Earlier this year, AB Science announced positive top-line resu­­­­­­lts from a Phase II/III trial of their lead candidate, the oral tyrosine kinase inhibitor masitinib, as adjunctive therapy in approximately 400 Amyotrophic lateral sclerosis (ALS) patients receiving treatment with current standard-of-care riluzole. Along with the FDA’s recent approval of Mitsubishi Tanabe Pharma’s Radicava, the masitinib data looked—at the time—to be another potential leap forward in the treatment of this devastating disease. However, just prior to the presentation of the detailed—and arguably unconventional—analyses of the ALS trial last month, Agence Nationale de Sécurité du Médicament (ANSM), the French National Agency for Medicines and Health Products Safety, suspended AB Science’s ongoing trials of masitinib in all indications pending the results of a compliance audit. In addition, the CHMP rendered a negative opinion for the drug in mastocytosis, citing failings in routine good clinical practice (GCP)—leaving many to wonder about the rigor of the ALS result.

In patients with a “normal” rate of ALS progression, masitinib appeared to slow the rate of functional decline by 27% versus placebo. In the protocol for the trial, AB Science prospectively allowed for segmentation based on enrolled ALS patients’ progression rate on the ALS Functional Rating Scale (ALSFRS-R) during the study. At the end of the trial, patients were divided for analysis into “normal” progressors (<1.1 points/month decline over 48 weeks) and “fast” progressors (>1.1 points/month decline), and a fixed sequence analysis was used to evaluate masitinib’s impact on ALSFRS-R progression by dose (4.5 and 3 mg/kg) and patient subtype. The primary end point was met under one condition only; in “normal” progressors, the higher dose of masitinib significantly reduced worsening of ALSFRS-R score at 48 weeks (by 27%, p=0.016) versus placebo. In this condition, drug treatment also led to improvement of some secondary end points over placebo, including quality of life the (ALSAQ-40), progression-free survival, and forced vital capacity. Interestingly, ALSFRS-R gains were better, on average, in “normal” progressors with shorter disease duration at baseline: 28% in patients with <24 months of disease, and 32% in patients with <18 months of disease). At 3mg/kg, the 24% slower decline in ALSFRS-R in “normal” progressors was not statistically significant, and no significant improvements on secondary end points other than quality of life were observed. Masitinib treatment failed to meet the primary end point in the total enrolled population—i.e., including “fast” and “normal” progressors.

Regulators could be compelled by masitinib, even if benefit is ultimately established only in early/milder ALS patients. The FDA’s recent approval of Mitsubishi Tanabe Pharma’s Radicava (edaravone) was notable because clinical data for the drug were mixed—only one trial, enrolling only early-stage patients, was positive—and the program did not include a single trial conducted in the United States. The agency’s receptivity to the data package for Radicava was likely supported, in part, by the pressing unmet need for new treatments in ALS—indeed, the FDA was proactive in soliciting the application. Furthermore, the agency ultimately applied a broad label to Radicava for the treatment of ALS, despite an evidence base supporting significant benefits in early-stage patients only. Although there are clear, meaningful differences between the design and analysis of the key pivotal trial for Radicava and AB Science’s trial of masitinib in ALS, masitinib projects a roughly similar efficacy profile. Thus, a rigorous demonstration of masitinib’s benefit in early/mild patients would likely support a successful regulatory application. However, it appears unlikely—perhaps increasingly so—that AB Science’s current evidence base for masitinib in ALS would hurdle any regulatory bar.

AB Science’s track record with masitinib in oncology indications breeds little confidence, and compliance violations may cast a long shadow. In 2013, the CHMP adopted a negative opinion on AB Science’s application for masitinib for treatment of gastrointestinal stromal tumor citing concerns over the drug’s limited safety data, quality control at the drug’s manufacturing facility, and study design. The following year, the CHMP rendered a negative opinion in pancreatic cancer, citing the need to confirm an observed subgroup benefit in a separate study, as well as manufacturing quality control issues. Last month, CHMP delivered another negative opinion of masitinib for systemic indolent mastocytosis—citing the most worrisome, and potentially far-reaching, concerns: serious failings in a routine GCP inspection at the study sites, major design changes during the study that precluded interpretation of results, and safety concerns owing in part to limited data. Days earlier, the ANSM suspended all clinical trials of masitinib in France, until compliance with GCP and proper pharmacovigilance monitoring is confirmed by external audits. Taken together, these developments put AB Science’s masitinib program in a deep hole to climb out of.

AB Science indicated that the ANSM actions do not affect the ALS study because the study was not conducted in France, and it benefitted from the early 2015 implementation of a new compliance and pharmacovigilance system. The company further states that no unreported adverse events were noted from 11 site inspections carried out by the regulatory authorities outside France since mid-2015; in particular, a site inspection performed by the Canadian Health Authority on the ALS Phase III study found it to be in compliance with GCP standards. Nonetheless, the CHMP’s issues surrounding the design and analysis of the company’s clinical studies in other indications will likely emerge for ALS trial, given the unique approach to patient segmentation that was required to uncover a significant benefit of masitinib the trial. Moreover, the ALS study initiated in 2013 and therefore, at least in part, could be affected by GCP issues prior to company’s 2015 steps to remedy compliance.

Interviewed experts remain apprehensive about both AB Science and masitinib. Several ALS experts in recent interviews cited concerns about AB Science’s history of flawed/obscure clinical designs, multiple failures, and apparent reluctance to broadly share full details of the trials it conducts. Some thought leaders also questioned the relevance of masitinib’s mechanism of action in ALS treatment, owing to doubts over the role of neuroinflammation in the pathophysiology of ALS. Nonetheless, most maintain that, if it shows reasonable clinical benefit and ever gets approved, they will be willing to prescribe masitinib to most of their patients.

Any path to masitinib’s approval for ALS won’t be a smooth ride. The FDA’s receptivity to Radicava bodes reasonably well for masitinib, as masitinib projects to offer, at best, mixed data and selective benefit within the ALS population (i.e., early/mild patients). However, complications surrounding GCP compliance can’t be ignored, even for a disease like ALS, and AB science must emerge cleanly from the GCP compliance audits to retain any lingering confidence/trust on the part of regulators and potential prescribers. Although AB Science’s plan for a regulatory filing for masitinib in the United States is yet unclear, the EMA’s regulatory decision on the conditional approval of masitinib in ALS is expected in Q4 2017. AB Science expects that the ongoing GCP audit in France will be complete prior to the inspections that support the regulatory decision for ALS. However, if history is any guide, the CHMP may be reticent to accept the design and analyses of the ALS trial—even for conditional approval—and results from a planned upcoming study may be required to support a more viable application.

To learn more about the ALS market, read our Niche & Rare Disease Landscape & Forecast | Amyotrophic Lateral Sclerosis | US/EU5 content.


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