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AB Sciences announced in a press release that an advisory committee to the European Medicines Agency (EMA) has leaned against recommending conditional approval of the company’s masitinib as an oral add-on treatment for amyotrophic lateral sclerosis (ALS).
The Committee for Medicinal Products for Human Use (CHMP) is due to meet in late June to make a formal decision, and AB Sciences said it would work with the CHMP to find the best way forward, which could include requesting a reexamination.
The decision was postponed for a second time earlier this year due to unresolved issues, with the committee seeking written answers to questions rather than verbal clarifications, slowing the evaluation process.
During a live webinar on May 30, AB Sciences said the CHMP had determined that masitinib was safe but “could not conclude on a favorable benefit.”
Masitinib is a small molecule that inhibits tyrosine kinase, a type of enzyme involved in the proliferation and activation of certain immune cells that drive ALS inflammation. By blocking the enzyme, masitinib reduces inflammation and damage, slowing disease progression and relieving symptoms.
AB Sciences’ application is based on data from the Phase 2/3 clinical trial AB10015 (NCT02588677), in which 394 adults with ALS received masitinib twice daily (3 or 4.5 mg/kg) in addition to the approved ALS treatment Rilutek (riluzole) compared with placebo.
In patients with so-called normal progression, meaning a decline in their ALS Functional Rating Scale-Revised (ALSFRS-R) score of less than 1.1 points per month, high-dose masitinib was significantly better than placebo at slowing disease progression. In these patients, treatment with 4.5 mg/kg masitinib reduced ALSFRS-R score decline by 27% after almost one year, but no change was seen in patients progressing faster than normal.
Regardless of the initial rate of disease progression, patients with mild or moderate ALS benefited the most, showing up to 42% less decline in ALSFRS-R scores compared to placebo.
CHMP Issues with Masitinib
Issues cited by the CHMP after a recent oral discussion of the data included deviations from Good Clinical Practice (GCP), the standard for designing, recording and reporting clinical trials.
The company said that while the deviations “cannot be corrected retroactively,” the risks and benefits of the drug could still be assessed because ALSFRS-R scores are reliable and continue to show benefit on reanalysis.
The CHMP also expressed concern that AB Sciences excluded patients with more advanced disease from its primary analysis, but the company argued that “more homogeneous samples need to be used in ALS drug development.” [consistent] A huge demographic opportunity [to reach the proposed follow-up time] It minimizes missing data.”
Another issue concerns the handling of missing data: according to the CHMP, the “jump to reference”, where outcomes for patients who drop out of the study are assumed to “jump” to those in the placebo group, should be applied in all discontinuation cases.
AB Sciences said it recorded reasons for discontinuation and applied “jump to reference” for discontinuation due to side effects, lack of efficacy, or travel. Results from the two alternative methods recommended by the CHMP were consistently positive.
Finally, to determine whether an analysis of patients with mild or moderate ALS is justified, it will be necessary to evaluate whether that group skews the results or whether it could provide a clearer understanding of how effective masitinib is.
AB Science cited EMA guidelines to justify its decision, which state: after [after the study is conducted] AB Sciences said it was a subgroup with compelling efficacy and risk-benefit profiles, whether or not the group was identified by the company itself, and noted that benefits in that group were observed across a range of clinical endpoints, including improved 12-month survival. [that] It cannot be ignored.”
AB Sciences also presented the issues Health Canada used to reject the ALS drug application for masitinib, which differed slightly from the issues raised by the EMA committee, the company said in a summary of the live webcast. Health Canada agreed to reconsider the application in April.
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