1030365 research-article20212021 TAN0010.1177/17562864211030365Therapeutic Advances in Neurological DisordersJS Mora, WG Bradley Therapeutic Advances in Neurological Disorders Original Research Long-term survival analysis of masitinib in Ther Adv Neurol Disord 2021, Vol. 14: 1–16 amyotrophic lateral sclerosis DOI: 10.1177/ https://doi.org/10.1177/17562864211030365 https://doi.org/10.1177/17562864211030365 17562864211030365 © The Author(s), 2021. Article reuse guidelines: Jesus S. Mora, Walter G. Bradley, Delia Chaverri, María Hernández-Barral, sagepub.com/journals- permissions Javier Mascias, Josep Gamez , Gisella M. Gargiulo-Monachelli, Alain Moussy, Colin D. Mansfield , Olivier Hermine and Albert C. Ludolph Abstract Correspondence to: Background: A randomized, placebo-controlled phase III study (AB10015) previously Albert C. Ludolph demonstrated that orally administered masitinib (4.5 mg/kg/day) slowed rate of functional Department of Neurology, University of Ulm, Oberer decline, with acceptable safety, in amyotrophic lateral sclerosis (ALS) patients having an ALS Eselsberg 45, Ulm 89081, Germany Functional Rating Scale-revised (ALSFRS-R) progression rate from disease onset to baseline German Center for of <1.1 points/month. Here we assess long-term overall survival (OS) data of all participants Neurodegenerative Diseases, Ulm, Germany from study AB10015 and test whether a signal in OS is evident in an enriched patient albert.ludolph@rku.de population similar to that prospectively defined for confirmatory study AB19001. Olivier Hermine Methods: Survival status of all patients originally randomized in AB10015 was collected from Department of Hematology, Necker participating investigational sites. Survival analysis (using the multivariate log-rank test and Hospital, University of Paris, 149 Rue de Sèvres, Cox proportional hazards model, with stratification factors as covariates) was performed on Paris 75015, France the intention-to-treat population and enriched subgroups, which were defined according to AB Science, Paris, France initial randomization, baseline ALSFRS-R progression rate and baseline disease severity. Laboratory of Cellular and Molecular Mechanisms Results: A significant survival benefit of 25 months (p = 0.037) and 47% reduced risk of death of Hematological (p = 0.025) was observed for patients receiving 4.5 mg/kg/day masitinib (n = 45) versus placebo Disorders and Therapeutic Implication, Imagine (n = 62) in an enriched cohort with ⩾2 on each baseline ALSFRS-R individual component Institute, INSERM UMR 1163 and CNRS ERL 8254, score (i.e. prior to any complete loss or severe impairment of functionality) and post-onset Hôpital Necker, Paris, ALSFRS-R progression rate <1.1 (i.e. exclusion of very fast progressors) [median OS of 69 France ohermine@gmail.com versus 44 months, respectively; hazard ratio, 0.53 [95% CI (0.31–0.92)]]. This corresponds to Jesus S. Mora the population enrolled in confirmatory phase III study, AB19001. ALS Unit, Hospital San Rafael, Madrid, Spain Conclusions: Analysis of long-term OS (75 months average follow-up from diagnosis) indicates Walter G. Bradley that oral masitinib (4.5 mg/kg/day) could prolong survival by over 2 years as compared with Department of Neurology, University of Miami School placebo, provided that treatment starts prior to severe impairment of functionality. of Medicine, Miami, FL, This trial was registered at www.ClinicalTrials.gov under identifier NCT02588677 (28 October USA Delia Chaverri 2015). María Hernández-Barral Javier Mascias ALS Unit, Department Keywords: clinical trials, masitinib, therapy, tyrosine kinase inhibitor of Neurology, University Hospital La Paz-Carlos III, Madrid, Spain Received: 25 February 2021; revised manuscript accepted: 17 June 2021. Josep Gamez Neurology Department, GMA Clinic, Autonomous University of Barcelona, European Reference Introduction primary endpoint of study AB10015, decline in Network on Rare Masitinib, a selective oral tyrosine kinase inhibi- ALS Functional Rating Scale-revised (ALSFRS-R) Neuromuscular Diseases (ERN EURO-NMD), tor, exerts experimental neuroprotection in both from baseline to week 48 (∆ALSFRS-R), showed Barcelona, Spain central and peripheral nervous systems.1–5 We benefit for masitinib administered at 4.5 mg/kg/ Gisella M. Gargiulo- report long-term survival data from the previously day as an add-on to riluzole over placebo in ALS Monachelli Hospital Universitario published masitinib phase IIb/III study (AB10015, patients having an ALSFRS-R progression rate CEMIC-CONICET Buenos ClinicalTrials.gov identifier: NCT02588677) in from disease onset to baseline (ΔFS) of <1.1 points/ Aires, Argentina Alain Moussy amyotrophic lateral sclerosis (ALS) (see Supple­ month. The between-group difference was 3.39 Colin D. Mansfield mentary Appendix for summary).6,7 Briefly, the [95% confidence interval (CI) 0.65–6.13; p = 0.016], AB Science, Paris, France journals.sagepub.com/home/tan 1 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Therapeutic Advances in Neurological Disorders 14 corresponding to a 27% slowing of ALSFRS-R Method deterioration over the 48-week treatment period. Details of the method and patient selection crite- This significant outcome was corroborated by ria of study AB10015 (ClinicalTrials.gov identi- numerous sensitivity analyses, including the con- fier: NCT02588677) have been published6 (see servative multiple imputation jump-to-reference Supplementary Appendix for additional informa- technique with a between-group difference of 2.80 tion). The protocol for study AB10015 was [95% CI (0.15–5.46); p = 0.039].6,7 approved by the institutional review board or eth- ics committee at each participating clinical site At the time of final readout for study AB10015, and was conducted in accordance with the overall survival (OS) data were too immature Declaration of Helsinki. All patients provided for interpretation. The rate of decline in written informed consent, which included provi- ALSFRS-R is considered a sensitive and inde- sion to review medical records for completion of pendent clinical prognostic parameter in ALS undetermined endpoints, such as OS. that correlates with OS8–11; nevertheless, median OS analysis remains the gold standard for dem- Figure 1 shows the relation between randomized onstration of a drug’s therapeutic benefit in treatment arms of study AB10015, cohorts used ALS. Hence, post-study long-term OS assess- for the AB10015 long-term OS analysis, and sub- ment represents a valuable complement to the populations of interest for the NPP long-term OS main study results. analysis. OS was defined as the time elapsed between randomization and death from any Included in the published results from study cause. OS p-values were calculated via the multi- AB10015 were subgroup analyses based on variate log-rank test using the covariates of age revised ALS trial guidelines that recommend and ALSFRS-R score at randomization, site of patients should be selected as early as possible onset (spinal versus bulbar), geographical region, in the course of their disease.12–14 This showed and ΔFS. All covariates were prespecified in the that initiation of masitinib at a less severe stage AB10015 protocol as randomization stratification of disease produced greater treatment effect.6,15 factors.6 Hazard ratios (HR) and 95% CIs were The benefit of patient enrichment strategies calculated via the Cox proportional hazards based on ALSFRS-R has also been recognized model using the abovementioned covariates. by other studies; for example, the edaravone, rasagiline and high-fat intervention clinical tri- als.16–18 Hence, findings from this analysis, in Procedure for long-term OS analysis of the conjunction with scientific advice from regula- AB10015 study population tory authorities, have been incorporated into the In the current analysis, vital status (i.e. survival sta- confirmatory masitinib study design (AB19001, tus of alive or dead, including date of death) of all ClinicalTrials.gov identifier: NCT03127267). patients originally randomized to study AB10015 Such a design is consistent with masitinib’s was collected from each participating investiga- therapeutic objective for conservation of neuro- tional site. As such, three patient groups were muscular functions as opposed to repair of exist- defined [see Figure 1(a)]: long-term high-dose ing neurological damage.1,19 (4.5 mg/kg/day) masitinib (referred to hereafter as ‘LT-M4.5’), long-term low-dose (3.0 mg/kg/day) Importantly, identification of this enriched popu- masitinib (referred to hereafter as ‘LT-M3.0’), and lation suggested that a long-term OS signal could long-term placebo (referred to hereafter as be detectable within the available AB10015 data- ‘LT-PBO’). Long-term assessment for study set given sufficient follow-up. The main objective AB10015 encompassed the prospectively declared of the current analysis was therefore to assess 48-week treatment period with associated double- whether a signal in OS is evident in an enriched blind extension (commencing in April 2013 until patient population, similar to that prospectively data readout), and a post-study (unblinded) follow- defined for the confirmatory phase III study up period (from November 2017 until June 2020) (AB19001). It also allowed us to explore reports [see Figure 1(b)]. Patients still alive at the time of of greatly improved survival from individual sites analysis were censored at the date of last contact. participating in an international early access Named Patient Program (NPP) using a larger, Long-term OS analysis was performed on the multicenter patient cohort.20 intention-to-treat (ITT) population (i.e. all those 2 journals.sagepub.com/home/tan JS Mora, WG Bradley et al. Figure 1. (a) Relationship between randomized treatment arms of study AB10015, cohorts used for the AB10015 long-term OS analysis, and subpopulations of interest for the NPP long-term OS analysis. (b) Time frame for study AB10015 long-term OS analysis showing a 75-month average duration of observation (time of diagnosis until cut-off of long-term OS analysis). LT, long term; NPP, Named Patient Program; OS, overall survival; PBO, placebo. patients randomized to study AB10015) as well initial randomization, ΔFS, and baseline disease as on enriched subgroups, the latter of which severity. For example, exclusion of patients with were defined after the prospectively declared high baseline disease severity was achieved by study period had ended, according to identifying those patients with any zero-point journals.sagepub.com/home/tan 3 Therapeutic Advances in Neurological Disorders 14 ALSFRS-R items or any one-point ALSFRS-R dose-escalation scheme.6,22 It is also important to items at baseline, corresponding to disease that note that only participants of study AB10015 has advanced to the point of a permanent loss of were included in this analysis of long-term OS. function or a severe impairment of functionality, respectively. In this manner, three enriched sub- The NPP permits comparison between patients groups were defined, namely: patients with randomized to either one of the AB10015 masi- ΔFS < 1.1 regardless of baseline ALSFRS-R tinib treatment arms and who continued to score; patients with ⩾2 on each baseline receive masitinib treatment under the NPP, versus ALSFRS-R item, regardless of baseline ΔFS; and patients from the AB10015 placebo arm that did patients with ⩾2 on each baseline ALSFRS-R not participate in the NPP and were therefore item and ΔFS < 1.1 (the latter cohort correspond- never treated with masitinib. This latter subpopu- ing most closely to the confirmatory AB19001 lation is referred to hereafter as the ‘masitinib- study population). Potential between-group base- naïve placebo (PBO) cohort’ [Figure 1(a)]. line bias in the enriched patient subgroups was Because only patients alive at the time of study assessed by comparison of baseline parameters data readout were available to enroll into the for each cohort. Supportive analyses using the NPP, it is necessary to apply a similar condition same patient cohorts were also performed accord- to the comparator placebo subpopulation, i.e. ing to the endpoints of ∆ALSFRS at week 48, and exclusion of patients who had died prior to 1 a time-to-event analysis referred to as progres- November 2017; thereby, avoiding bias arising sion-free survival (PFS) (an endpoint driven by from the implicit condition that patients had sur- both death and a fixed disease progression on the vived at least the randomized study period prior ALSFRS-R scale, the latter being defined in study to entering the NPP. AB10015 as a nine-point deterioration of ALSFRS-R from baseline). To define NPP subpopulations for long-term OS analysis, all patients enrolled into the NPP retained their initial treatment-arm designations. Procedure for long-term OS analysis of the For example, patients from the AB10015 masi- Named Patient Program subpopulations tinib 4.5 and 3.0 mg/kg/day treatment arms who Following data readout for the main protocol continued to receive masitinib on the NPP, were period of study AB10015, treatment assignment designated as the ‘NPP-M4.5’ and ‘NPP-M3.0’ was unblinded and an optional, open-label, early subpopulations, respectively [Figure 1(a)]. access NPP was initiated. This allowed those Likewise, patients from the AB10015 placebo patients still receiving masitinib to continue treat- arm who started masitinib treatment as part of ment, while also allowing patients from the the NPP were designated as the ‘NPP-PBO’ sub- AB10015 placebo arm to begin masitinib treat- population. Further cohorts of interest were ment. NPPs typically concern individual patients, patients pooled from both masitinib treatment- designated by name, and are issued at the request arms (i.e. ‘NPP-M4.5’ plus ‘NPP-M3.0’, referred of the prescribing physician. Such programs are to hereafter as the ‘NPP-M(pooled)’ subpopula- not clinical trials or compassionate use programs tion), and also patients pooled from all NPP as per the European Union regulations but are groups (i.e. ‘NPP-M4.5’ plus ‘NPP-M3.0’ plus intended to allow patients access to medicinal ‘NPP-PBO’, referred to hereafter as the ‘NPP- products that have not yet received a marketing ALL’ subpopulation). NPP long-term OS analy- authorization. Conditions required to run such a ses were performed regardless of baseline ΔFS or program are that the product must be intended individual ALSFRS-R component scores. for treatment of a serious or orphan disease, there Potential sources of baseline bias in the NPP sub- must be an absence of a suitable therapeutic alter- populations of interest were assessed by compari- native available, and the efficacy/safety ratio can son of baseline parameters for each cohort. be presumed favorable based on available evi- Because any treatment effect during the rand- dence.21 Another feature distinct to NPPs is that omized study period is expected to have impacted dosing decisions are made solely by the prescrib- on ALSFRS-R, respiratory function and dura- ing physician, albeit based on best available tion-related variables, comparison of NPP base- evidence, such as results from study AB10015 line characteristics is made at the time of and recommendations on use of a masitinib randomization rather than at NPP enrolment. 4 journals.sagepub.com/home/tan JS Mora, WG Bradley et al. Table 1. Disposition of populations for long-term OS analysis of study AB10015 and its associated NPP. Cohort PBO (n) M4.5 (n) M3.0 (n) Total (n) Overall (mITT) population 133 130 131 394 Survival status verified less than 7 months prior to cut-offa 128 (96.2%) 124 (95.4%) 126 (96.2%) 378 (95.9%) Survival status older than 7 months 5 (3.8%) 6 (4.6%) 5 (3.8%) 16 (4.1%) Patients available for NPP OS analysisb 25 (18.8%) 29 (22.3%) 30 (22.9%) 84 (21.3%) Patients not available for NPP OS analysis 108 (81.2%) 101 (77.7%) 101 (77.1%) 310 (78.7%) aSurvival status (also referred to as vital status) verified by investigational site within 7 months prior to cut-off (June 2020) for long-term OS analysis. bPatients from study AB10015 that entered the optional NPP. NPP, Named Patient Program; OS, overall survival; PBO, placebo. Results survival status, is shown in Table 1. A summary of the overall population’s average follow-up time Patients and follow-up analysis and disease duration at various stages of study This long-term survival analysis encompassed all AB10015 and its post-study follow-up period is participants randomized to study AB10015. A presented in Figure 1(b) and Table 2. Based on total of 394 patients from 34 sites in nine countries the inclusion criterion of patients having less than were available for the main study efficacy analysis 36 months disease duration from baseline, the (133, 131, and 130 patients in the placebo, masi- overall average time from diagnosis until rand- tinib 3.0 mg/kg/day, and masitinib 4.5 mg/kg/day omization was 9.5 ± 7.5 months. The average treatment arms, respectively). All investigational follow-up of patients on study AB10015 and its sites from study AB10015 were contacted with a associated double-blind extension period, i.e. request for an update on each patient’s vital (sur- from randomization of the first patient (April vival) status. As of June 2020, 96% of patients 2013) until date of study data readout (November (378/394) had their vital status verified (Table 1). 2017), was 34.1 ± 10.1 months. The duration of The remaining 16 patients (4%) had a status that observation with respect to diagnosis (i.e. time dated back further than 7 months from this cut-off, elapsed from diagnosis until date of study data with a patient distribution that was evenly spread readout, regardless of patient censoring) was across treatment arms (five, five, and six patients in 43.4 ± 24.4 months. The duration of the the placebo, masitinib 3.0 mg/kg/day, and masi- unblinded post-study follow-up period, including tinib 4.5 mg/kg/day treatment arms, respectively). optional NPP, was an additional 32 months, i.e. November 2017 until June 2020. Hence, from Concerning the NPP, a total of 84 patients from 19 the date of diagnosis, patients have been under sites in eight countries chose to enter the program long-term OS observation for an average duration following unblinding of study AB10015 and were of approximately 75 months. therefore available for NPP long-term OS analysis. This included 19% (25/133) of patients from the placebo arm switching to receive masitinib, 23% Baseline characteristics (30/131) of patients from the masitinib 3.0 mg/kg/ Treatment arms for the primary efficacy analysis day treatment arm, and 22% (29/130) of patients population of study AB10015 were well balanced, from the masitinib 4.5 mg/kg/day treatment arm. A with patients having been randomized using a com- total of 53/133 (40%) patients from the placebo puterized central randomization system and mini- arm were alive at November 2017 but did not par- mization method according to the covariates of ticipate on the masitinib NPP, and were thereby ALSFRS-R score, age, geographical region, site of defined as the ‘masitinib-naïve PBO’ cohort. onset (spinal versus bulbar), and post-onset ΔFS.6 Patient disposition from study AB10015 and the Representative data for the long-term M4.5 masitinib NPP, including breakdown of updated cohorts showing the smallest and greatest levels of journals.sagepub.com/home/tan 5 Therapeutic Advances in Neurological Disorders 14 Table 2. Summary of study AB10015 time intervals showing a 75-month average duration of long-term OS observation (time of diagnosis until cut-off of long-term OS analysis). PBO (n = 133) M4.5 (n = 130) M3.0 (n = 131) Average duration from diagnosis until randomization 9.0 ± 6.8 9.7 ± 8.4 10.0 ± 7.4 (months) (mean ± SD) Average duration from disease onset until 18.1 ± 8.6 19.2 ± 9.6 19.2 ± 8.2 randomization (months) (mean ± SD) Overall study population (n = 394) Overall average duration from diagnosis until 9.5 months ± 7.5 randomization (months) (mean ± SD) Overall average duration of study follow-up (April 34.1 months ± 10.1 2013 – end of study) (mean ± SD) Duration of post-study follow-up (November 2017 – 32 months long-term OS cut-off June 2020) Average duration of long-term OS observation from 75.6 months date of diagnosis (estimate) M3.0, masitinib at 3.0 mg/kg/day treatment arm; M4.5, masitinib at 4.5 mg/kg/day treatment arm; OS, overall survival; PBO, placebo; SD, standard deviation. enrichment are presented in Table 3. As expected, masitinib-naïve PBO cohort (average ΔFS at ran- the overall population (i.e. LT-M4.5, regardless domization of 0.5 versus 0.62, respectively, a rela- of baseline ΔFS or individual ALSFRS-R compo- tive difference of 19%). This situation could nent scores), maintained balanced baseline char- potentially favor survival in the masitinib cohort. acteristics between treatment arms. Balance was Conversely, a higher proportion of bulbar onset also observed for the enriched patient subgroup of patients opted into the NPP-M4.5 cohort relative LT-M4.5 with ⩾2 on each baseline ALSFRS-R to the masitinib-naïve PBO cohort (20.7% versus item and ΔFS < 1.1, for which the only notable 11.3%, respectively, a relative difference of 83%), difference (>10%) was that the masitinib arm had which could potentially favor survival in the mas- a longer average disease duration from time of itinib-naïve PBO cohort because bulbar onset is diagnosis compared with placebo (8.2 versus an independent risk factor for poor survival.23 7.6 months, respectively). Baseline characteristics for additional long-term M4.5 enriched patient Hence, overall baseline characteristics were simi- subgroups and the long-term M3.0 cohorts are lar across treatment arms with no indication of presented in Tables S1 and S2, respectively. bias due to self-selection. Considering baseline parameters from represent- ative NPP subpopulations, i.e. NPP-M4.5 and Results from long-term OS analysis of the masitinib-naïve PBO, it is seen that the majority AB10015 study population of baseline characteristics (e.g. ALSFRS-R score, A summary of long-term median OS results for age, respiratory function, and disease duration various patient cohorts of the AB10015 study from diagnosis) showed no indication of self- population is presented in Table 5. No long- selection bias (see Table 4). Some imbalance term survival advantage was observed for the between treatment arms had been introduced overall masitinib 4.5 mg/kg/day cohort of study regarding the distribution of ALS diagnosis (El AB10015 (i.e. LT-M4.5, regardless of baseline Escorial diagnostic criteria), site of onset (bul- ALSFRS-R scores or ΔFS) over placebo. Median bar), and post-onset ΔFS. More specifically, OS for masitinib (n = 130) and placebo (n = 133) patients opting into the NPP-M4.5 cohort were was 33 months [95% CI (21–48)] versus progressing at a slower rate than patients in the 37 months [95% CI (27–44)], respectively; 6 journals.sagepub.com/home/tan JS Mora, WG Bradley et al. Table 3. Baseline characteristics for the overall (ITT) masitinib 4.5 mg/kg/day cohort versus associated placebo group (regardless of baseline ΔFS or individual ALSFRS-R component scores) and for the enriched cohort most closely matched to the AB19001 study design. M4.5, regardless of baseline ALSFRS-R or ΔFS M4.5 (⩾2 each baseline ALSFRS-R item, ΔFS < 1.1) PBO (N = 133) M4.5 (N = 130) Deltab (%) PBO (N = 62) M4.5 (N = 45) Deltab (%) Sex; n (%) Male 80 (60.2) 83 (63.8) +3.6 39 (62.9) 31 (68.9) −6.0 ΔFS < 1.1; n (%) Yes 114 (85.7) 106 (81.5) −4.2 62 (100.0) 45 (100.0) 0 Average ΔFS (points/month) Mean ± SD 0.71 ± 0.69 0.73 ± 0.63 +2.8 0.41 ± 0.23 0.39 ± 0.25 −4.9 Range 0.05; 5.00 0.03; 3.69 0.05; 1.07 0.03; 1.01 Average ALSFRS-R score Mean ± SD 38.1 ± 5.5 37.5 ± 5.5 −1.6 42.0 ± 3.2 42.2 ± 3.1 +0.5 Range 21.0; 47.0 23.0; 47.0 34.0; 47.0 36.0; 47.0 Age (years) Mean ± SD 55.2 ± 10.6 55.5 ± 10.6 +0.5 55.0 ± 10.1 55.6 ± 11.5 +1.1 Range 27.0; 75.0 24.0; 79.0 28.0; 73.0 24.0; 78.0 ALS diagnosis; n (%) Definite 79 (59.4) 76 (58.5) +0.9 39 (62.9) 25 (55.6) −7.3 Probable 43 (32.3) 44 (33.8) −1.5 19 (30.6) 16 (35.6) +5.0 Probable, lab 11 (8.3) 10 (7.7) +0.6 4 (6.5) 4 (8.9) +2.4 Disease durationa (months) Mean ± SD 9.0 ± 6.8 9.7 ± 8.4 +7.8 7.3 ± 5.9 8.2 ± 7.6 +12.3 FVC (predicted) Mean ± SD 89.2 ± 18.7 87.5 ± 16.9 +1.9 92.9 ± 17.9 93.8 ± 17.0 +1.0 Site of onset; n (%) Spinal 109 (82.0) 107 (82.3) +0.3 46 (74.2) 35 (77.8) +3.6 Bulbar 24 (18.0) 23 (17.7) −0.3 16 (25.8) 10 (22.2) −3.6 Region; n (%) North America and 86 (64.7) 81 (62.3) −2.4 35 (56.5) 24 (53.3) −3.2 Western Europe Eastern Europe 8 (6.0) 8 (6.2) +0.2 4 (6.5) 4 (8.9) +2.4 Other countries 39 (29.3) 41 (31.5) +2.2 23 (37.1) 17 (37.8) +0.7 aAverage disease duration from time of diagnosis. bDelta,relative difference between treatment arms (%) with respect to placebo. ALSFRS-R, Amyotrophic Lateral Sclerosis Functional Rating Scale-revised; FVC, forced vital capacity; M4.5, masitinib 4.5 mg/kg/day; PBO, placebo; SD, standard deviation; ΔFS, ALSFRS-R progression rate from disease onset to baseline. journals.sagepub.com/home/tan 7 Therapeutic Advances in Neurological Disorders 14 Table 4. Baseline patient characteristics for the NPP subgroup analysis. Masitinib-naïve NPP-M4.5 Deltab (%) NPP-M(pooled) Deltab (%) NPP-ALL Deltab (%) PBO (N = 53) (N = 29) (N = 59) (N = 84) Sex; n (%) Male 33 (62.3) 20 (69.0) +6.7 39 (66.1) +3.8 55 (65.5) +3.2 ΔFS < 1.1; n (%) Yes 48 (90.6) 28 (96.6) +6.0 57 (96.6) +6.0 80 (95.2) +4.6 Average ΔFS (points/month) Mean ± SD 0.62 ± 0.7 0.5 ± 0.5 −19.4 0.46 ± 0.39 −25.8 0.46 ± 0.38 −25.8 ALSFRS-R score Mean ± SD 38.5 ± 5.1 40.4 ± 5.6 +4.9 40.1 ± 4.8 +4.2 40.2 ± 4.8 +4.4 Age (years) Mean ± SD 54.0 ± 10.8 50.0 ± 9.7 −7.4 50.7 ± 9 .7 −6.1 50.9 ± 10.0 −5.7 ALS diagnosis; n (%) Definite 34 (64.2) 13 (44.8) −19.4 29 (49.2) −15.0 36 (42.9) −21.3 Probable 12 (22.6) 14 (48.3) +25.7 22 (37.3) +14.7 38 (45.2) +22.6 Probable, lab 7 (13.2) 2 (6.9) −6.3 8 (13.6) +0.4 10 (11.9) −1.3 Disease durationa Mean ± SD 9.5 ± 7.1 10.0 ± 10.0 +5.3 11.2 ± 9.3 +17.9 10.7 ± 8.7 +12.6 FVC (% predicted) Mean ± SD 91.7 ± 20.6 93.9 ± 15.9 +2.4 91.4 ± 15.7 −0.3 92.7 ± 15.4 +1.1 Site of onset; n (%) Bulbar 6 (11.3) 6 (20.7) +9.4 10 (16.9) +5.6 14 (16.7) +5.4 Region; n (%) Other countries 21 (39.6) 10 (34.5) −5.1 23 (39.0) −0.6 25 (29.8) −9.8 Eastern Europe 6 (11.3) 2 (6.9) −4.4 2 (3.4) −7.9 2 (2.4) −8.9  North America/Western 26 (49.1) 17 (58.6) +9.5 34 (57.6) +8.5 57 (67.9) +18.8 Europe aAverage disease duration from time of diagnosis. bDelta, relative difference between treatment arms (%) with respect to masitinib-naïve PBO. ALSFRS-R, Amyotrophic Lateral Sclerosis Functional Rating Scale-revised; FVC, forced vital capacity; masitinib-naïve PBO, cohort from AB10015 placebo arm (regardless of baseline ΔFS or baseline ALSFRS-R scores) who were alive at 1 November 2017 and did not enter the NPP; NPP M4.5, cohort from study AB10015 M4.5 treatment arm (regardless of baseline ΔFS or baseline ALSFRS-R scores) who continued receiving masitinib as part of NPP; NPP, Named Patient Program; SD, standard deviation; ΔFS, ALSFRS-R progression rate calculated from disease onset to baseline. 8 journals.sagepub.com/home/tan JS Mora, WG Bradley et al. Table 5. Long-term OS from study AB10015 according to Kaplan–Meier survival analysis, including assessment of enriched subgroups and subpopulations of the associated NPP. Cohort MAS (n) PBO (n) Deaths Median OS (95% CI) ΔOS p-value (months) (log-rank) MAS PBO MAS PBO (months) (months) Study AB10015 high-dose masitinib arm versus placebo LT-M4.5 (regardless of baseline 130 133 80 (62%) 88 (66%) 33 (21; 48) 37 (27; 44) −4 0.196 ALSFRS-R or ΔFS) LT-M4.5 (ΔFS < 1.1, any baseline 106 114 59 (56%) 72 (63%) 47 (30; 69) 41 (28; 49) +6 0.102 ALSFRS-R score) LT-M4.5 (⩾2 each baseline 50 63 24 (48%) 38 (60%) 69 (44; NE) 44 (31; 62) +25 0.037 ALSFRS-R item, any ΔFS) LT-M4.5 (⩾2 each baseline 45 62 20 (44%) 38 (61%) 69 (47; NE) 44 (31; 62) +25 0.037 ALSFRS-R item, ΔFS < 1.1) Study AB10015 low-dose masitinib arm versus placebo LT-M3.0 (regardless of baseline 131 133 91 (69%) 88 (66%) 30 (25; 40) 37 (27; 44) −7 0.70 ALSFRS-R or ΔFS) LT-M3.0 (⩾2 each baseline 46 62 27 (59%) 38 (61%) 48 (26; 62) 44 (31; 62) +4 0.70 ALSFRS-R item, ΔFS < 1.1) NPP subpopulations (regardless of baseline ALSFRS-R or ΔFS) NPP-M4.5 versus masitinib-naïve 29 53 6 (21%) 22 (42%) 73 (69; NE) 62 (49; NE) +11 0.008 PBO NPP-M(pooled) versus masitinib- 59 53 16 (27%) 22 (42%) 73 (69; NE) 62 (49; NE) +11 0.008 naïve PBO NPP-ALL versus masitinib-naïve 84 53 27 (32%) 22 (42%) NR (69; NE) 62 (49; NE) NE 0.016 PBO p-value calculated using the log-rank test. LT, long-term; M3.0, masitinib at 3.0 mg/kg/day treatment arm; M4.5, masitinib at 4.5 mg/kg/day treatment arm; MAS, masitinib; masitinib-naïve PBO, cohort from AB10015 placebo arm (regardless of baseline ΔFS or baseline ALSFRS-R scores) that were alive at 1 November 2017 and did not enter the NPP; NE, non-estimable; NPP, Named Patient Program; NPP-ALL, all patients that entered the NPP (NPP-M4.5 plus NPP-M3.0 plus NPP-PBO); NPP-M(pooled), cohort of pooled masitinib-treated patients from AB10015 (NPP-M4.5 plus NPP-M3.0) who continued receiving masitinib as part of NPP; NPP-M4.5, cohort from study AB10015 M4.5 treatment arm (regardless of baseline ΔFS or baseline ALSFRS-R scores) who continued receiving masitinib as part of NPP; NR, not reached; OS, overall survival; PBO, placebo; ΔFS, ALSFRS-R progression rate calculated from disease onset to baseline; ΔOS, between-group difference in median OS (MAS minus PBO). p = 0.196 [Figure 2(a)]. However, as enrichment of death for masitinib-treated patients compared of patient selection was applied, an increasing with those originally randomized to placebo improvement in median OS for masitinib with [HR, 0.56 (95% CI (0.33–0.97)); p = 0.037] respect to placebo was observed. Statistical sig- (Table 6). A similar survival advantage in favor nificance was reached for the cohort ‘LT-M4.5 of masitinib was seen for the cohort correspond- with ⩾2 on each baseline ALSFRS-R item, ing most closely to the confirmatory AB19001 regardless of baseline ΔFS’, with a median OS study population, i.e. ‘LT-M4.5 with ⩾2 on for masitinib (n = 50) of 69 months [95% CI each baseline ALSFRS-R item and ΔFS < 1.1’, (44–NE)] versus 44 months [95% CI (31–62)] with a significant median OS difference of for placebo (n = 63). This corresponds to a 25 months in favor of masitinib, p = 0.037 median OS difference of 25 months in favor of [Figure 2(b)] and a significant 47% reduced risk masitinib, p = 0.037. HR analysis was also sig- of death [HR, 0.53 (95% CI (31–92)); p = 0.025] nificant for this cohort with a 44% reduced risk (Table 6). journals.sagepub.com/home/tan 9 Therapeutic Advances in Neurological Disorders 14 Table 6. Multivariate Cox proportional hazards ratio analysis, including assessment of enriched subgroups and subpopulations of the associated NPP. Cohort MAS (n) PBO (n) Hazard ratio 95% CI Reduced p-value risk of death (%) Study AB10015 high-dose masitinib arm versus placebo LT-M4.5 (regardless of 130 133 0.82 0.60–1.13 18 0.226 baseline ALSFRS-R or ΔFS) LT-M4.5 (ΔFS < 1.1, any 106 114 0.78 0.54–1.11 22 0.161 baseline ALSFRS-R score) LT-M4.5 (⩾2 each baseline 50 63 0.56 0.33–0.97 44 0.037 ALSFRS-R item, any ΔFS) LT-M4.5 (⩾2 each baseline 45 62 0.53 0.31–0.92 47 0.025 ALSFRS-R item, ΔFS < 1.1) Study AB10015 low-dose masitinib arm versus placebo LT-M3.0 (regardless of 131 133 1.02 0.75–1.38 0 0.903 baseline ALSFRS-R or ΔFS) LT-M3.0 (⩾2 each baseline 46 62 1.00 0.60–1.66 0 0.996 ALSFRS-R item, ΔFS < 1.1) NPP subpopulations (regardless of baseline ALSFRS-R or ΔFS) NPP-M4.5 versus masitinib- 29 53 0.33 0.12–0.88 67 0.027 naïve PBO NPP-M(pooled) versus 59 53 0.58 0.28–1.19 42 0.134 masitinib-naïve PBO NPP-ALL versus masitinib- 84 53 0.71 0.38–1.31 29 0.267 naïve PBO LT, long-term; M3.0, masitinib at 3.0 mg/kg/day treatment arm; M4.5, masitinib at 4.5 mg/kg/day treatment arm; MAS, masitinib; masitinib-naïve PBO, cohort from AB10015 placebo arm (regardless of baseline ΔFS or baseline ALSFRS-R scores) who were alive at 1 November 2017 and did not enter the NPP; NPP, Named Patient Program; NPP-ALL, all patients who entered the NPP (NPP-M4.5 plus NPP-M3.0 plus NPP-PBO); NPP-M(pooled), cohort of pooled masitinib-treated patients from AB10015 (NPP-M4.5 plus NPP-M3.0) who continued receiving masitinib as part of NPP; NPP-M4.5, cohort from study AB10015 M4.5 treatment arm (regardless of baseline ΔFS or baseline ALSFRS-R scores) who continued receiving masitinib as part of NPP; PBO, placebo; ΔFS, ALSFRS-R progression rate calculated from disease onset to baseline. In contrast, results from the low-dose masitinib and the placebo comparator arm, indicating a arm of study AB10015 (LT-M3.0) showed that consistent survival advantage in favor of masitinib none of the enriched patient subgroups tested (Figure 3). For example, the subpopulations of produced a significant improvement in median ‘NPP-M4.5’ (n = 29) versus ‘masitinib-naïve OS with respect to placebo (Tables 5 and 6). PBO’ (n = 53) showed a significant difference in median OS of 11 months (p = 0.008) [Figure 3(a); Table 5]. The corresponding hazard ratio analysis Results from long-term OS analysis of the showed a significant 67% reduced risk of death in Named Patient Program subpopulations favor of masitinib [HR, 0.33 [95% CI (0.12– A summary of long-term median OS results for 0.88)]; p = 0.027] (Table 6). Of note, this analysis subpopulations of the AB10015 NPP is presented effectively compares patients that have remained in Table 5. Kaplan–Meier survival curves visually in their assigned treatment arms following study showed divergence between NPP subpopulations AB10015 data readout, i.e. those originally 10 journals.sagepub.com/home/tan JS Mora, WG Bradley et al. Figure 2. Kaplan–Meier survival curves from masitinib study AB10015 long-term survival analysis. (a) Overall masitinib 4.5 mg/kg/day cohort versus placebo (regardless of baseline ΔFS or individual component scores). (b) Enriched* masitinib 4.5 mg/kg/day cohort versus placebo (⩾2 on each baseline ALSFRS-R individual component score and post-onset ΔFS < 1.1). randomized to active treatment compared with Likewise, the analysis of ‘NPP-M(pooled)’ (n = 59) versus those originally randomized to placebo, and ‘masitinib-naïve PBO’ (n = 53) also showed a signifi- therefore avoids possible confounding effects cant difference in median OS (p = 0.008) with a related to treatment switch-over (i.e. placebo between-group difference of 11 months and a 42% patients switching to masitinib). reduced risk of death [HR, 0.58 [95% CI journals.sagepub.com/home/tan 11 Therapeutic Advances in Neurological Disorders 14 Figure 3. Kaplan–Meier survival curves from masitinib NPP subgroup long-term OS analysis. (a) NPP-M4.5 versus masitinib-naïve PBO. (b) NPP-ALL versus masitinib-naïve PBO. (0.28–1.19)]; p = 0.134] (Tables 5 and 6). Considering, Supportive analyses for masitinib patient the subpopulation of ‘NPP-ALL’ (n = 84) versus ‘mas- enrichment itinib-naïve PBO’ (an analysis that estimates the NPPs The enriched patient cohorts used for long-term overall impact on OS), a significant difference between OS analysis of study AB10015 were also tested in survival curves (p = 0.016) and 29% reduced risk of the context of that study’s main endpoints, i.e. death (p = 0.267) was seen in favor of masitinib, despite ∆ALSFRS-R at week-48 and PFS (respectively, inevitable dilution from placebo patients that had Tables S3 and S4). The between-group difference switched [Figure 3(b); Tables 5 and 6]. in both ∆ALSFRS-R and PFS improved with 12 journals.sagepub.com/home/tan JS Mora, WG Bradley et al. increasing degrees of enrichment. Considering the It should be noted that the current OS analysis cohort most closely matched to the target popula- represents new data, which were unavailable at the tion of study AB19001 (i.e. ‘M4.5 with ⩾2 on time when masitinib was considered for marketing each baseline ALSFRS-R item and ΔFS < 1.1’), authorization by the European Medicine Agency ∆ALSFRS-R for masitinib was −6.36 versus Committee for Medicinal Products for Human −11.03 for placebo, corresponding to a significant Use; an application that was based on interim 42% slowing in rate of decline (p = 0.018), while results from study AB10015.24 An advantage of PFS for this cohort showed a trend improvement of the current analysis is that OS is considered a 13 months in favor of masitinib (p = 0.060). robust and reliable endpoint; highly accurate for the event and time, relatively simple to collect and One concern when performing subgroup analysis assess, and of unquestionable clinical relevance. is whether an observed treatment effect (i.e. a sig- Nevertheless, the nature of long-term survival data nificant difference in favor for masitinib relative does also present a number of challenges. For to placebo) in a given subgroup, is simply reflected example, these data were not generated under con- in an opposite sense for its complement subgroup ditions of a randomized clinical trial but rather as (i.e. a significant difference in favor for placebo part of an open-label follow-up period that also relative to masitinib). This was tested in a cohort incorporated an optional NPP. Furthermore, long- with suitably large enriched subgroup and com- term observational studies following clinical trials plement subgroup sample sizes (see Supplemental are susceptible to selection bias from missing data Appendix and Table S5). Results showed that because of patient discontinuation or loss to fol- there was no discernable (non significant) differ- low-up. This risk has been mitigated in the current ence for the complement subgroup, therefore, analysis via confirmation of vital status in all supporting plausibility of the significant treat- patients from the overall study population (Table ment effect observed in the enriched subgroup. 1); information for 96% of patients being verified less than 7 months prior to cut-off, while 4% had a status older than 7 months. A threshold of 5% for Discussion missing data (which would be a worst-case sce- Findings from this long-term OS analysis are con- nario for these censored patients) is commonly sistent with the favorable results from study reported to represent a low risk of bias25–27; moreo- AB10015.6 Notably, a statistically significant sur- ver, these patients were distributed evenly across vival benefit of over 2 years and 47% reduced risk treatment arms (see Table 1) and represents a of death for patients receiving masitinib (4.5 mg/ small proportion (at least 10-fold fewer) relative to kg/day) as compared with placebo was observed the outcome event rate (i.e. number of deaths). for the enriched cohort of ‘⩾2 on each baseline There is also a risk of introducing baseline bias ALSFRS-R item and ΔFS < 1.1’ (Tables 5 and when comparing subgroups taken from a larger 6). This subgroup is comprised of ALS patients randomized population; however, assessment of that have not suffered a complete loss or severe baseline parameters showed that enriched patient impairment of ALSFRS-related functionality at subgroups maintained a good balance between the time of masitinib treatment initiation and treatment-arm baseline variables. Likewise, there have not experienced a rapid (ΔFS ⩾ 1.1) was no indication that patient self-selection had ALSFRS-R progression rate from disease onset to introduced confounding bias to the NPP analysis baseline. Likewise, a substantial effect was (Table 4). For those parameters that did show observed in the endpoints of ∆ALSFRS-R at some baseline imbalance between treatment arms, week 48 and PFS for this enriched cohort relative distribution of bulbar onset patients could have to the overall population of study AB10015 potentially favored survival in masitinib-naïve PBO (Tables S3 and S4), supporting the premise of cohorts, whereas a slower post-onset ΔFS could greater treatment effect when masitinib is initi- have potentially favored masitinib cohorts. ated at an earlier stage of disease. Additionally, Distribution of baseline El Escorial diagnostic clas- long-term OS results from the low-dose (3.0 mg/ sification is unlikely to have generated bias as this is kg/day) masitinib treatment arm are consistent not a predictive indicator of survival.23 Hence, with an observed dose-dependency in the 48-week despite the risk of bias associated with data gener- endpoint analysis, confirming that a target dose of ated outside of a prospectively declared randomized at least 4.5 mg/kg/day is necessary to produce protocol, it would appear that long-term OS analy- clinically meaningful improvement.6 sis of the AB10015 study population is robust. journals.sagepub.com/home/tan 13 Therapeutic Advances in Neurological Disorders 14 A significant masitinib effect on OS and HR was scores). Results were also in agreement with our also apparent for the NPP-M4.5 subpopulation previous observation of dose-dependent efficacy as compared with patients that received no form between target doses of 3.0 and 4.5 mg/kg/day, of masitinib treatment (i.e. the masitinib-naïve which in turn supports the higher target dose of placebo subpopulation) (Tables 5 and 6). This the AB19001 study design (i.e. 6.0 mg/kg/day provides valuable insight into the potential long- administered using a titrated dosing scheme for term treatment benefits of masitinib in a broader enhanced safety) on the premise that this could ALS population (i.e. regardless of baseline ΔFS yield an optimized benefit–risk balance. or individual ALSFRS-R component scores). Results from the NPP dataset also showed a sig- In conclusion, findings from this long-term OS nificant treatment effect for the NPP-M(pooled) and analysis, with an average follow-up of 75 months NPP-ALL subpopulations, indicating that thera- since diagnosis, indicate that oral masitinib peutic benefit was possible for those patients (4.5 mg/kg/day) could prolong survival by over switching to masitinib (4.5 mg/kg/day) from either 2 years and reduces risk of death by at least 44% as the placebo or low-dose masitinib arms, despite compared with placebo, provided that treatment there being a delay in receiving this treatment. starts early in disease (i.e. prior to severe impair- ment of functionality). Confirmatory study One limitation of this analysis is that no informa- AB19001 is ongoing with a primary endpoint of tion on the post-study use of tracheostomy or decline in ALSFRS-R from baseline to week 48 in invasive ventilation was collected, nor was infor- the enriched patient population described herein. mation regarding which drugs were taken follow- Considering the consistency of significant treat- ing withdrawal from study AB10015 or its ment effect in terms of median OS, HR of death, associated NPP. Regarding the latter point, no ∆ALSFRS-R and PFS, a benefit to patients in the other drug has been convincingly shown to current NPP can be strongly presumed. improve OS, with the exception of riluzole, to which masitinib was administered as an add-on. Acknowledgements Edaravone is the only other drug to have received We thank the study participants, their families marketing authorization for ALS in certain coun- and caregivers. We also thank all investigators tries, but this drug was not available to the vast and collaborators from study AB10015. majority of the AB10015 population.16,28 Hence, the risk that these currently reported OS results Authors’ contributions have been confounded by subsequent successful JSM, DC, MHB, JM, JG, GMGM and AM con- treatment with other drugs is small. It is of inter- tributed to data collection and conception of the est that 25 placebo patients switched to masitinib work. JSM, ACL, WGB, OH, AM and CDM did as part of the NPP; however, any impact from this the initial data interpretation. CDM wrote the cross-over would manifest as a bias in favor of the manuscript with contributions from JSM, ACL, study’s overall placebo arm and does not there- WGB, AM and OH. The sponsor collected and fore weaken the AB10015 long-term OS results. analyzed the data in conjunction with the authors, who contributed to manuscript draft revisions, The magnitude of the observed OS signal for mas- provided critical comment, and approved sub- itinib (4.5 mg/kg/day) as compared with placebo is mission for publication. encouraging and also provides evidence that the main efficacy outcomes of study AB10015, i.e. Conflict of interest statement ∆ALSFRS-R at week 48 (according to the pri- Masitinib is under clinical development by the mary endpoint and sensitivity analyses based on study funder, AB Science. AM, OH and CDM are multiple imputation jump-to-reference tech- employees and shareholders of AB Science. JSM niques) and PFS, are legitimate surrogate end- has received research funding from AB Science. All points for long-term OS. It is equally encouraging remaining authors have no competing interests. in terms of having an optimized design for the cur- AL, an Associate Editor of Therapeutic Advances rent confirmatory phase III study (AB19001), the in Neurological Disorders, is an author of this primary efficacy population of which will be ALS paper, therefore, the peer review process was man- patients with mild or moderate impairment of aged by alternative members of the Board and the functionality at baseline (i.e. a score of at least submitting Editor was not involved in the decision- two on each ALSFRS-R individual component making process. 14 journals.sagepub.com/home/tan JS Mora, WG Bradley et al. Funding 20–22 June 2018, Oxford, England: Abstract The authors disclosed receipt of the following C35, https://www.encals.eu/meetings/encals- financial support for the research, authorship, meeting-2018-oxford-england/ (2018, accessed 7 and/or publication of this article: AB Science, July 2020). 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