Masitinib in Inflammatory Diseases



Severe Asthma

The severity of asthma can be graded from mild intermittent disease, with little impact on everyday life, through to severe disease with permanent symptoms and serious limitation of normal activities.

Data suggests that mast cells are involved in allergic and anaphylactic reactions, playing an important role in hypersensitivity and inflammatory processes of the disease and also tissue remodeling of the airways.

Masitinib is currently investigated both in severe asthma uncontrolled by oral corticosteroids (OCS) and severe asthma uncontrolled by high dose inhaled corticosteroids (ICS).

Asthma uncontrolled by oral corticosteroid is the most severe form of asthma (step 5 of the GINA guidelines for asthma management) and represents a high unmet medical need. Quality-of-life for such patients is severely affected, with major reduction in lung function, restrictions on activities of daily living, frequent asthma exacerbations and greater risk of life-threatening asthma exacerbations.


The ability and effect of masitinib to inhibit mast cell function in asthma was explored in a classical murine model of allergic airway inflammation. The results showed a dose response effect of masitinib on mast cells recruitment in lung tissue. 
 
Mast cells appear to play a central role in the pathogenesis and persistence of asthma, and thus in severe asthma uncontrolled by oral corticosteroids. There is a growing consensus that airway inflammation is a critical element in the pathogenesis of asthma, and that asthma is in fact a chronic inflammatory syndrome in which inflammation promotes airway hyperresponsiveness and airway obstruction. The growing awareness that these common features are important resulted in the current NAEP definition of asthma (National Asthma Education Program, 1991), which emphasizes that asthma is characterized by reversible obstruction and hyper- responsiveness of the airways with both of these physiological abnormalities occurring on a background of airway inflammation.
 
A classical view of the pathogenesis of the asthmatic inflammation is that, following the immunization phase and the development of an immune response, allergens initiate the inflammatory process by triggering IgE-bearing pulmonary mast cells. Mast cell activation leads to the release of multiple mediators which produce a localized allergic response, and subsequently, secrete various cytokines which then participate in the local recruitment and activation of other inflammatory cells such as eosinophils, basophils, T lymphocytes and mononuclear phagocytes. These recruited cells, in turn, contribute to the development of an inflammatory response, which may then become persistent, and thereby perpetuate the asthmatic symptoms.
 
Masitinib, by inhibiting mast cells activation is expected to show clinical benefits in patients with moderate to severe asthma and to be an alternative to ineffective corticosteroid therapy.

 

Summary of severe asthma clinical program with masitinib

Phase Design Population Primary Target Patient Target IDMC recommandation Study Status Related publications
2a Double-blind, placebo-controlled, parallel-group study Patients with severe corticosteroid dependent asthma

Change from baseline in corticosteroids doses, after

4 months of treatment
44 NA Study completed Humbert, 2009
2/3 Prospective, double-blind, placebo-controlled, 2-parallel groups study Patients with severe asthma uncontrolled with oral corticosteroids Severe Asthma exacerbation rate adjusted on the available person-time (time to end of treatment) 420 Continuation of the study without resampling option (based on interim analysis and safety data) Recruitment completed -
3 Prospective, double-blind, placebo-controlled, 2-parallel groups study Patients with severe asthma uncontrolled with high dose of inhaled corticosteroids and with elevated eosinophil levels Severe Asthma exacerbation rate adjusted on the available person-time (time to end of treatment) 350 Continuation of the study (based on safety data) Recruitment completed  



Phase 2a proof of concept

Clinical phase 2a proof of concept with masitinib in asthma supported the development of masitinib in severe asthma uncontrolled with corticosteroids. In this phase 2a study, a comparable reduction in oral corticosteroids was achieved with masitinib and placebo at 16 weeks of treatment (median reduction of 78% and 57% in the masitinib and placebo arms, respectively). However, when focusing on the truly dependent corticosteroids asthma patients, meaning patients receiving > 15mg equivalent prednisone per day, a significant difference was observed. In this subgroup of patients, doses of corticosteroids were reduced by 52% in masitinib treated patients compared to 28% in placebo treated patients. In parallel, the number of patients experiencing at least one exacerbation during the study period was 42.4% and 54.5% in the masitinib-treated and placebo groups, respectively. Additionally, an improved asthma control was observed in masitinib- treated patients, the Asthma Control Questionnaire score was significantly better in the masitinib arm as compared to placebo with a reduction by 0.99 unit at week 16 vs 0.43 unit in the placebo arm.


Phase 3 studies

First phase 3 study

AB Science launched a phase 3 study to assess the safety and efficacy of masitinib in severe asthma uncontrolled by oral corticosteroids.
The Independent Data Safety and Monitoring Committee (IDMC) has, on each occasion, recommended the continuation of this phase 3 study based on the analysis of the safety data.
 
In February 2017, an interim analysis was performed and the IDMC did not request implementation of the protocol resampling option.
 
Recruitment was completed with 420 enrolled patients.

 

Second phase 3 study

AB Science has initiated a second pivotal phase 3 study in asthma uncontrolled by high-dose inhaled corticosteroid and with elevated eosinophil levels.
 
This second study has been launched on the basis of preclinical data from mice and cats that showed masitinib can reduce eosinophil levels in the context of asthma [Lee-Fowler, 2012].This effect in eosinophil levels coupled with the existing clinical data of masitinib in severe asthma justifies investigation of the therapeutic use of masitinib in this subpopulation.
 
The IDMC has, on each occasion, recommended the continuation of this phase 3 study based on the analysis of the safety data.
 
Recruitment was completed with 347 enrolled patients.
Asthma uncontrolled by oral corticosteroid represents the most severe form of asthma and represents a high unmet medical need. The quality of life of these patients is severely impacted, with major reduction in lung function, restrictions on activities of daily living, work absenteeism, night-time awakening several times a week, frequent exacerbations and greater risk of life-threatening asthma exacerbations. The target population in adult patients is estimated at 70,000 in the USA and in the EU.
 
The patient population in asthma uncontrolled by high-dose inhaled corticosteroid plus long-acting beta-agonists (LABAs) and with elevated eosinophil level is much broader and is estimated to affect 1,500,000 adults in the USA and Europe.
Masitinib, a c-kit/PDGF receptor tyrosine kinase inhibitor, improves disease control in severe corticosteroid-dependent asthmatics.
Humbert M, de Blay F, Garcia G, Prud'homme A, Leroyer C, Magnan A, Tunon-de-Lara JM, Pison C, Aubier M, Charpin D, Vachier I, Purohit A, Gineste P, Bader T, Moussy A, Hermine O, Chanez P.
Allergy. 2009 Aug;64(8):1194-201. doi: 10.1111/j.1398-9995.2009.02122.x.

The tyrosine kinase inhibitor masitinib blunts airway inflammation and improves associated lung mechanics in a feline model of chronic allergic asthma.
Lee-Fowler TM, Guntur V, Dodam J, Cohn LA, DeClue AE, Reinero CR. Int Arch Allergy Immunol. 2012;158(4):369-74.

Mastocytosis

Mastocytosis is a rare disease characterized by proliferation and accumulation of mast cells in various tissues, causing a wide variety of clinical symptoms. Indolent systemic mastocytosis, including the subvariant of smouldering systemic mastocytosis, is a lifelong condition associated with reduced quality-of-life.

Masitinib is being developed in severely symptomatic indolent systemic mastocytosis, which accounts for about 35%of disease’s total population. AB Science has completed a phase 3 study in this patient population with promising results. These findings have been published in The Lancet medical journal. A confirmatory phase 3 study will be launched in 2019. Masitinib is currently the only drug in advanced clinical development for treatment of indolent systemic mastocytosis with severe symptoms.

In recognition of the critical need for new treatments, masitinib received orphan drug designation for mastocytosis from both the European Medicine Agency (EMA) and the U.S. Food and Drug Administration (FDA).


Scientific rationale for masitinib development in mastocytosis

Mastocytosis (also referred to as mast cell disease) is defined as a clonal, neoplastic proliferation and accumulation of mastocytes in one or multiple organs. Clinical signs and symptoms result from the release of chemical mediators and by the infiltration of organs by neoplastic mast cells. Accumulation of mastocytes in body organs can inhibit the functionality of the organ and eventually cause degeneration. Mastocytosis typically involves the skin and the bone marrow but may also involve other organs.
 
Symptoms of mastocytosis are caused by the uncontrolled accumulation of mastocytes and release of their mediators. Deregulated activity of the c-KIT/SCF pathway in mastocytosis is related to mutations in the c- KIT receptor [Tsujimura, 1994; Longley, 2001]. It has been shown that between 70% and 90% of patients with systemic mastocytosis carry the gain-offunction Asp-816-Val (D816V) mutation in the kinase (phosphotransferase) domain of c-KIT, with the remainder (10% and 30%) carrying mutations in other domains of the molecule, such as the transmembrane domain. The D816V c-KIT mutation is also found in some patients with cutaneous mastocytosis. This mutation is associated with ligand-independent constitutive activation of c-KIT/SCF signaling, leading to uncontrolled mast cell proliferation, resistance to apoptosis and mediator release.
 
As demonstrated in vitro, masitinib is an effective anti-mast cell agent by exerting a direct anti-proliferative and pro-apoptotic action on mast cells through inhibition of wild-type and D816V mutated c-KIT/SCF signaling, but also by regulating the activation of mast cells through its targeting of Lyn, Fyn and Lck. Masitinib may represent a promising effective therapeutic strategy to alleviate symptoms and slow the progression of mastocytosis and related diseases.

Summary of mastocytosis clinical program with masitinib

Phase Design Population Primary Target Patient Target IDMC recommandation Study Status Related publications
2a

Prospective, open-label,
2-parallel group study

Patients with mastocytosis with handicap and bearing activating point mutations in the phosphotransferase domain of c-Kit (D816V) Masitinib efficacy on 2 out of these 4 variables : Pruritius, Flush, Hamilton score and Fatigue Impact Scale 21 NA

Study completed

-
2a Open-label,
2-parallel group study
Patients with systemic indolent mastocytosis with handicap and not bearing activating point mutations in the phosphotransferase domain of c-Kit (D816V)

Masitinib efficacy on Pruritius, Flush, Pollakyuria, Number of stools, QLQ-C30 score and Hamilton Score

25 NA Study completed -
 3 Prospective, double-blind,
2-parallel group study
Patients with documented smouldering or indolent systemic mastocytosis with severe handicap Cumulative response by handicap (Pruritius, Flush, Hamilton score and Fatigue Impact Scale). Response on a handicap is defined as an improvement ≥ 75%  130 NA  Study completed  Lortholary, 2017
(The Lancet)



Phase 2a proves of concept

Clinical phase 2a proves of concept with masitinib in mastocytosis supported the development of masitinib in mastocytosis. These two phase 2a studies enrolled a total of 46 patients in two sub-populations of patients suffering from indolent mastocytosis with handicap: one study in patients who did not carry the D816V mutation on the c-Kit gene and another in patients who did carry this mutation.
 
In the study with patients carrying the D816V mutation, the percentage change from baseline at week 12 in number of flushes per day, depression (Hamilton score) and pruritus was 55%, 49% and 45% respectively.
 
In the study with patients not carrying the D816V mutation, the percentage change from baseline at week 12 in number of flushes per day, depression (Hamilton score) and pruritus was 64%, 43% and 36% respectively.

 

Phase 3 study

AB Science completed a pivotal phase 3 study to compare masitinib plus optimal symptomatic treatment versus placebo plus optimal symptomatic treatment in adult patients with severe systemic mastocytosis.
 
In the predefined subpopulation including patients with smouldering or indolent systemic mastocytosis with severe handicaps, the study results showed that masitinib was superior to placebo, as measured by the cumulative 75% response rate until week 24 on the handicaps of pruritus or flushes or depression or fatigue (4H75% response). The 4H75% response was 18.7% for the masitinib treatment-arm versus 7.4% for the placebo treatment-arm (p=0.0076) in the mITT population.
A reduction in the tryptase, which is an objective biological marker of mast cell burden and activity was also observed. The mean change in tryptase level relative to baseline was minus 18.0% for the masitinib treatment-arm versus +2.2% for the placebo treatment-arm (p=0.0001).
Masitinib induced a disappearance of the Darier’s sign, which visually flags the presence of activated mast cells in the skin. The disappearance of Darier’s sign from those patients having this symptom at baseline was 18.9% for masitinib treated patients versus 2.7% for placebo treated patients, (p=0.0187).
The treatment effect observed with masitinib within the first 6-month treatment period was sustainable over 2 years.
 
These results have been published in The Lancet.
 
In order to confirm the findings from this first phase 3 study, AB Science plans to launch a second phase 3 study in smouldering or indolent systemic mastocytosis with severe handicaps.

 

Mastocytosis is an orphan disease characterized by an abnormal proliferation or activation of mast cells either in the skin or in bone marrow or other organs. Mastocytosis comes in two main forms: indolent and aggressive. Indolent forms of mastocytosis can be either cutaneous or systemic. The prevalence of indolent systemic mastocytosis, including smouldering systemic mastocytosis, is estimated to be 1/26,000 in Europe. The symptoms and handicaps are severe in about one third of the patients; hence, an estimated target population for masitinib of approximately 1/78,000 of the general population.
 
Since the prevalence of indolent forms of systemic mastocytosis is reputed to be comparable across countries, the target population for masitinib could reach 10,000 adult patients in the USA and in Europe.

 

Masitinib for treatment of severely symptomatic indolent systemic mastocytosis: a randomised, placebo-controlled, phase 3 study.
Lortholary O, Chandesris MO, Bulai Livideanu C, Paul C, Guillet G, Jassem E, Niedoszytko M, Barete S, Verstovsek S, Grattan C, Damaj G, Canioni D, Fraitag S, Lhermitte L, Georgin Lavialle S, Frenzel L, Afrin LB, Hanssens K, Agopian J, Gaillard R, Kinet JP, Auclair C, Mansfield C, Moussy A, Dubreuil P, Hermine O.
Lancet. 2017 Feb 11;389(10069):612-620. doi: 10.1016/S0140-6736(16)31403-9. Epub 2017 Jan 7.

Depression in patients with mastocytosis: prevalence, features and effects of masitinib therapy.
Moura DS, Sultan S, Georgin-Lavialle S, Pillet N, Montestruc F, Gineste P, Barete S, Damaj G, Moussy A, Lortholary O, Hermine O.
PLoS One. 2011;6(10):e26375. doi: 10.1371/journal.pone.0026375. Epub 2011 Oct 21.

Masitinib for the treatment of systemic and cutaneous mastocytosis with handicap: a phase 2a study.
Paul C, Sans B, Suarez F, Casassus P, Barete S, Lanternier F, Grandpeix-Guyodo C, Dubreuil P, Palmérini F, Mansfield CD, Gineste P, Moussy A, Hermine O, Lortholary O.
Am J Hematol. 2010 Dec;85(12):921-5. doi: 10.1002/ajh.21894.

Mast cell leukemia: identification of a new c-Kit mutation, dup(501-502), and response to masitinib, a c-Kit tyrosine kinase inhibitor.
Georgin-Lavialle S, Lhermitte L, Suarez F, Yang Y, Letard S, Hanssens K, Feger F, Renand A, Brouze C,
Canioni D, Asnafi V, Chandesris MO, Aouba A, Gineste P, Macintyre E, Mansfield CD, Moussy A, Lepelletier Y, Dubreuil P, Hermine O.
Eur J Haematol. 2012 Jul;89(1):47-52. doi: 10.1111/j.1600-0609.2012.01761.x. Epub 2012 Apr 28.


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