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 programme during a session on amyloid beta (Aβ) and other targeted therapies in AD on 20 March. As part of the session, new data were presented from the drug’s Phase II/III GAIN trial (NCT03823404) that add support to the novel mechanism of action (MOA) of COR388 for AD.

COR388, a novel, orally-administered, small molecule, is a bacterial protease inhibitor targeting gingipains produced by the periodontal pathogen Porphyromonas gingivalis (P gingivalis). There is growing evidence—epidemiological, pre-clinical and clinical—supporting the potential role of P gingivalis as an upstream driver of AD. Previously presented data from the GAIN trial showed that treatment with COR388 was correlated with slowed cognitive decline in mild to moderate AD.

In the overall trial population, the study failed to show significant results, not meeting its co-primary endpoints as measured by the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog11) and Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL), throwing some doubt on exactly how beneficial this MOA will be as a disease-modifying therapy (DMT) for AD. But in the subgroup of patients who had P gingivalis detectable in their saliva at baseline, COR388 treatment did result in a significant slowing of cognitive decline measured using ADAS-Cog11; the ADCS-ADL measure was not significant in this population. Based on these results, Cortexyme has focused on this patient subpopulation when presenting further data from the study.

Cortexyme presented new biomarker results from the GAIN trial at the AD/PD 2022 conference with the aim of further supporting the MOA of COR388 in the treatment of AD. Data showed that treatment with COR388 resulted in an increase in cerebral spinal fluid (CSF) Aβ 42/40 ratio (Aβ40 is the most common variant in the CSF, while Aβ42 is associated with plaques; therefore, a decrease in Aβ 42/40 ratio is a marker of AD), as well as trends in CSF tau biomarkers (phosphorylated tau and total tau) correlated with the observed slowing in disease progression. Aβ and tau protein accumulation are both hallmark pathologies of AD, so it is important for Cortexyme to show that COR388 has an effect on associated biomarkers in order to validate its novel MOA and demonstrate its role as a DMT.

In addition, new data at AD/PD 2022 showed that patients treated with COR388 demonstrated a reduced decrease in bilateral hippocampal volume, cortical thickness and whole brain volume, which correlated with lower rates of disease decline, measured through ADAS-Cog11 and ADCS-ADL. Although Cortexyme pointed to the weight of all these different biomarker trends to support the positive effect of treatment with COR388, most of the data points still failed to be statistically significant—both in the intent-to-treat and P gingivalis-positive populations. In contrast, new biomarker data presented at AD/PD 2022 by Biogen on its controversial AD drug, Aduhelm (aducanumab), which was approved by the US FDA last June based on biomarker data as opposed to clinical effect, was statistically significant.

The data presented by Cortexyme focused on the efficacy of COR388 in the subgroup of patients where P gingivalis was detected in saliva, and as such, GlobalData expects that it will only be used in patients with comorbid oral infection with P gingivalis. Given the questions that remain surrounding COR388’s true efficacy, GlobalData forecasts that if it launches, the drug will generate global sales of $47m by 2030.

On top of negative clinical data, a further obstacle to the development of COR388 came in January this year, when the FDA placed a full clinical hold on the drug’s investigational new drug application. Although Cortexyme did not announce the reason behind this, the FDA imposed a partial clinical hold last month following a review of hepatic adverse events. It remains to be seen what this will mean for the future of the drug; however, further data from the GAIN trial is expected to be announced later this year.

Cortexyme has also developed a second-generation version of the drug, COR588, which is currently in a Phase I trial (NCT04920903). In preclinical studies, COR588 demonstrated a better safety profile compared with COR388, as well as an improved pharmacologic profile, allowing for once-daily dosing instead of twice-daily. While it appears there is some promise behind the novel MOA of COR388, it is unlikely that Cortexyme will continue to pursue this particular drug, instead choosing to focus on COR588. But if COR588 is to be successful as a novel DMT for AD, it will need to demonstrate stronger efficacy than COR388 has so far been able to.