Masitinib: first drug to demonstrate a significant effect on progressive forms of MS

[ActiveMSers]

Pretty cool. -D

A selective tyrosine kinase inhibitor being studied for primary progressive multiple sclerosis (PPMS) and nonactive secondary progressive MS showed a 37% reduction in the risk of progression to disability at its lower dose, according to phase 2b/3 study results released Sunday at MSVirtual 2020: 8th Joint ACTRIMS-ECTRIMS Meeting.
https://www.ajmc.com/view/tyrosine-k...-to-disability

AB Science Presents Phase 2B/3 Study Results in Progressive Multiple Sclerosis at the World's Largest Multiple Sclerosis Research Conference

Email Print Friendly Share
September 14, 2020 00:58 ET | Source: AB Sciencemultilang-release

Paris, September 14, 2020, 7am

Press release

AB Science Presents Phase 2B/3 Study Results in Progressive Multiple Sclerosis at the World's Largest Multiple Sclerosis Research Conference

• 50% of patients suffering from multiple sclerosis have one of the progressive forms of the disease, for which there is no satisfactory treatment to date
• Masitinib, a tyrosine kinase inhibitor developed by AB Science, provides the first clinical evidence that targeting the innate immune system is an effective strategy for the treatment of progressive forms of multiple sclerosis.

AB Science SA (Euronext - FR0010557264 - AB), a pharmaceutical company specialized on the research, development and commercialization of protein kinase inhibitors (PKIs), announced today that it has presented the world's first key results from its Phase 2B/3 study (AB07002) evaluating its lead product, masitinib, in both progressive forms of multiple sclerosis¹ during the 8^th Joint Meeting of the European (ECTRIMS) and American (ACTRIMS) Committees for Treatment and Research in Multiple Sclerosis (MS). The congress was held in virtual format this year (MSVirtual2020) due to the COVID-19 pandemic.

Presented by Patrick Vermersch (MD, PhD), Professor of Neurology at the University of Lille, France, principal coordinator of study AB07002 and a recognized expert in multiple sclerosis, the results of this study demonstrate, for the first time, the efficacy of a therapeutic product in the treatment of patients suffering from both progressive forms of multiple sclerosis.

"These results are the start of a possible revolution in the treatment of multiple sclerosis, as it is the first time a treatment has shown efficacy in both progressive forms of this pathology," commented Professor Patrick Vermersch. "To date, there is no treatment capable of effectively targeting the cells that play a major role in the evolution of the progressive forms of multiple sclerosis. In addition, masitinib can be administered on a long-term basis as it is not an immunosuppressive treatment, which is particularly important in patients who are to receive long-term treatment and who, for some, have already an immune system weakened by previous treatments or because of their age. I am looking forward to continuing the development of this product and to seeing the realization of new therapeutic hope for these patients.”

A strong medical need for the progressive forms of multiple sclerosis

Multiple Sclerosis is an autoimmune disease of the central nervous system that affects more than 100,000 people in France and for which no definitive treatment exists to date. It is characterized by a progressive degradation of the nerve cells of the central nervous system by the patient's immune system and comes in two main forms.

The relapsing-remitting form characterized by relapses of the disease. During these relapses, patients experience the onset of new symptoms or the worsening of symptoms already present. These flare-ups are usually followed by recovery periods of varying length, after which some symptoms may persist. The relapsing-remitting forms of multiple sclerosis are mostly associated with dysfunctions of adaptive immunity² (B cells and T cells).

The progressive form, characterized by a constant and regular worsening of the symptoms of the disease, without a distinct relapse or period of recovery. The rate of onset of severe, disabling, and irreversible disability is much higher in the progressive forms of the disease than in the relapsing remitting forms. In progressive multiple sclerosis, innate³ immune cells such as macrophages, microglia or mast cells have been shown to probably play a major role.

To date, the vast majority of treatments for the management of multiple sclerosis target the patient's adaptive immune system and therefore apply mainly to the relapsing remitting forms of the disease. However, patients suffering from a progressive form of the disease currently account for approximately 50% of MS cases.

Masitinib: first drug in the world to demonstrate a significant effect on progressive forms of multiple sclerosis

AB Science's lead product, masitinib, is an oral tyrosine kinase inhibitor that specifically targets the innate immunity of patients with multiple sclerosis. In the Phase 2B/3 study, AB07002, conducted in 301 patients, masitinib at a dose of 4.5 mg/kg/day slowed disease progression in patients, which was the study’s primary objective. Masitinib also demonstrated a significant reduction in the risk of reaching a level of disability severe enough to require wheelchair mobility.

"With this conclusive study, AB Science is now on the verge of becoming the first biotech company in the world to propose a new approach for the treatment of progressive forms of multiple sclerosis. We will of course continue the development of this product and will as soon as possible initiate the process to start a confirmatory study, a necessary step to definitively validate the therapeutic potential of masitinib in a broader population" concludes Professor Olivier Hermine, Chairman of the Scientific Committee of AB Science and member of the French Academy of Sciences.

[ActiveMSers]

The neuros at Barts MS Blog had this to say about Masitinab:

https://multiple-sclerosis-research....msvirtual2020/

[ActiveMSers]

FC04.01 – MASITINIB IN PRIMARY PROGRESSIVE (PPMS) AND NON-ACTIVE SECONDARY PROGRESSIVE (NSPMS) MULTIPLE SCLEROSIS: RESULTS FROM PHASE 3 STUDY AB07002

Authors

• P. Vermersch
• O. Hermine

BACKGROUND
Masitinib (MAS) is a small molecule drug targeting KIT, LYN and CSF1R. Proof-of-concept that MAS slows progressive multiple sclerosis (MS) was previously demonstrated.

OBJECTIVES
Assessment of oral MAS as a treatment for progressive MS. Study AB07002 (NCT01433497) evaluated 2 independent parallel groups; 4.5 mg/kg/d vs matched placebo (PBO), and titrated MAS dose of 6.0 mg/kg/d vs PBO.

METHODS
Randomized (2:1), double-blinded, placebo-controlled, 2-parallel group trial. Eligible patients (pts) aged 18–75 years, with baseline Expanded Disability Status Scale (EDSS) 2.0–6.0, regardless of time-from-onset, and diagnosed with primary progressive (PPMS) or non-active secondary progressive (nSPMS) MS, were treated for 96 weeks. Primary endpoint was overall EDSS change from baseline using repeated measures (GEE model, timeframe W12–W96, measured every 12 weeks). Results are expressed as least-squares means difference (δEDSS, positive value indicates worsening), with treatment-effect reported as between-group difference (ΔLSM, negative value favors MAS). A key sensitivity analysis was the 3-level ordinal EDSS model (±1 or 0, repeated measures), which simultaneously measures improved, stable, or worsening outcomes over duration of treatment.

RESULTS
MAS (4.5mg/kg/d) (n=199, median EDSS=5.5, mean age=49.3±9.6 years) showed significant benefit over PBO (n=101) with δEDSS of 0.001 vs 0.098, respectively, and ΔLSM of -0.097(95%CI[-0.192,-0.002]);p=0.0256. This treatment-effect was numerically maintained for the subgroups of nSPMS (MAS n=120 vs 56) and PPMS (MAS n=79 vs 45) with ΔLSM of -0.104(95%CI[-0.198,-0.008]; p=0.032) and -0.128(95%CI [-0.285,0.0282];p=0.108), respectively. All EDSS sensitivity analyses were convergent with the primary outcome, including the conservative jump-to-reference approach with ΔLSM of -0.089 (95%CI[-0.173,-0.006];p=0.0367). Ordinal EDSS analysis showed a significant 39% relative probability of either reduction in EDSS progression or increase in EDSS improvement (hazard ratio (HR) 0.610 (95%CI[0.376,0.988];p=0·0446). Analysis of EDSS time-to-progression showed a significant reduced relative risk of 42% with MAS for first progression (HR 0.58, 95%CI[0.35,0.96];p=0.034), and a reduced relative risk of 37% with MAS for 12-week confirmed (HR 0.63, 95%CI[0.33,1.20];p=0.159). The proportion of pts presenting at least one adverse event (AE) was 94.5% for MAS (4.5 mg/kg/d) vs 87.1% for PBO. Safety was consistent with the known profile for MAS, common treatment-emergent AEs being diarrhea, nausea, rash, and hematological assessments. Efficacy results from the MAS high-dose parallel group (titrated 6.0 mg/kg/d) were inconclusive and no new safety signal was observed.

CONCLUSIONS
MAS (4.5 mg/kg/d), a first-in-class TKI targeting the innate immune system via inhibition of mast cell and microglia/macrophage activity, may provide a new treatment option for PPMS and nSPMS