with baseline Expanded Disability Status Scale (EDSS) 2.0-6.0, and regardless of time from onset were treated for 96 weeks. The primary end point was overall EDSS change from baseline using repeated measures (generalized estimating equation, timeframe W12-W96, measured every 12 weeks), with positive values indicating increased clinical deterioration. Efficacy and safety were assessed in all randomly assigned and treated patients.

Results: A total of 611 patients were randomized; 301 in the masitinib 4.5 mg/kg/d parallel group and 310 in the uptitrated masitinib 6.0 mg/kg/d parallel group. Masitinib (4.5 mg/kg/d) (n = 199) showed significant benefit over placebo (n = 101) according to the primary end point, 0.001 vs 0.098, respectively, with a between-group difference of -0.097 (97% CI -0.192 to -0.002); p = 0.0256. Safety was consistent with masitinib’s known profile (diarrhea, nausea, rash, and haematologic events), with no elevated risk of infection. Efficacy results from the independent uptitrated masitinib 6.0 mg/kg/d parallel group were inconclusive, and no new safety signal was observed.

Discussion: Masitinib (4.5 mg/kg/d) can benefit people with PPMS and nSPMS. A confirmatory phase 3 study will be initiated to substantiate these data.

Trial registration information: The first participant was randomized to study AB07002 on August 25, 2011. The trial was registered with the European Clinical Trials Database (#EudraCT 2010-021219-17) on July 1, 2011 (clinicaltrialsregister.eu/ctr-search/trial/2010-021219-17/ES) and with ClinicalTrials.gov (#NCT01433497) on September 14, 2011 (clinicaltrials.gov/ct2/show/NCT01433497).

Classification of evidence: This study provides Class II evidence that masitinib 4.5 mg/kg/d decreased progression of disability, measured by the EDSS, in adults with PPMS or patients with nSPMS (with no exacerbations in the last 2 years).

Also see. Vermersch P, Benrabah R, Schmidt N, Zéphir H, Clavelou P, Vongsouthi C, Dubreuil P, Moussy A, Hermine O. Masitinib treatment in patients with progressive multiple sclerosis: a randomized pilot study. BMC Neurol. 2012 Jun 12;12:36. doi: 10.1186/1471-2377-12-36.

About the author

MouseDoctor

2 comments

  • I like this bit 🙂

    suggesting there is no really clear understanding how it is working

    More or less like metformin ,and statins

    nice work

  • Efficacy calculated using ‘modified’ ITT ie ignore those who discontinued. Why? Would results have been significant if used ITT data?
    No idea what’s going on with 4.5mg vs 6mg

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