According to a statement made by Cortexyme, the partial hold was placed on the development program for atuzaginstat after an FDA review of the trial data identified hepatic adverse events.
Atuzaginstat has been put on partial clinical hold.
The U.S. Food and Drug Administration (FDA) has placed a partial clinical hold on Cortexyme’s atuzaginstat (COR388), a small molecule novel virulence factor inhibitor, which the company says will impact the open-label extension phase of its Phase II/III Alzheimer’s disease (AD) trial.
Cortexyme’s atuzaginstat targets gingipains, or toxic proteases, which are produced by Porphyromonas gingivalis and have been found in 90% of patients with AD. This Gram-negative bacterium has been shown to produce neurodegeneration in animal models.
According to a statement made by Cortexyme, the partial hold was placed on the development program for atuzaginstat after an FDA review of the trial data identified hepatic adverse events.
As a result of the partial clinical hold on atuzaginstat, Cortexyme will halt enrollment of any new participants in the open-label extension phase of the GAIN (GingipAIN Inhibitor for Treatment of Alzheimer’s Disease) trial.
The double-blind, randomized, placebo-controlled trial has been fully enrolled at 643 participants with AD. These participants will continue to receive atuzaginstat at their assigned dose. Top-line results from the GAIN trial are expected in the fourth quarter of 2021.
While the hepatic events are concerning, Cortexyme notes that they have been reversible and show no risk of any long-term adverse effects on participants. To get back on track, the company states it will continue to work with the FDA on the development program for atuzaginstat.
“Cortexyme’s highest priority is the safety of study participants,” said Casey Lynch, Cortexyme’s chief executive officer, co-founder and chair. “The ongoing double-blind GAIN Trial in mild to moderate Alzheimer’s disease will provide a critical assessment of efficacy and safety in the treatment of this devastating disease.”
In December, an independent Data Monitoring Committee (DMC) recommended that Cortexyme continue the GAIN trial to the planed one-year endpoint, following an interim analysis of the trial data. “We are pleased with the DMC recommendation, which we believe supports the study design and statistical powering of the GAIN Trial,” said Cortexyme’s Chief Medical Officer, Michael Detke, M.D., Ph.D. “The totality of evidence around P. gingivalis and gingipain inhibition shows that blocking this upstream target may impact multiple aspects of disease progression and neurodegeneration.”
Cortexyme presented preclinical data in July 2020 showing atuzaginstat’s potential impact on both cardiovascular disease and neurodegeneration associated with AD. The Phase Ib clinical data, presented in two poster presentations at AAIC 2020, showed that atuzaginstat demonstrated therapeutic potential in blocking AD-associated ApoE fragmentation.
“Building on strong prior research linking P. gingivalis to cardiovascular disease, our research shows improvements in lipid deposition, progression of atherosclerosis and levels of systemic inflammation in the P. gingivalis-infected groups treated with atuzaginstat,” said Hatice Hasturk, D.D.S., Ph.D., director of the Center for Clinical and Translational Research at the Forsyth Institute and principal investigator of the presented research. “These data are highly suggestive that atuzaginstat may have therapeutic potential in mitigating cardiovascular disease in people with P. gingivalis infection, a common oral infection thought to effect more than 50% of the adult population, which is capable of promoting systemic infection and inflammation.”
