France’s AB Science has developed masitinib for the treatment of amyotrophic lateral sclerosis (ALS).
Canada was the first country in the world to proceed with an application for masitinib. Health Canada, which accepted a New Drug Submission (NDS) for the drug, launched the review in late May 2022. The review, conducted under the notice of compliance with conditions (NOC/c) policy, will take a maximum of 200 days (plus an additional 35 days for some procedures). Thus, if approved by the regulator, masitinib will become available around mid-January 2023.
The presumptive brand name for masitinib for amyotrophic lateral sclerosis is Alsitek.
Meanwhile, in mid-June 2022, Health Canada was also the first in the world to approve Albrioza (sodium phenylbutyrate + ursodoxicoltaurine), developed by Amylyx Pharmaceuticals for the treatment of ALS.
Albrioza: New Drug for Amyotrophic Lateral Sclerosis Treatment
Amylyx Pharmaceuticals proposed mixture of sodium phenylbutyrate and tauroursodeoxycholic acid for ALS treatment.
By the way, it is appropriate to position AB as a single-molecule pharmaceutical company: all of the company’s activities are tied to the study of masitinib. The clinical validation program for masitinib is extensive, AB is trying to prove its applicability in the treatment of a wide variety of pathologies: ALS, Alzheimer’s disease, progressive forms of multiple sclerosis, severe asthma uncontrolled by corticosteroids, indolent systemic mastocytosis, mast cell activation syndrome, and cancers such as pancreatic and prostate cancers.
In late 202, AB disclosed positive results from a clinical trial of masitinib in Alzheimer’s treatment.
Masitinib for Alzheimer’s Disease: It Did Work!
Masitinib by AB Science has curbed cognitive deterioration in Alzheimer-type dementia. And that’s a new hope.
Alsitek: Efficacy and Safety of ALS Treatment With Masitinib
The NCT02588677 phase 3 (randomized, double-blind, placebo-controlled, multicenter, international) clinical trial invited adult patients (n=391) with amyotrophic lateral sclerosis, familial or sporadic.
Participants had to receive a stable dose of riluzole (100 mg/day) for at least 30 days before screening.
Among the main requirements for subjects: duration of disease less than 36 months from first symptoms (any progressive focal weakness or atrophy); forced vital capacity (FVC) of at least 60% of total capacity.
For 48 weeks, subjects continuing on riluzole therapy were given placebo or masitinib at a daily dose of 3.0 mg/kg or 4.5 mg/kg.
The primary endpoint of therapeutic efficacy was determined by a change in the total score on the Amyotrophic Lateral Sclerosis Functionality Rating Scale (ALSFRS-R), which assesses disease progression and severity.
The evaluation was conducted in a cohort of patients (n=99) taking a 4.5-mg dose of masitinib and characterized by normal ALS progression, that is, in whom each component of the ALSFRS-R scale was initially ≥ 2 points (patients with complete loss of function or severe deterioration were excluded) and whose rate of progression after onset was < 1.1 ALSFRS-R points (patients with rapid progression of ALS were excluded).
Treatment of amyotrophic lateral sclerosis with Alsitek was found to provide a clinically significant 27% reduction in ALS progression when compared with the control group.
In the masitinib group, the ALSFRS-R total score decreased by 9.24 points — versus a decrease of 12.63 points in the placebo group. The statistically significant difference was 3.39 points (95% CI: 0.65 to 6.13; p=0.016).
Administration of Alsitek resulted in improved progression-free survival (PFS) in the form of a 25% delay in the onset of severe worsening of ALS (reduction in ALSFRS-R by 9 points) or death: 20 months to event — vs. 16 months (p=0.016).
In the Alsitek group, a 22% reduction in FEV was observed relative to the control group: a decrease of 26.45 — vs. a decrease of 33.99 (p=0.03).
Use of Alsitek was reflected in a 29% delay in worsening of quality of life compared to the placebo group (p=0.008), according to the Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40).
The safety profile of Alsitek cannot be called completely favorable. Among the most common adverse events when taking a 4.5-mg dose of masitinib were nausea (in 12% of patients), weight loss (11%), respiratory failure (10%), falls (9%), maculopapular rash (9%), rash (8%), diarrhea (8%), dyspepsia (8%), peripheral edema (7%), and iron deficiency anemia (7%). Serious adverse events were experienced by 31% of patients receiving Alcitek and severe adverse events by 29.5%.
The decision to discontinue treatment completely due to adverse events was made by 16% of the subjects, to temporarily discontinue treatment by 12%, and to reduce the dose of masitinib by 33%.
Follow-up at a median of 75.6 months from randomization found that use of Alsitek for the treatment of ALS resulted in a life prolongation of more than 1.5 times.
Thus, the median overall survival (OS) in the masitinib group was 69 months — versus 44 months in the placebo group: a statistically significant (p=0.037) difference of two years (25 months). Alsitek reduced the risk of death by 47%: hazard ratio (HR) 0.53 (95% CI: 0.31 to 0.92; p=0.025).
Masitinib Against ALS: What’s Next
The 48-week phase 3 (randomized, double-blind, placebo-controlled, multicenter, international) clinical trial NCT03127267 is ongoing to conclusively confirm the therapeutic efficacy of masitinib (4.5 mg or 6.0 mg daily on riluzole) in the treatment of ALS, familial or sporadic.
The inclusion criteria for the study are made more stringent so that participants’ disease is not initially too severe and/or rapidly progressive. For example, the duration of ALS from the time of diagnosis must be 24 months or less and each component of the ALSFRS-R scale must score at least 2.
The study is scheduled for completion in late 2023.
Alsitek: Mechanism of Action of Masitinib in ALS
The exact molecular pathway causing motor neuron degeneration in amyotrophic lateral sclerosis is unknown. Nevertheless, as in other neurodegenerative diseases, it probably involves a complex interaction between several pathogenic cellular mechanisms that may not be mutually exclusive. Possible mechanisms include genetic factors, excitotoxicity, oxidative stress, mitochondrial dysfunction, impaired axonal transport, neurofilament aggregation, protein aggregation, inflammatory dysfunction, and contributions from non-neuronal cells.
There are three things whose role is underestimated in the pathogenesis of neurodegenerative diseases: the blood-brain barrier (BBB),  neuroinflammation,  mast cells. And they are closely related to each other.
Mast cells are located on both sides of the BBB and can rapidly cross it, building up their own population in response to a number of stimuli.    Mast cells play an important role in maintaining the inflammatory network of the central nervous system,  including through the release of large amounts of proinflammatory mediators and the ability to modulate the permeability of the BBB.  All this has therapeutic implications, since a defective BBB is quite common in neuroinflammatory and neurodegenerative diseases such as ALS.
Oral masitinib (AB1010) is a small-molecule selective inhibitor of receptor tyrosine kinases (RTKs) class III; those belonging to the platelet-derived growth factor receptor (PDGFR) family. Masitinib, primarily targeted against the c-Kit proto-oncogene, also shows activity against PDGFR, lymphocyte-specific protein tyrosine kinase (Lck), colony stimulating factor 1 receptor (CSF1R, FMS), Fyn-related kinase (FRK, PTK5), LYN proto-oncogene, discoidin domain receptor tyrosine kinase 2 (DDR2, CD167b).
By the way, according to the Gini coefficient, masitinib is one of the most highly selective kinase inhibitors. In other words, this allows hoping for an improved safety profile among drugs related to tyrosine kinase inhibitors.
The proposed mechanism of action of masitinib in ALS is as follows.
First, masitinib acts on neuroglia by inhibiting CSF1R, a receptor located on glial cells. There is strong evidence that neuronal damage in ALS is associated with microglia, particularly the appearance of aberrant glial cells. This process is regulated by the CSF1/CSF1R signaling pathway. Masitinib, affecting this pathway, inhibits the proliferation of glial cells, including aberrant microglial cells, which are closely associated with the motor neuron degeneration, and also slows down the migration of microglia cells.
Second, masitinib acts on mast cells by inhibiting the c-Kit/SCF and Lyn/Fyn signaling pathways. Masitinib inhibits mast cell survival, differentiation, and degranulation, including the cross-talk between mast cells and microglia, and thereby mediates control of an array of proinflammatory and vasoactive mediators by inhibiting their release. Such regulation of the neuroinflammatory network is reflected by modulation of the permeability (in this case, restoration of the integrity) of both the BBB and the blood-spinal cord barrier (BSCB) with concomitant containment of neuroinflammation by blocking the flow of inflammatory and vasoactive mediators into the brain and spinal cord.
Evidence of the consistency of the mechanism of action of masitinib has been demonstrated in a number of preclinical studies on SOD1-G93A transgenic rodents, which act as animal models of ALS.    
Thus, masitinib had a protective effect on the central nervous system. Masitinib reduced microgliosis and the number of aberrant glial cells, prevented degeneration of motor neurons, and significantly prolonged the survival of post-paralytic rodents.
Masitinib had a protective effect on the peripheral nervous system. Masitinib-mediated mast cell inhibition significantly reduced the rate of neuromuscular junction denervation and motor deficits, prevented mast cell and neutrophil infiltration, axonal pathology, secondary demyelination, and loss of type 2B muscle fibers, and reduced the reactivity of ALS-specific Schwann cell phenotypes in post-paralytic rodents.
Masitinib for ALS Treatment: Expert Comments
In late July 2018, the European Medicines Agency (EMA) refused to approve Alsitek for the treatment of amyotrophic lateral sclerosis (in combination with riluzole) based on key results from clinical trial NCT02588677 (no data on overall survival). A Marketing Authorization Application (MAA) for Alsitek was submitted by AB in mid-September 2016. According to the EMA’s Committee on Medicinal Products for Human Use (CHMP), the study did not provide robust evidence of the benefit of masitinib in ALS in terms of slowing disease progression.
Thus, the positive effect of Alsitek on ALS symptoms was observed in the group of patients in whom the disease progressed at a normal rate, but not in those patients in whom the disease progressed fast. The experts of the European regulator considered that this way of classifying patients is arbitrary and does not reflect real clinical practice. In addition, the experts pointed to the fact that there was no reason why masitinib would work in one group of patients and not in another.
An inspection of two clinical trial sites in Spain and Argentina found flaws in its implementation, raising questions about the validity of the data. The Committee also expressed concern about the way data from patients who withdrew from treatment were handled, which may have biased the results in favor of Alsitek.
AB is in no hurry to send a New Drug Application (NDA) for masitinib in ALS to the U.S. Food and Drug Administration (FDA). The French pharmaceutical company obviously understands the severity of the upcoming regulatory review.
However, AB hopes that Health Canada will be much more sympathetic. Especially in the mid-June 2022, the Canadian regulator approved Albrioza, developed by Amylyx for ALS treatment, while the FDA is delaying with the appropriate decision, citing insufficient evidence of the therapeutic usefulness of this drug. Thus, setting a precedent in Canada increases the chances of Alsitek appearing in that country.
Perhaps additional results on prolonging overall survival in patients with ALS will help secure regulatory approval for masitinib. It is possible that the Canadian regulator will restrict in some way the use of Alsitek, which has no therapeutic benefit in fast progressive ALS (ALSFRS-R decreasing by more than 1.1 points per month). There are approximately 15%–20% of such patients. Masitinib is also unlikely to help in advanced ALS, when too much time has passed since the manifestation of symptoms.
In any case, the deterrence of ALS progression demonstrated by Alsitek, even if relatively modest, offers new hope. ALS patients have to cling to every opportunity to stay alive, which is why masitinib, which prolongs life by about 1.5 times, can organically complement a set of such drugs, such as riluzole, Radicava/Radicava ORS (edaravone) by Japan’s Mitsubishi Tanabe Pharma, and Albrioza, which can prolong life by 2–3 months, twice, and at least 2.3 times, respectively.
The current commercial activity of AB is mainly in the sale of masitinib for veterinary medicine. The drug, approved in Europe in November 2008 as Masivet (masitinib), is used in the treatment of dogs with inoperable mastocytoma (with confirmed mutated c-Kit tyrosine kinase receptor).
In December 2015, veterinary Kinavet (masitinib) lost its U.S. approval, where it had been conditionally approved in December 2010 to treat dogs with recurrent or inoperable cutaneous mastocytoma: AB did not provide clinical data within five years that would conclusively confirm the drug’s effectiveness.
hello, can this medicine be made for ALS and is it reliable and safe? thank you. my mother is 67 years old with this disease in advanced stage
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