*Cortexyme owns worldwide rights to all programs
Cortexyme’s pipeline includes proprietary drug candidates for the treatment of a variety of degenerative diseases where P. gingivalis infection plays an integral role. This includes indications for central nervous system (CNS) disorders, including Alzheimer’s disease, periodontal disease, as well as oncology applications for the potential treatment of high-risk oral potentially malignant disorders such as oral/head and neck squamous cell cancer (O/HNSCC), high-risk oral pre-malignant dysplasia (PmD), proliferative verrucous leukoplakia (PVL), and carcinoma-in-situ (CIS). The company’s pipeline also includes a proprietary irreversible protease inhibitor under development for the treatment of coronavirus infection. The company’s expanding portfolio of gingipain inhibitors are orally administered, brain-penetrating small molecules.
In September 2021, Cortexyme expanded its proprietary development pipeline with the initiation of a Phase 1 single ascending dose (SAD) / multiple ascending dose (MAD) clinical trial of COR588, a second-generation small-molecule lysine-gingipain inhibitor differentiated from the company’s lead drug candidate atuzaginstat (COR388) by its improved safety and pharmacokinetic properties and once daily oral administration. Cortexyme plans to advance COR588 for use in the treatment of mild to moderate Alzheimer’s disease.
In the SAD portion of the Phase 1 trial, preliminary results indicate COR588 was well-tolerated across all four cohorts in the dose range from 25 mg to 200 mg with no serious adverse events. No clinically significant findings were observed on other safety measures, including vital signs, laboratory findings, telemetry, or ECGs. In the study, COR588 exhibited an 11-to-12-hour half-life consistent with once daily dosing and a dose-proportional pharmacokinetic profile that achieved and exceeded the targeted exposure predicted for therapeutic efficacy.
Cortexyme expects to present the full data set from the COR588 Phase 1 clinical trial in the second quarter of 2022. Following the Phase 1 study, the company plans to advance COR588 to a Phase 2 trial to assess dose ranging, biomarker response, and further evaluate the safety profile.
The GAIN Clinical Trial
Completed in October 2021, the GAIN Trial (GingiPAIN inhibitor for treatment of Alzheimer’s disease) was a Phase 2/3 randomized, double-blind, placebo-controlled study that assessed the efficacy, safety, and tolerability of two dose levels of atuzaginstat oral capsules in subjects with mild to moderate Alzheimer’s disease. Randomized participants entered a screening period of up to six weeks, a 48-week treatment period, and a completed a safety six-week follow-up.
The GAIN Trial enrolled 643 participants in the United States, France, Spain, Poland, United Kingdom, and Netherlands.
Cortexyme reported top-line results from the GAIN Trial that demonstrated a relationship between reduction of P. gingivalis infection and slowing of cognitive decline. While not meeting statistical significance on its co-primary cognitive and functional endpoints in the overall cohort, prespecified cohorts representing up to half of the GAIN Trial participants based on P. gingivalis infection level showed trends to approximately 50% slowing of cognitive decline in the 12-month study. The GAIN Trial included a sub-study for proof of efficacy in periodontal disease, which demonstrated a trend to benefit on the primary clinical endpoint of pocket depth in the same pre-specified sub-group with P. gingivalis DNA detectable in saliva. Most adverse events were mild to moderate in severity. The most common were gastrointestinal, such as diarrhea in up to 16% and nausea in 6% of participants treated with atuzaginstat vs. 3% and 2% of placebo participants, respectively. Atuzaginstat was associated with dose-related liver enzyme elevations >3X the upper limit of normal: 2% on placebo, 7% on 40 mg BID, and 15% on 80 mg BID. These elevations alone were not clinically significant, and virtually all participants were asymptomatic. Two participants in the 80 mg BID arm had concomitant bilirubin elevations without alternative explanation. Lab changes resolved while participants remained on drug or after withdrawal without any known long-term adverse effects. Atuzaginstat treated groups showed no increase in ARIA (amyloid-related imaging abnormalities), including microhemorrhage and edema, or superficial siderosis.
Visit www.GAINtrial.com for more information.