Presentation on masitinib in ALS delivered at 2023 AAN Annual Meeting

Masitinib Shows Prolonged Survival in Amyotrophic Lateral Sclerosis (ALS) Patients with Mild or Moderate Disease Severity at Baseline Albert C. Ludolph Department of Neurology, University of Ulm, Ulm; German Center for Neurodegenerative Diseases, Ulm, Germany Conflict of Interest Disclosure • Dr. Ludolph is the Steering Committee chair of the current masitinib trial (AB19001, AB Science) • Dr. Ludolph has received personal compensationin the range of $500-$4,999 for servingas a Consultant for Novartis. Dr. Ludolph has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen . Dr. Ludolph has received personal compensationin the rangeof $500-$4,999 for servingas a Consultant for Roche PharmaAG . Dr. Ludolph has received personal compensationin the range of $500-$4,999 for servingon a Scientific Advisoryor Data Safety Monitoring board for Biogen.Dr. Ludolph has received personal compensationin the range of $500-$4,999 for servingon a Scientific Advisoryor Data Safety Monitoring board for Roche Pharma.Dr. Ludolph has received personal compensationin the range of $500-$4,999 for servingon a Speakers Bureau for Biologix FZCo.. Dr. Ludolph has received personal compensationin the rangeof $500-$4,999 for servingon a Speakers Bureau for Biologix FZCo.. Dr. Ludolph has received personal compensationin the rangeof $500-$4,999 for serving on a Speakers Bureau for Biologix FZCo .. Dr. Ludolph has received personal compensationin the range of $500-$4,999 for servingon a Speakers Bureau for Biogen.Dr. Ludolph has received personal compensationin the range of $500-$4,999 for servingon a Speakers Bureau for Biogen.Dr. Ludolph has received personal compensationin the range of $500-$4,999 for servingon a Speakers Bureau for Biogen.Dr. Ludolph has received personal compensationin the rangeof $500-$4,999 for servingon a Speakers Bureau for Teva. Masitinib modulates inflammation  Masitinib exerts a potential protective effect on the central nervous system  Regulates microglia, cells with well-known pathogenic role during ALS progression  Reduction of microgliosis and aberrant glial cells through CSF-1R inhibition 32nd International Symposium on ALS/MND Virtual (7 - 10 December 2021)  Masitinib exerts a protective effect on the peripheral nervous system  Mast cell infiltration and degranulation contribute to neuromuscular pathology in post-paralytic SOD1G93A rats  Masitinib-induced mast cell inhibition significantly reduced rate of motor and neuromuscular junction (NMJ) deficits  Mast cell infiltration was observed in muscle and sciatic nerve of ALS patients  Mechanistic evidence suggests masitinib would provide better outcomes if administered early in disease course  Masitinib significantly reduced terminal Schwann cell loss and preserved motoneuron sprouting capacity Study AB10015 overview ❖ Double blind, placebo controlled, randomized 1:1:1, oral BID, 48 weeks  Masitinib 4.5 mg/kg/day + riluzole  Masitinib 3.0 mg/kg/day + riluzole  Placebo + riluzole ❖ Main Inclusion Criteria  Sporadic or familial ALS  Stable dose of riluzole  Disease duration ≤36 mo, FVC ≥60% ❖ Primary endpoint Change in the ALSFRS-R score at 48 weeks (ΔALSFRS-R) ❖ Primary efficacy population Cohort receiving masitinib 4.5 mg/kg/d with ΔFS <1.1 ❖ 394 patients, 9 countries, 34 sites ❖ Study AB10015 was a placebo controlled phase 3 trial of masitinib in ALS  Masitinib 4.5 mg/kg/d administered as an add-on to riluzole significantly slowed the rate of functional decline in ALS patients having an ALSFRS-R progression rate from onset to baseline (ΔFS) of <1.1 points/month  The safety and risk profile of masitinib was manageable in patients with ALS https://doi.org/10.1080/21678421.2019.1632346 Long-term follow-up of study AB10015 Objectives: 1. Perform long-term survival analysis on a post-hoc survival dataset o Overall survival (OS) was a key efficacy endpoint of study AB10015 o At time of unblinding, OS data were too immature to interpret Estimate survival in an enriched population that excludes severe and/or very severe patients o Consistent with the idea (current ALS trial recommendations) to select ALS patients as early as possible in the course of their disease o The moderate (non severe) ALS subgroup* is similar to prospectively defined patient population for ongoing confirmatory study AB19001 Enriched patient populations analyzed (ΔFS <1.1) ALS (functional) severity at baseline ALSFRS-R score 1 *Moderate ALS No complete loss or severe impairment of function ≥2 on each item 2 Moderate–Severe ALS No complete loss of function ≥1 on each item 3 Moderate–Severe–Very Severe Corresponds to population of study AB10015 any score Long-term survival study design ❖ Cut-off date for survival data: 14 June 2020, in 100 % of patients survival status ❖ Survival (vital) status collected from each participating investigational site (patients still alive at the time of analysis censored at the date of last contact) PBO (n) M4.5 (n) M3.0 (n) Total (n) Overall (mITT) population 133 130 131 394 Survival status <7 mo prior to cut-off 128 (96%) 122 (94%) 124 (95%) 374 (95%) Survival status older than 7 mo 5 (4%) 8 (6%) 7 (5%) 20 (5%) ❖ Follow-up incorporated a masitinib treatment ‘compassionate use’ with inclusion of 59 pts from masitinib arms and 25 pts (crossover) from the placebo arm ❖ 95% of patients had survival status verified less than 7 months prior to cut-off ❖ Results reported here are based on the hard database lock (9/2021) ❖ Survival analysis of all patients randomized in study AB10015 for an average observation period of 75 months (date of diagnosis – cut-off) Long-term survival analysis results N Deaths Median OS [95%CI] ΔOS (months) P- value MAS PBO MAS PBO MAS PBO Moderate ALS (ΔFS<1.1) 45 62 21 (47%) 38 (61%) 69 [45;NE] 44 [33;62] +25 < 0.05 Moderate/Severe ALS (ΔFS<1.1) 85 104 44 (52%) 66 (63%) 53 [36;NE] 43 [31;49] +10 < 0.05 Moderate/Severe/Very severe ALS (ΔFS<1.1) 106 114 60 (57%) 73 (64%) 46 [33;69] 40 [30;48] +6 NS ❖ Median overall survival analysis ❖ Kaplan-Meier survival analysis❖ Hazard ratio (HR) analysis ❖ Baseline characteristics from enriched populations were balanced Number of patients at risk 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 Time since randomization (M onths) 0 10 20 30 40 50 60 70 80 90 100 S urvival probability (%) 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 Time since randomization (M onths) 0 10 20 30 40 50 60 70 80 90 100 S urvival probability (%) Masitinib 4.5 Placebo Moderate ALS (≥2 each baseline ALSFRS-R item) ΔFS<1.1 –––– Placebo –––– Masitinib 4.5 mg/kg/d Impact of enrichment on ∆ALSFRS-R & PFS ❖ Enriched populations showed consistency of treatment-effect on the main dataset of study AB10015: ∆ALSFRS-R at week 48 (primary endpoint) & PFS (secondary endpoint) ❖ Long-term OS, ∆ALSFRS-R and PFS showed the same pattern of greater treatment- effect when masitinib was initiated at an earlier stage of disease Increasing benefit Consistent Pattern Increasing benefit Masitinib 4.5 mg/kg/d vs placebo (ΔFS<1.1) Moderate / Severe / Very Severe ALS Moderate / Severe ALS Moderate ALS (M4.5=106; PBO=114) (M4.5=85; PBO=104) (M4.5=45; PBO=62) ∆ALSFRS-R mLOCF (Primary analysis) Delay in progression -27% -31% -42% Diff. of mean 3.39 4.04 4.68 p-value 0.016 0.006 0.018 ∆ALSFRS-R (sensitivity) Multiple Imputation Diff. of mean 3.44 3.52 3.94 p-value 0.020 0.027 0.068 ∆ALSFRS-R (sensitivity) Jump to Reference Diff. of mean 2.80 3.01 3.33 p-value 0.039 0.040 0.088 Median PFS (Secondary analysis) Gain in Median PFS + 4 months + 9 months + 13 months Median [95% CI] 20 [14,30] vs 16 [11,19] 25 [17,NE] vs 16 [11,19] 30 [22,NE] vs 17 [11,33] p-value 0.016 0.006 0.060 Median OS (Long term survival) Gain in Median OS + 6 months +10 months + 25 months Median OS [95% CI] 46 [33,69] vs 40 [30,48] 53 [36,NE] vs 43 [31,49] 69 [45,NE] vs 44 [33,62] Reduced risk 23% 30% 44% Hazard Ratio [95% CI] 0.77 [0.55,1.10] 0.70 [0.48,1.03] 0.56 [0.32,0.96] ALS prior to any complete loss of function ❖ New analyses based on ALS population with >0 on each item of the ALSFRS-R o Unlike previous analyses, includes both ‘Normal’ (ΔFS <1.1 ) and ‘Fast’ (ΔFS ≥1.1 ) Progressors o Accounts for ~80% of the AB10015 population; balanced baseline characteristics o Exclusion of these pts is justified in the context of treating neurodegenerative disease and consistent with masitinib’s neuroprotective mechanism ❖ Treatment-effect seen across multiple endpoints, including: Relative benefit (masitinib vs control) p-value CAFS 18.4% 0.035 ΔALSFRS-R 25% 0.027 Median OS* Not reached n/a LT median OS** +8 months 0.068 ΔFVC 20.4% 0.022 ΔALSAQ-40 19.8% 0.025 * Study cut-off: December 2016. **LT OS cut-off: June 2020; adjusted for pts switching to masitinib (censored at crossover) o Significant CAFS (joint rank analysis of function and survival) – 18.4% relative benefit in favor of masitinib (p=0.035). • Significant also for ΔALSFRS-R alone at W48 (p=0.027) • Median OS not reached at study cut-off o Long-term (LT) median OS showed a trend of +8 months (46.0 [30; 69] vs 38.0 [29; 49]) (p=0.068) in favor of masitinib (adjusting for placebo pts who switched to masitinib) o Statistically significant on respiratory function (ΔFVC) and quality of life (ΔALSAQ-40) Summary Masitinib significantly prolonged OS relative to control, provided that patients have not suffered severe impairment of ALSFRS-related functionality at the time of treatment initiation o Masitinib is most effective in patients with ‘Moderate ALS’ and prior to any complete loss of function (defined as a score of zero on any item of the ALSFRS-R) o Both of these enriched patient populations have demonstrated consistent treatment effects across measures of physical function, QoL and survival o Findings are consistent with masitinib’s neuroprotective mechanism of action [Harrison et al. Neurobiol Dis. 2020] o Confirmatory phase 3 trial (AB19001; NCT03127267) is ongoing, recruiting the same population that is expected to derive greatest benefit from masitinib We thank all patients, their families, and investigators of study AB10015

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