Positive Interim Report on Fosgonimeton, Lower ASPECTS Scores Impact Efficacy of EVT, FDA Extends Review of Tofersen

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Welcome to this special edition of Neurology News Network. I’m Marco Meglio.

After an unblinded interim efficacy and futility analysis of fosgonimeton proved to be positive, an independent data monitoring committee recommended the continuation of the agent into the phase 3 LIFT-AD study of patients with mild-to-moderate Alzheimer disease (AD). Athira Pharma, the developer of fosgonimeton, noted that it is targeting to complete enrollment in mid-2023, with a topline data readout in early 2024.The unblinded interim analysis, which featured 100 individuals not on background AChEI therapy, was conducted to corroborate observations from the pivotal phase 2 ACT-AD study (NCT04491006) and to ensure that LIFT-AD is powered to determine the clinical efficacy of fosgonimeton. Given the preliminary effect size observed, it was determined that a total enrollment of less than 300 patients without background therapy would suffice to power the primary end point of Global Statistical Test. Fosgonimeton, a small molecule hepatocyte growth factor (HGF) and MET enhancer, originally failed to meet its primary or secondary end points in the phase 2 ACT-AD study when used with standard-of-care AChEIs.

Findings from a secondary analysis of the RESCUE-Japan LIMIT study showed that endovascular therapy (EVT) was not associated with improvement in functional outcomes at 90 days in patients post stroke with Alberta Stroke Program Early Computed Tomography Scores (ASPECTS) 3 or less and was associated with a significantly higher incidence of intracranial hemorrhage within 48 hours.Of patients with ASPECTS scores of 3 or less, 21.4% of those in the EVT group and 18.0% of those who did not receive EVT had a modified Rankin Scale (mRS) score of 0 to 3, considered good functional outcome. In comparison, for those with ASPECTS scores of 4 to 5, 43.2% of patients on EVT and 7.7% of those without EVT achieved similar scores at 90 days. The original findings from RESCUE-Japan LIMIT suggested efficacy of EVT in patients with a large ischemic core—ASPECTS scores of 3 to 5—however, there was still a difference in disease severity in patients within that score range, and thus, the goal of this new assessment was to understand the threshold of when EVT stops being beneficial.

After originally scheduling a PDUFA date of January 25, 2023, the FDA announced it has extended its review period for Biogen’s investigational agent tofersen, a drug designed to treat patients with a SOD1 mutation-mediated amyotrophic lateral sclerosis (ALS). The new updated PDUFA date is April 25, 2023. There are currently no approved therapies for patients with SOD1 mutation, and only a handful of approved therapies for ALS in general. Tofersen, an antisense oligonucleotide, had its new drug application (NDA) accepted in July 2022, with data from a phase 1 study of healthy volunteers, a phase 1/2 dose ascending study, the pivotal phase 3 VALOR study, and its open label extension (OLE), serving as the basis for the NDA. VALOR, a large-scale study that included 108 participants with SOD1 ALS, showcased tofersen’s impact on neurofilament light and SOD1 protein. Although it failed to meet its primary end point of statistically significant change from baseline in Revised ALS Functional Rating Scale (ALSFRS-R) after 28 weeks of treatment, it continued to demonstrate positive effects across multiple secondary and exploratory end points that were observed over a 12-month treatment period.

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