The Phase III Results for Masitinib Are Now In. But Experts Remain Divided.

Target: neuroinflammation. Masitinib aims to slow progression of ALS by reducing microglia-based inflammation of motor neurons in the brain and spinal cord (Trias et al., 2016). The drug is currently being evaluated as a potential treatment for a wide-range of diseases including some forms of multiple sclerosis.

Masitinib may be of benefit to some people with ALS according to phase 3 clinical trial results presented on May 18 at the 2017 European Network to Cure ALS (ENCALS) meeting in Slovenia. The 48-week randomized placebo-controlled trial, which took place at 35 sites in Europe and Canada, found that people with ALS with a progression rate less than -1.1 ALS-FRS-R points/month experienced a 27% reduction in functional decline compared to placebo (p < 0.0157). Those with a faster rate of progression did not benefit. A total of 394 people with ALS participated in the study.

The strategy, being developed by AB Science in France, aims to slow progression of ALS by reducing microglia-mediated inflammation.

“An estimated 80% to 85% of patients, categorized as normal (including slower) progressors showed significant and clinically meaningful benefit to masitinib treatment,” wrote the leader of the study Jesús Mora of Hospital Carlos III, Madrid, Spain to the ALS Research Forum.

But according to Barrow Neurological Institute’s Jeremy Shefner in Phoenix, Arizona, although these results are promising, another phase 3 clinical trial is needed to determine whether the drug slows the progression of ALS in some people with the disease.

“My general feeling is that this is very promising, and we should be excited about it,” said Shefner. But key questions in regards to the trial results “make it imperative that we study the drug again.”

Reacting to inflammation

The proliferation of activated glial cells is a hallmark of neurodegenerative diseases including ALS. This process, known as reactive gliosis, is emerging as a key instigator of inflammation, which drives progression of the disease (Henkel et al, 2004; Boillee et al., 2006; Gomez-Nicola et al., 2013). In hopes to reduce inflammation in ALS, Institut Pasteur de Montevideo’s Luis Barbeito in Uruguay turned to existing cancer medicines that may stop the proliferation of these immune cells.

Reduce, reuse, recycle. Masitinib, used to treat mast cell tumors in dogs, reduced the proliferation of microglia in a mouse model of ALS. [Trias et al., 2016 under CC BY 4.0 license]

Barbeito’s team found that one of these medicines, masitinib, did just that in a rat model of SOD1 ALS (Trias et al., 2016). Treatment with 30 mg/kg masitinib daily 1 week after the onset of paralysis prolonged survival by 40%. “What we found was quite exceptional compared to [other] clinical drugs,” said Barbeito.

Subsequent confocal and immunohistochemical analysis indicated that treatment with masitinib inhibited microgliosis in the degenerating spinal cord. And, reduced motor neuron loss by 33%. The findings suggested that masitinib may help slow the progression of ALS by reducing inflammation – at least in the spinal cord.

The strategy, which is being developed by AB Science for multiple indications, is thought to reduce inflammation by blocking colony-stimulating factor 1 receptor (CSF1R) – a key receptor tyrosine kinase critical for the proliferation of microglia (Gomez-Nicola et al., 2013; Trias et al., 2016).

The approach builds on previous preclinical studies led by University of Southampton’s Diego Gomez-Nicola in England which found that blocking CSF1R signaling reduced microgliosis and the progression rate of mouse models of ALS and Alzheimer’s disease (Gomez-Nicola et al., 2013; Olmos-Alonso et al., 2016; Martinez-Muriana et al., 2016).

The Trial

Based on these preclinical results, a research team led by Hospital Carlos III‘s Jesus Mora in Spain launched a phase 3 clinical trial in 2013 in Europe and Canada. The study, which began at the phase 2 stage in Spain, aimed to determine whether masitinib could slow the progression of ALS.

CNS Space Invaders? Masitinib may also help protect peripheral nerves in ALS according to a preliminary preclinical analysis presented by Barbeito at ENCALS 2017. The findings build on previous results from Gomez-Nicola’s team in England which found that blocking CSF1R signaling with GW 2580 reduced infiltration of macrophages into the peripheral nerves in a mouse model of ALS. [Martinez-Muriana et al., 2016 under CC-BY-4.0 license].

Clinical trial participants were randomized 1:1:1 to masitinib 3.0 mg/kg/day, 4.5 mg/kg/day, or placebo, for 48 weeks. The primary endpoint was change in the rate of progression on the ALSFRS-R rating scale. Secondary outcome measures included forced vital capacity (FVC), the combined assessment of function and survival (CAFS) and quality of life (ALSAQ-40). People with probable or definite ALS within 3 years of diagnosis, who were on a stable dose of riluzole for at least 30 days took part in the study.

The researchers divided clinical trial participants into two pre-specified groups based on progression rate for the purposes of analysis: (1) normal progressors (NPs) who progressed less than 1.1 points per month and (2) fast progressors (FPs) who progressed 1.1 points or more per month. Rates were based on the difference between ALSFRS-R score at the first clinical visit and at enrollment.

A total of 330 people with ALS with normal progression rates and 64 people with fast progression rates participated. About two thirds of participants completed the 48-week study.

Treatment with high-dose masitinib (4.5 mg/kg/day) reduced functional decline 27% in people who progressed less than 1.1 points/month during the 48-week treatment period (-9.2 vs. -12.6 points at 48 weeks; 95%CI 0.6–6.1; P=0.0158). Significant reductions in the loss of forced vital capacity (22%; p=0.0296) and improvement of quality of life (28.5%; p=0.0078) were also noted.

The researchers, however, detected no statistical difference in CAFS and overall survival said CEO Alain Moussy during a subsequent webcall held in France by AB Science. “We know that to see a significant difference in survival would require more patients or a longer follow-up,” explained Moussy. “This study was not designed to demonstrate that.”

Common side effects included rash, nausea, diarrhea, and weight loss. These effects, however, can typically be managed by temporarily reducing the dose of masitinib according to Mora.

One word: neoplastic. Masitinib reduces microgliosis at least in part, by blocking CSF1R signaling [IC50 = 90 ±35 nM] (Trias et al., 2016). The inhibitor, however, also blocks other tyrosine kinases that regulate proliferation including c-Kit and PDGF-R (Dubreuil et al, 2009). The strategy aims to zero in on neurotoxic glia by targeting cells that are actively dividing.[Trias et al., 2016 under CC BY 4.0 license]

Treatment of NPs with the low-dose masitinib, 3.0 mg/kg/day, did not significantly reduce the functional decline (ALS-FRS, FVC, CAFS) but did significantly improve quality of life during the 48-week study period (34%; p=0.0057). Researchers detected no significant benefit for either dose in people with a fast progression rate, or in the study cohort as a whole.

The results suggest according to Mora that masitinib may be “an important new therapeutic option” for people with ALS progressing at 1.1 points or less per month. But Barrow Neurological Institute’s Jeremy Shefner cautions additional studies of masitinib are needed before making these conclusions.

A key question is why no effect is observed in people with faster progressing disease. It is in this subset of patients, according to Shefner, that the effect of a therapy is most likely to be detected.

“If you look at a subgroup, and try to figure out which subgroup is likely to be most sensitive to a disease-modifying therapy,” said Shefner, “usually it is the other way around: the faster progressors are the people in whom you would see an effect most easily.”

But according to Mora, this subset may simply have a different form of ALS that is driven by a distinct mechanism.

Another concern, according to Shefner, is that people with ALS in the placebo group appeared to progress faster than expected which may confound the interpretation of the clinical trial results.

Among the normal progressors, whose lead-in rate of progression was 0.5 points per month on the ALS-FRS-R rating scale, those randomized to placebo declined at 1.1 points per month during the treatment phase, while the slope of decline of the group taking masitinib changed very little, explained Shefner. “So one could interpret these data as the placebo group progressing more quickly than you’d anticipate, rather than the treatment group actually doing better.”

Another trial is needed according to Shefner to determine whether the drug is of significant benefit to people with the disease. If the benefit observed in these clinical trial participants is real, “it is highly meaningful for ALS patients.” said Shefner. “But it is very hard to judge, and that is the perfect reason to do a well-designed, well-conducted, and well-monitored phase 3 trial, including at sites in the United States.”

The Next Trial, and Regulatory Steps Ahead
That is, in fact, exactly what AB Science is planning to do according to Angela Genge of Montreal Neurological Institute and Hospital in Canada, who was involved in the recently completed phase 3 clinical trial and will lead the next phase 3 clinical study.

Gathering strength. Researchers will to in part, measure the strength of key muscles to determine whether masitinib reduces functional decline in some people with ALS. The emerging endpoint may enable scientists to evaluate efficacy of potential therapies in smaller samples and in shorter times (see May 2017 news). [Image: Douma et al., 2014 under CC BY 2.0 license.]

The randomized double-blind placebo-controlled phase 3 clinical trial is to take place in Canada, the US and Europe. “We expect the ALSFRS-R will again be the primary outcome measure, with the same secondary measures plus strength testing,” said Genge.

The drug will be evaluated separately in people with ALS with distinct progression rates, similar to the first phase 3 clinical trial. “But whether we will stick with the cut-off point of 1.1 points per month, or go as low as 0.9 per month, remains to be decided,” said Genge.

Emerging ALS biomarkers will be used to facilitate the analysis of the results of the second study. The choice of these markers, however, is still under discussion.

The clinical trial is scheduled to launch in the third quarter of this year. But it is likely to be delayed according to Genge in order to complete regulatory work in Europe.

In the meantime, masinitib is currently being considered for approval for the treatment of ALS by the European Medical Agency (EMA). The decision could be made as early as Q4 2017. The agency, explained Genge, has the option of granting conditional marketing authorization based on risk-benefit analysis, unmet medical need, and the expectation of further data submission. “That may change the development program completely. We are just waiting to hear what the final outcome is from the regulators.”

Meanwhile, in the US, AB Science is preparing to submit the phase 3 clinical trial results to the FDA, and discuss next steps according to AB Science’s Alain Moussy. Whether the FDA will require the company to further evaluate masitinib in people with ALS before considering approval remains unclear.

“I would have said in the past they would have to,” Genge said, but with the recent approval of edaravone based on a trial in a much smaller number of patients, as well as recent approvals of drugs for Duchenne muscular dystrophy on equally small trials, “I don’t think we can say that anymore.”


Trias E, Ibarburu S, Barreto-Núñez R, Babdor J, Maciel TT, Guillo M, Gros L, Dubreuil P, Díaz-Amarilla P, Cassina P, Martínez-Palma L, Moura IC, Beckman JS, Hermine O, Barbeito L. Post-paralysis tyrosine kinase inhibition with masitinib abrogates neuroinflammation and slows disease progression in inherited amyotrophic lateral sclerosis. J Neuroinflammation. 2016 Jul 11;13(1):177. [PubMed].

Martínez-Muriana A, Mancuso R, Francos-Quijorna I, Olmos-Alonso A, Osta R, Perry VH, Navarro X, Gómez-Nicola D, López-Vales R. CSF1R blockade slows the progression of amyotrophic lateral sclerosis by reducing microgliosis and invasion of macrophages into peripheral nerves. Sci Rep. 2016 May 13;6:25663. [PubMed].

Olmos-Alonso A, Schetters ST, Sri S, Askew K, Mancuso R, Vargas-Caballero M, Holscher C, Perry VH, Gómez-Nicola D. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology. Brain. 2016 Mar;139(Pt 3):891-907. [PubMed].

Gómez-Nicola D, Fransen NL, Suzzi S, Perry VH. Regulation of microglial proliferation during chronic neurodegeneration. J Neurosci. 2013 Feb 6;33(6):2481-93. [PubMed]

Dubreuil P, Letard S, Ciufolini M, Gros L, Humbert M, Castéran N, Borge L, Hajem B, Lermet A, Sippl W, Voisset E, Arock M, Auclair C, Leventhal PS, Mansfield CD, Moussy A, Hermine O. Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. PLoS One. 2009 Sep 30;4(9):e7258. [PubMed].

Boillée S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G, Kollias G, Cleveland DW. Onset and progression in inherited ALS determined by motor neurons and microglia. Science. 2006 Jun 2;312(5778):1389-92. [PubMed].

Henkel JS, Engelhardt JI, Siklós L, Simpson EP, Kim SH, Pan T, Goodman JC, Siddique T, Beers DR, Appel SH. Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue. Ann Neurol. 2004 Feb;55(2):221-35. [PubMed].

Further Reading

Gowing G, Lalancette-Hébert M, Audet JN, Dequen F, Julien JP. Macrophage colony stimulating factor (M-CSF) exacerbates ALS disease in a mouse model through altered responses of microglia expressing mutant superoxide dismutase. Exp Neurol. 2009 Dec;220(2):267-75. [PubMed].

clinical trial clinical trial design disease-als inflammation masitinib neuroinflammation topic-clinical topic-randd
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