AB Science to launch new Phase 3 trial of masitinib for ALS
AB23005 will replace AB19001 study, which has struggled to enroll patients
AB Science will launch a new Phase 3 clinical trial to test its investigational oral therapy masitinib in people with amyotrophic lateral sclerosis (ALS) whose disease is progressing normally and who haven’t completely lost physical function, according to a company update.
The trial, called AB23005, will replace the AB19001 Phase 3 clinical trial (NCT03127267) that was hindered by slow recruitment. U.S. and European regulators recommended that the company should launch a new study that addresses some of the limitations that were causing enrollment issues, instead of updating AB19001’s protocol.
AB23005’s design has been validated by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), and both agencies have authorized the confirmatory study. AB Science believes enrollment can be completed in less than a year and the study completed in two years, according to a company presentation.
Masitinib is an oral inhibitor of tyrosine kinases, a group of enzymes that are important for the function of immune cells thought to drive inflammation and damage in ALS. By blocking the cells’ activation, it’s believed that masitinib will ease inflammation and slow ALS progression.
Evaluating masitinib in ALS
A previous Phase 2/3 clinical trial (NCT02588677) tested two daily doses of masitinib (3 or 4.5 mg/kg) against a placebo in nearly 400 adults with ALS. The treatment was administered as an add-on to the approved ALS therapy Rilutek (riluzole) for nearly a year, or 48 weeks.
The study mainly sought to evaluate changes in disease progression, as assessed by the ALS Functional Rating Scale-Revised (ALSFRS-R), among patients with typically progressing disease, defined as a monthly ALSFRS-R score decline of less than 1.1 points from disease onset to the study’s start. The study met its main goal, with the high dose of masitinib slowing disease progression by 27% compared with a placebo among normally progressing patients.
Additional analyses indicated a particular benefit was seen in patients with mild or moderate disease who’d lost fewer functional abilities. Among those patients progressing normally who hadn’t yet completely lost function on any individual component of the ALSFRS-R, the high dose of masitinib was associated with about a year’s survival benefit relative to a placebo.
Long-term follow-up of patients treated with masitinib in compassionate use programs also showed that the survival of patients treated with masitinib in the clinical trial is surpassing what would be predicted in the natural course of disease.
The company previously sought conditional approval of masitinib in the European Union and Canada based on the Phase 2/3 trial findings, but the applications were generally met with negative opinions. AB believes that, while regulators didn’t find the data sufficient for a regulatory approval, they do support the launch of a confirmatory Phase 3 study involving patients most likely to benefit from treatment.
That was the goal of AB19001, which is testing the 4.5 mg/kg dose and a higher dose of 6 mg/kg, but recruitment has been slow, according to AB. The company noted several challenges to enrollment with the trial’s design, including a run-in period before starting masitinib in order to exclude people with fast-progressing disease and the inclusion of only patients with moderate ALS.
AB19001 also prohibited the use of Radicava or Radicava ORS (edaravone), ALS therapies approved in the U.S., and Relyvrio (sodium phenylbutyrate and taurursodiol), which has been removed from the U.S. market. These factors also hindered U.S. enrollment, the company maintains.
Changes with AB23005
AB23005, with similar intentions, is designed to overcome these challenges. There won’t be a run-in period, it will include people with moderate or severe ALS, and using edaravone and riluzole-based therapies is allowed.
Based on the findings from the Phase 2/3 study, participants will have normally progressing disease and will not have completely lost physical function, as assessed by scores of at least 1 on all 12 items of the ALSFRS-R scale.
The study plans to enroll 408 patients, who will be randomly assigned to masitinib (4.5 mg/kg) or a placebo for 48 weeks, followed by an open-label extension where all can receive masitinib. Its main goals will be to evaluate disease progression, as assessed by the Combined Assessment of Function and Survival (CAFS) and ALSFRS-R. Data on quality of life, survival, and disease biomarkers will also be collected.
With the launch of this new trial, AB19001 will become a supportive and exploratory study to evaluate the safety and efficacy of the 6 mg/kg dose, the company noted.
AB has also announced that it’s continuing masitinib’s development as a potential treatment for other neurological diseases, including multiple sclerosis and Alzheimer’s disease.
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