Masitinib treatment in patients with progressive multiple sclerosis: a randomized pilot study

Abstract

BackgroundTreatment options for patients suffering from progressive forms of multiple sclerosis (MS) remain inadequate. Mast cells actively participate in the pathogenesis of MS, in part because they release large amounts of various mediators that sustain the inflammatory network. Masitinib, a selective oral tyrosine kinase inhibitor, effectively inhibits the survival, migration and activity of mast cells. This exploratory study assessed the safety and clinical benefit of masitinib in the treatment of primary progressive MS (PPMS) or relapse-free secondary progressive MS (rfSPMS).MethodsMulticenter, randomized, placebo-controlled, proof-of-concept trial. Masitinib was administered orally at 3 to 6 mg/kg/day for at least 12 months, with dose adjustment permitted in event of insufficient response with no toxicity. The primary response endpoint was the change relative to baseline in the multiple sclerosis functional composite score (MSFC). Clinical response was defined as an increase in MSFC score relative to baseline of > 100%.ResultsThirty-five patients were randomized to receive masitinib (N = 27) or placebo (N = 8). Masitinib was relatively well tolerated with the most common adverse events being asthenia, rash, nausea, edema, and diarrhea. The overall frequency of adverse events was similar to the placebo group, however, a higher incidence of severe and serious events was associated with masitinib treatment. Masitinib appeared to have a positive effect on MS-related impairment for PPMS and rfSPMS patients, as evidenced by an improvement in MSFC scores relative to baseline, compared with a worsening MSFC score in patients receiving placebo; +103% ± 189 versus -60% ± 190 at month-12, respectively. This positive, albeit non-statistically significant response was observed as early as month-3 and sustained through to month-18, with similar trends seen in the PPMS and rfSPMS subpopulations. A total of 7/22 (32%) assessable masitinib patients reported clinical response following 12 months of treatment (according to the modified intent-to-treat population, observed cases) compared with none in the placebo group. The Expanded Disability Status Scale remained stable for both treatment groups.ConclusionThese data suggest that masitinib is of therapeutic benefit to PPMS and rfSPMS patients and could therefore represent an innovative avenue of treatment for this disease. This exploratory trial provides evidence that may support a larger placebo-controlled investigation.

Multikinase Inhibitor-Induced Hand–Foot Skin Reaction: A Review of Clinical Presentation, Pathogenesis, and Management

“…Imatinib, a potent PDGFR inhibitor, rarely causes HFSR [61]. Masitinib, also an inhibitor of PDGFR, has a low incidence of HFSR [25]. Moreover, PDGFR and KIT are localized in the ductal epithelium of eccrine sweat glands, providing an additional explanation for its palmar-plantar distribution [62,63].…”

“…Indications for kinase inhibitors have recently expanded beyond malignancies to various autoimmune diseases, such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, asthma, and multiple sclerosis [25,26]. Therefore, it is likely that we will encounter the development of many more MKIs to suppress immune cells in years to come.…”

“…Several MKIs are found to have multitargeting effects because of the structural homolog among adenosine triphosphate (ATP)-binding sites of kinases [13]. Sorafenib, sunitinib, pazopanib, cediranib, regorafenib, axitinib, vandetanib, cabozantinib, masitinib, and telatinib are small-molecule, anti-angiogenic inhibitors of the tyrosine kinase with multi-targeting inhibition [14][15][16][17][18][19][20][21][22][23][24][25]. Table 1 summarizes and lists in order of frequency (high to low) the types of anti-angiogenic MKIs, their therapeutic indications and targets, and the incidence of all-grade and high-grade (grade 3) HFSRs [14][15][16][17][18][20][21][22][23].…”

Evidence for mast cells contributing to neuromuscular pathology in an inherited model of ALS

“…Accordingly, clinical trials have shown therapeutic effects of masitinib in cases of mastocytosis, a rare disease characterized by abnormal accumulation and activation of mast cells in various tissues and organs (28). Masitinib was also shown to beneficially modulate CNS function in multiple sclerosis (29), stroke (30), and Alzheimer' s disease (31). In addition, a recent phase III clinical trial with masitinib in ALS has shown promising therapeutic effects in a significant group of patients, slowing the deterioration of motor functions and reducing the decline in quality of life (32).…”

Therapeutic Advances and Future Prospects in Progressive Forms of Multiple Sclerosis

“…Increasing evidence suggests that mast cells actively play a role in pathogenesis of MS by releasing vasoactive mediators that sustain inflammatory cascade, disrupting the BBB, and stimulating activated T cells, amongst other mechanisms [93,94]. In a phase IIa proof-of-concept trial, masitinib was, overall, well tolerated and found to have positive but not statistically significant effect on clinical progression in patients with progressive MS [95]. A phase IIb/III study of masitinib in patients with relapse-free SPMS or PPMS is in progress (NCT01433497).…”