A prospective, multicenter, randomised, double-blind, placebo-controlled, parallel groups, phase 3 study to compare the efficacy and safety of masitinib in combination with Riluzole versus placebo in combination with Riluzole in the treatment of patients suffering from Amyotrophic Lateral Sclerosis (ALS)

Masitinib (AB1010) is a small molecule drug of low molecular weight, belonging
to the tyrosine kinase inhibitor (TKI) family [6, 7]. Within this development,
masitinib is intended for the treatment of adult patients with ALS. The exact
molecular pathways causing motor neuron degeneration in ALS remain unknown, but
as with other neurodegenerative diseases, it is likely to involve a complex
interplay between multiple pathogenic cellular mechanisms.
Masitinib selectively inhibits specific tyrosine kinases such as
colony-stimulating factor 1 receptor (CSF-1R), c-Kit, LYN, FYN, and
platelet-derived growth factor receptor (PDGF-R) * and *, in the submicromolar
range [7; 8]. At the cellular level, masitinib is a potent inhibitor of
CSF-1R-dependent cell proliferation (IC50 90 nM), of wild-type (WT)
c-Kit-dependent cell proliferation (IC50 100-300 nM), of LYN- and FYN-dependent
cell proliferation (IC50 225-240 nM), and of PDGF-R-dependent cell
proliferation (IC50 0.25-20 nM). Two large-scale independent studies show
masitinib to have the highest selectivity from a wide range of protein kinase
inhibitors, including all those approved or under clinical development at the
time of publication [6; 8]. Selectivity generally indicates how safe a given
targeted treatment will be, the greater the number of kinases inhibited (i.e.
lower selectivity) the greater the potential for off-target effects and
toxicity.
Hence, because of its potent and selective activity against CSF-1R, masitinib
is able to inhibit the CSF1/CSF-1R signalling pathway thereby regulating
CSF-1R-dependent cells such as microglia, the immune cells of the central
nervous system that play a well know pathogenic role during ALS progression [9].
By merit of its activity against c-Kit, LYN and FYN, masitinib is also able to
inhibit mast cells, an effector immune cell key in chronic inflammatory
processes [10].
The development of masitinib in ALS is therefore based on the pharmacological
action of masitinib in microglia and mast cells, thereby slowing
microglial-related disease progression, reducing neuro-inflammation, and
modulating the degenerative neuronal microenvironment in both central (CNS) and
peripheral nervous systems (PNS). It is hypothesised that this multifaceted
therapeutic approach produced by masitinib, appears capable of generating the
beneficial treatment effects observed in humans (as evidenced by significant
improvement in relevant clinical measures of disease progression from clinical
assessment) and also from appropriate preclinical animal studies (as
exemplified by the significantly improved survival of SOD1G93A rats in a
post-paralysis therapeutic setting) [11-13].
Microglia play a fundamental pathogenic role during ALS disease progression. It
is now well-established in the literature that proliferation and accumulation
of microglial cells (microgliosis), which also promotes the emergence of
aberrant glial cells, is a major neuropathological feature of SOD1G93A ALS
animal models [14, 15]. Microglial cells are regulated by the CSF1/CSF-1R
signalling pathway. Additionally, evidence suggests that ALS is a
neurodegenerative disorder in which cross-talk between mast cells, microglia
and astrocytes may result in motor neuron damage [16]. Thus, while microglia
and mast cells individually play important roles in sustaining the inflammatory
network of the PNS and CNS, the existence of mast cell-microglia cross-talk is
likely to further contribute to the exacerbation of neurodegenerative disease
and to accelerate disease progression [16]. Microglia and mast cells therefore
represent potential therapeutic targets in ALS for a pharmacological agent
capable of simultaneously modulating their pathogenic roles.
Mast cells orchestrate inflammatory processes and contribute to the
neuroinflammatory cascade by merit of the wide array of pro-inflammatory
mediators they release. Indeed, mast cells represent one of the main CNS
sources of cytokines and chemokines [17; 19]. In both CNS and PNS, as in other
tissues, activated mast cells may undergo explosive degranulation or may
steadily release granules into their microenvironment. Following activation,
mast cells remain intact and viable to resynthesize their granules. Secretory
granules store a wide variety of mediators, which when released into the CNS
can alter the function of both neural and vascular elements. The importance of
c-Kit, LYN and FYN for mast cell function and activation is well-known.

The objective is to evaluate the efficacy and safety of two doses of masitinib
(4.5 mg/kg/day and 6.0 mg/kg/day) versus matching placebo in patients diagnosed
with ALS treated with Riluzole (50 mg bid).
The primary objective is to demonstrate statistically significant improvement
from baseline in ALSFRS-R after 48-week treatment of two doses of masitinib
versus matching placebo in patients diagnosed with ALS treated with Riluzole.
Secondary objectives are to assess the efficacy and safety of two doses of
masitinib versus matching placebo in the treatment of patients diagnosed with
ALS treated with Riluzole:
Clinical assessments:
* Progression-free survival (PFS): decline of more than 9-points in ALSFRS-R
score from baseline or death from baseline to last patient last W48 visit
* Change in % of FVC from baseline to week 48
* Change from baseline in evaluation of upper- and lower-limb muscle strength
using hand-held dynamometry (HHD) at week 48
* Combined Assessment of Function and Survival (CAFS)
* Overall Survival (OS) from baseline to last patient last W48 visit
Quality of Life assessment:
* Change from baseline in ALSAQ- 40 at week 48
Clinical Global Impression assessment:
* Change in each component of Clinician-rated CGI from baseline to week 48
Safety:
* Occurrence of Adverse Events (AE), changes on clinical examination including
vital signs (blood pressure, heart rate) and weight, Electrocardiogram (ECG)
and safety laboratory results (biochemistry, haematology and urinalysis) during
the study period
Pharmacodynamic/biomarker(s):
* Identification of pharmacodynamic biomarker(s) is needed to fully
characterize the potential disease modifying effects of masitinib in ALS
patients. The aim is to assess, before and during study treatment,
cerebrospinal fluid (CSF) in up to 30 ALS patients and serum biomarkers in all
randomized ALS patients known to be associated with the evolution of the
disease and potentially modulated by masitinib treatment
Pharmacogenomic (in case of severe neutropenia and/or severe skin toxicity):
* Determination of the genetic polymorphisms, including HLA polymorphisms that
could be associated with an increased risk of masitinib-induced severe
neutropenia and severe skin toxicity
*Measurement of pharmacokinetic parameters of masitinib and Riluzole in up to
10 ALS patients per group and validate population PK model for masitinib

AB19001 is a multicenter, randomized, double-blind, placebo-controlled, phase 3
study to compare the efficacy and safety of two doses of masitinib (4.5
mg/kg/day or 6.0 mg/kg/day) in combination with Riluzole (50 mg b.i.d) versus
matching placebo in combination with Riluzole (50 mg b.i.d) in the treatment of
patients diagnosed with ALS.
Patients enrolled will be randomised in 3 groups :
- Group 1: 165 patients will receive a dose of masitinib (starting from 3.0
mg/kg/day during 4 weeks followed by a dose of 4.5 mg/kg/day for 4 weeks
followed by a dose of 4.5 mg/kg/day of masitinib and 1.5 mg/kg/day of placebo)
as add-on therapy to Riluzole at 50 mg b.i.d.
- Group 2: 165 patients will receive a dose of masitinib (starting from 3.0
mg/kg/day during 4 weeks followed by a dose of 4.5 mg/kg/day for four weeks
followed by a dose of 6.0 mg/kg/day) as add-on therapy to Riluzole at 50 mg
b.i.d.
- Group 3: 165 patients will receive a dose of matching placebo as add-on
therapy to Riluzole at 50 mg b.i.d.

NA

ALS is a rare progressive, fatal motor neuron disease characterised by axonal
degeneration and progressive loss of the upper and lower motor neurons
throughout the central nervous system. Patients with ALS experience progressive
denervation and atrophy of skeletal muscles and in the majority of cases die
from respiratory failure.
To date, therapeutic options are still very limited. Riluzole is the only
approved medication for modifying disease progression in ALS and apart from
that treatment is mainly palliative. Although relatively well tolerated, there
are hepatotoxicity concerns associated with Riluzole, and its efficacy remains
insufficient. Considering the seriousness of the disease and the limited
options for treatment, there is still a high unmet medical need for patients
suffering from ALS.
Study AB10015 assessed a 48-week treatment with oral masitinib administered in
addition to standard of care for treatment of ALS patients. The Trial enrolled
a credible number of patients (n=394) and applied broad inclusion criteria in
terms of disease duration (<36 months) and as well as baseline ALSFRS-R score
for inclusion (no restriction).
Study AB10015 presented some methodological limitations, and the conduct and
the analysis of Study AB10015 were considered by the CHMP not sufficiently
robust to support registration on the basis of a single clinical study, based
on interim data and safety data that were not final at the time of the final
decision of the CHMP.
However, this study clearly indicated positive treatment effects on change in
ALSFRS, PFS, FVC, and Quality of life is the so called normal progressors,
accounting for 85% of the study population. There was no benefit on survival.
There was no benefit the overall normal + fast population based on the
inclusion criteria of AB10015 study.
Study AB10015 also showed significant potential benefits for patients with less
advanced stage of the disease. In these patients with a baseline score of at
least 1 on each of the 12 items of the ALSFRS-R score, a statistically
significant treatment effect (reduction in rate of progression compared to
active control group of 20.3%; p=0.0315) were considered as clinically relevant
in the overall normal + fast progressor. This analysis in patients with a
baseline score of at least 1 on each of the 12 ALSFRS score items accounted for
80% of the overall study population and included both Normal and Fast
Progressors (>10%). This result strongly suggests of stronger treatment effect
of masitinib when patients are treated at an earlier stage of the disease.
In Study AB10015, the overall safety of masitinib at 3.0 and 4.5mg/kg/in ALS
patients was comparable to results observed in other indications. Most patients
on masitinib sustained well documented self-limited adverse reactions which
were more prevalent at the start of therapy and manageable with simple dose
interruption or reduction. These included frequent gastrointestinal symptoms,
peripheral fluid retention, and skin rashes typically observed with other
tyrosine kinase inhibitors. Because of the nature of these reactions, and
because their impact can be mitigated with dose titrations, these reactions do
not represent a safety concern in a population of ALS patients.
A total of 67 patients had at least one fatal SAEs including 33 patients during
the main protocol period and 34 patients during the extension period (up to the
data lock point). In addition of these 67 patients who died during the planned
study period, 14 patients died after the data lock point. A review of the
causes of these 67 and 14 deaths revealed that most patients died of
progression of disease, cardiac and respiratory complications, and infections
related to ALS. The death rates related to fatal SAEs during the main protocol
period were comparable amongst study treatment groups, with a trend towards
lower rates in masitinib groups compared to placebo (i.e. 7.8% in masitinib 4.5
mg/kg/days and 8.4% in masitinib 3.0 mg/kg/days versus 9.0% in placebo). During
the extension period, a reverse trend was observed with higher rates in
masitinib groups compared to placebo (10.9% in masitinib 4.5 mg/kg/days and
9.9% in masitinib 3.0 mg/kg/days versus 5.3% in placebo).
In the subgroup of patients matching the inclusion criteria to be applied for
AB19001, a total of 15 patients had at least one fatal SAEs including 7
patients during the main protocol period and 8 patients during the extension
period (up to the data lock point) . The death rates related to fatal SAEs
during the main protocol period was 3.1% in masitinib 4.5 mg/kg/days and 9.1%
in masitinib 3.0 mg/kg/days versus 11.1% in placebo. During the extension
period, The death rates related to fatal SAEs was 12.5% in masitinib 4.5
mg/kg/days and 0.0% in masitinib 3.0 mg/kg/days versus 11.1% in placebo.
As seen in AB10015 as well as in other indications, a smaller number of
patients taking masitinib may sustain more severe and potentially
life-threatening reactions. Those included primarily severe skin reactions,
severe neutropenia and agranulocytosis, and drug induced liver injuries.
Although not frequent and fully recoverable, these reactions do represent a
safety concern. With a large safety database, it has been demonstrated that the
impact of those reactions on patients can be efficiently reduced with adequate
risk minimization measures. These measures include exclusion of patients with
pre-existing risk factors, training of study personnel, frequent monitoring
assessments, reduced dosing regimens and specific dose modifications scheme
adjusted to each risk. Despite the serious nature of these reactions, both
their impact and frequency can be reduced with adequate measures, and
therefore, those risks are considered to be acceptable for the studied
indication. In particular, the number of patients experiencing any severe
skin-related AEs for the overall population was reduced from 36 for the first
500 patients to 1 last 500 patients, and the number of patients experiencing
any events related to severe neutropenia and related terms for the overall
population was reduced from 16 for the first 500 patients to 8 last 500
patients. Based on preclinical studies, potential important risks associated
with masitinib exposure have been detected, including risks of cardiac
toxicity, renal toxicity and carcinogenicity. These risks have not yet been
confirmed in the clinical development of masitinib. In AB10015, an apparent
higher-than-expected mortality was observed in the masitinib arms compared to
placebo. Thorough analyses were performed to evaluate the cause of these
deaths. There was no conclusive evidence found that these deaths were
associated with any cardiotoxic effect of masitinib. The most plausible cause
for these deaths appeared to be ALS worsening.
A set of monitoring measures have been implemented in all studies of masitinib
in order to minimize those important potential risks, which include i)
Restriction of eligibility criteria, ii) Dose titration, iii) Strict dose
adjustment and discontinuation rules, and iv) Implementation of a Data Safety
Monitoring Board (DSMB) for periodic benefit risk assessment.
Overall, considering the impact of ALS on the life prognosis of patients
suffering from the disease, the urgent need for developing more efficacious ALS
therapeutic alternatives, and based on the study results from AB10015, the
potential benefit associated with masitinib outweigh the known and potential
risks of masitinib in treating patients with ALS to start a confirmatory phase
3 study.