Science : First Half of 2017 results

Paris, August 31 2017, 6pm

1. Key events for the first half of 2017

   Clinical study results

   • Amyotrophic lateral sclerosis (ALS)

     The phase 2/3 study AB10015 of masitinib in amyotrophic lateral sclerosis (ALS) has met its pre-specified primary endpoint, which confirms the interim analysis. In accordance with study protocol, the final analysis was performed based on 394 patients treated for 48-weeks and randomly allocated to three different treatment arms: masitinib at 4.5 mg/kg/day, versus masitinib at 3 mg/kg/day, versus placebo, each administered as an add-on to riluzole.

     The primary endpoint was based on the change from baseline to week 48 in the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). Also consistent with EMA guidance, Progression Free Survival (PFS) was included as a key secondary endpoint for registration, with progression being defined as ALSFRS-R deterioration of more than 9 points or death. A stepwise sequence of analysis was predefined to first test masitinib at 4.5 mg/kg/day versus placebo, and then masitinib at 3 mg/kg/day versus placebo.

     For masitinib at 4.5 mg/kg/day:

     • Primary analysis on the change in ALSFRS-R score at week 48 (mLOCF methodology) is statistically significant with a P-value of 0.014.

     • Sensitivity tests on the primary analysis consisted in two models to impute a value at week 48 for any patients who discontinued treatment before week 48. Those sensitivity analyses are also significant with a P-value of 0.020.

     • The key secondary analysis on PFS was statistically significant with a P-value of 0.016.

     • Quality-of-life measured by change in ALSAQ score was also statistically significant with a p-value

       For masitinib at 3 mg/kg/day:

     • There was a trend in favor of masitinib versus placebo for change in ALSFRS score at week 48 (LOCF methodology) and likewise for the two imputation models (sensitivity analyses) and in PFS (secondary analysis).

     • The change in quality-of-life was statistically significant (p-value

     The adverse events observed for masitinib in study AB10015 were consistent with its known safety profile. There were no new safety events at final analysis as compared with interim analysis.

     AB Science filed an application for marketing authorization of masitinib in ALS at EMA in September 2016.

     Full efficacy and safety data have been presented at the European Network for the Cure of ALS (ENCALS) annual meeting in Ljubljana, Slovenia (18 - 20 May, 2017).

   • Systemic severe mastocytosis

     The Committee for Medicinal Products for Human Use (CHMP) of the European Medicine Agency (EMA) has adopted a negative opinion for masitinib in the treatment of adult patients with smouldering or indolent systemic severe mastocytosis unresponsive to optimal symptomatic treatments.

     The objections precluding a recommendation of marketing authorization by the CHMP pertained to the following principal deficiencies:

     • The CHMP was concerned about the reliability of the study results because a routine GCP (good clinical practice) inspection at the study sites revealed serious failings in the way the study had been conducted.

     • In addition, major changes were made to the study design while the study was ongoing, which made the results difficult to interpret.

     • Finally, data on the safety of the medicine were limited and there were concerns regarding the medicine's side effects, including neutropenia (low levels of white blood cells) and harmful effects on the skin and liver, which were of relevance particularly because the medicine was to be used long term.

       AB Science will ask for a re-examination based on the following grounds. GCP Findings

       The deficiencies concerning inspection findings have been corrected by AB Science and do not modify the study conclusions, both in terms of efficacy and safety assessment.

       Changes in the Study Design

       As it was detailed on the publication of the phase 3 results in The Lancet, protocol amendments were implemented between 3.5 years and 2 years prior to database unmasking, in order to increase benefit risk balance of the study. The main changes were the following:

     • Restrict the study to the patient population with greatest medical need, i.e. only patients with smouldering or indolent systemic mastocytosis with severe baseline symptoms of mast cell mediator release;

     • The threshold for positive treatment response was increased from 50% to 75%, thereby enhancing the clinical relevance of improvement;

     • Change in statistical methodology for the study primary analysis, from patient response at week 24 to overall response during week 8 to week 24 based on patient x handicap.

   The first two changes were reviewed by the CHMP during a scientific advice procedure and were deemed acceptable and in principle desirable. The third change was not discussed through scientific advice but was in line with EMA guideline on clinical trials in small populations (CHMP/EWP/83561/2005). In the re-examination procedure, AB Science will highlight that the original analysis on 75% patient response at week 24 remained positive considering the original sample size (25.8% % with masitinib versus 13.1% with placebo, p- value=0.0238), proving that this third modification did not modify the study conclusion.

   Benefit-risk assessment and SAG

   The size of the safety database is acceptable for orphan disease. In the re-examination procedure, AB Science will provide the CHMP with updated 2017 data from other studies, demonstrating that the long-term safety profile is acceptable.

   The re-examination should lead the CHMP to deliver a second opinion in Q4 2017.

   • Primary and secondary progressive forms of multiple sclerosis

     The masitinib phase 3 trial for the treatment of patients with primary progressive or relapse-free secondary progressive multiple sclerosis has passed the non-futility test at 2 years.

     The ongoing phase 3 trial is a double-blind, randomized, placebo-controlled study (AB07002) designed to assess the safety and efficacy of masitinib in patients with primary progressive or relapse-free secondary progressive multiple sclerosis. The treatment period is 96 weeks.

     The trial is testing 2 doses of masitinib, masitinib 4.5 mg/kg/day and masitinib 4.5 mg/kg/day escalating to 6 mg/kg/day, versus placebo (randomization 2:1).

     The primary efficacy endpoint is the change over 96 weeks in EDSS (Expanded Disability Status Scale), which is a scale used for quantifying disability in multiple sclerosis and monitoring changes in the level of disability over time.

     Based on these results, the Independent Data Safety Monitoring Committee (IDMC) has recommended the continuation of the study.

     The study enrolled 600 evaluable patients as planned. The study is therefore now closed to patient enrolment.

     The next step for this study is the interim analysis expected with 50% of patients having reached the 96 week treatment duration period. This interim analysis is anticipated the first half of 2018. Final results are expected in Q2 2019.

   • Severe asthma uncontrolled by oral corticosteroids

     The phase 3 study in severe persistent asthma uncontrolled by oral corticosteroids has completed its recruitment.

     The first phase 3 trial (AB07015) is a double-blind, randomized, placebo controlled study evaluating the safety and efficacy of masitinib in severe asthma uncontrolled by oral corticosteroids. The primary endpoint of this study is the rate of severe asthma exacerbations over the treatment period. The duration of treatment predefined by the protocol is 36 weeks. The planned recruitment is for 350 assessable patients.

     Final results will be available at the end of 2017.

     Given the success in recruiting the targeted number of patients, AB Science has decided to continue the study until completion, even in the event of the interim analysis being successful, in order to provide evidence of efficacy in a sufficiently large number of patients for registration. This decision has been communicated to the Independent Data Monitoring Committee (IDMC) prior to the study's interim analysis, which was planned with 50% of the patients.

     Consequently, the IDMC has not communicated to AB Science the interim analysis results but has indicated that the study can continue on the basis of the safety data and did not request implementation of the protocol resampling option.

     As a reminder, the protocol provided for a resampling option (possibility of doubling the number of patients to be included) to be implemented should any positive trend observed at the interim analysis be insufficient for the study to be successful with the initial number of planned patients, thereby necessitating recruitment of additional patients to obtain a statistically significant demonstration.

     In order to expand the asthma franchise, AB Science has initiated a new phase 3 study (AB14001) in asthma uncontrolled by high-dose inhaled corticosteroid plus long-acting beta-agonists (LABAs) and with elevated eosinophil level. This study has recruited its first patients. This new indication is much broader and is estimated to affect 1,500,000 adults in the USA and Europe.

   • ANSM decision to suspend clinical studies in France

     The Agence Nationale de la Sécurité des Médicaments (ANSM) requested on May 11, 2017 the suspension of the ongoing masitinib studies in France. That decision was based on previously identified deviations from Good Clinical Practice (GCP) as well as on findings from an inspection that was carried out as part of the procedure for the marketing authorization of masitinib in mastocytosis, which showed deviations in the conduct of the mastocytosis pivotal study (AB06006) and deviations related to the pharmacovigilance system.

     In order to lift this suspension, AB Science proposed the following action plan to ANSM:

   • Correction of the deviations observed in previous inspections. AB Science implemented corrective and preventive actions in order to address this finding.

   • External and independent audit of the pharmacovigilance (PV) system. The PV system audit has been completed with no major or critical findings identified.

   • External and independent audits of the other quality systems (Clinical Operations, Biometry, Data Management). These audits have been completed with no critical finding identified.

   • Implementation of an upgraded Quality Management System (QMS). The QMS implementation is ongoing with the support of external consultants.

   • Medical reassessment of all safety data that will be included in the 2017 Investigator Brochure. The medical reassessment has been completed by an external company and the update of the Investigator Brochure is ongoing.

   • External and independent audits of mastocytosis and amyotrophic lateral sclerosis (ALS) studies. These clinical site audits have been completed and have not identified any under-reporting of safety data.

   AB Science is actively collaborating with ANSM in order to restart the recruitment of patients in clinical studies in France. ANSM indicated to AB Science that a new inspection was needed in order to consider lifting the recruitment suspension. On the basis of findings from this new inspection, ANSM should make a decision by the end of 2017.

   • As of 30 June 2017, the clinical development program of masitinib is as follows:

     Area Indication Study Status

     Oncology / Hematology

     GIST in first-line treatment Phase 3 On-going

     GIST in second-line treatment Phase 3 On-going Metastatic melanoma with JM mutation of c-KIT Phase 3 On-going Pancreatic cancer Phase 3 On-going

     Relapsed metastatic colorectal cancer Phase 3 On-going Relapsed multiple myeloma

     Metastatic Castrate Resistant Prostate Cancer

     in first line

     Phase 3 On-going

     Relapsed metastatic ovarian cancer Phase 3 On-going Relapsed peripheral T-cell lymphoma Phase 3 On-going

     Severe asthma uncontrolled by oral

     corticosteroids Phase3

     Severe asthma uncontrolled by oral corticosteroids

     Recruitment

     completed

     Inflammatory and neurodegenerative diseases

     and with elevated eosinophil level Phase 3 On-going

     Alzheimer disease Phase 3 On-going

     Progressive forms of multiple sclerosis Phase 3 Recruitment

     completed

     Amyotrophic lateral sclerosis Phase 3 Study completed

     Other events

   • Equity financing facility

     On January 13, 2017, AB Science used the Equity Line set up with Crédit Agricole Corporate and Investment Bank ("Crédit Agricole CIB") and authorised by the Shareholders' Meeting held on 22 June 2015. AB Science proceeded with the issue of 520,091 new shares, for the price of €14.62 per share. The net commission income for AB Science amounts to €7.4 million.

   • Capital increase through private placements

   AB Science successfully completed two ordinary shares private placements that resulted in gross proceeds for the

   Company of €34 million. The net commission income for AB Science amounts to €33 million.

   A first private placement was completed on March 27, 2017, that resulted in gross proceeds for the Company of EUR 15 million. This private placement was subscribed by qualified investors and a total of 982,962 new ordinary shares were issued, through a capital increase without shareholders' preemption rights. Following an