At the AD/PD 2022 International Conference on Alzheimer’s disease (AD) and Parkinson’s disease (PD), Cortexyme presented new data from its COR388* (atuzaginstat) clinical program, highlighting positive numerical trends seen with the treatment and key biomarkers of AD, including amyloid-beta (Aβ) and tau protein.

GlobalData notes that both proteins are hallmark pathologies of AD, so while it is important for Cortexyme to show that COR388 has an effect on associated biomarkers to help validate its novel mechanism of action (MoA), few of these outcomes were statistically significant and doubts still remain over the drug’s efficacy given its failure to meet the co-primary endpoints of its Phase II/III GAIN trial (NCT03823404). As such, the leading data and analytics company forecasts that, if COR388 launches, it will generate global sales of only $47 million by 2030.

Philippa Salter, Neurology Analyst at GlobalData, comments: “Although Cortexyme pointed to the weight of multiple different biomarker trends from the GAIN trial to support the positive effect of treatment with COR388, without evidence of statistical significance, it remains difficult to estimate the potential for this product. In contrast, new biomarker data presented at the conference by Biogen on its controversial AD drug, Aduhelm (aducanumab), which was approved by the FDA based on biomarker data as opposed to clinical effect adds to our understanding of its clinical profile.”

A further obstacle to the development of COR388 came in January 2022 when the FDA placed a full clinical hold on COR388’s investigational new drug application. Although Cortexyme did not announce the reason behind this recent clinical hold, previously, in February 2021, a partial clinical hold was imposed by the FDA following a review of hepatic adverse events. It remains to be seen what this event will mean for the future of COR388, when combined with its mixed clinical data so far. However, Cortexyme is developing a second-generation version of the drug, COR588, which could allow the potential of COR388’s MoA to be carried forward.

Significantly, in preclinical studies, COR588 demonstrated a better safety profile compared with COR388, as well as an improved pharmacologic profile, allowing for more convenient once daily dosing instead of twice daily.

Salter adds: “The reason Cortexyme continues to move forward with this MoA is likely due to a finding that, among patients in the GAIN trial whose saliva was positive for P. gingivalis, there was a statistically significant difference in one measure of cognitive decline (ADAS-Cog11**) between COR388 and placebo.

“While there may be some promise behind this novel MoA, it seems unlikely that Cortexyme will continue to pursue this particular drug, instead choosing to focus on COR588. The positive biomarker trends seen in the COR388 trial will likely help support the understanding of the MoA of COR588. However, questions remain whether COR588 will be able to demonstrate stronger efficacy than COR388. This of course is necessary for the drug to to enter as a novel disease modifying therapy into the AD market.”

* COR388, a novel, orally administered, small molecule, is a bacterial protease inhibitor targeting gingipains produced by the periodontal pathogen Porphyromonas gingivalis. There is growing evidence—epidemiological, pre-clinical, and clinical—supporting the potential role of P. gingivalis as an upstream driver of AD.

** Alzheimer’s Disease Assessment Scale–Cognitive Subscale.