1
Initiation of the Phase 2/3 GAIN trial of COR388, a novel bacterial virulence factor inhibitor for the treatment of Alzheimer’s Disease based on Phase 1 a/b safety, PK, biomarker, and efficacy data Michael Detke, MD PhD 1 , Casey Lynch 1 , Leslie J. Holsinger, PhD 1 , Shirin Kapur, PhD 1 , Dave Hennings, PhD 1 , Debasish Raha, PhD 1 , Florian Ermini, PhD 1 , Ursula Haditsch, PhD 1 , Mark Ryder, DDS 2 , Ira Goodman, MD 4 , Stephen Thein, MD 4 , Stephen Dominy, MD 1 1 Cortexyme, S. San Francisco, CA; 2 UCSF, San Francisco, CA; 3 Bioclinica, Orlando, FL; 4 Pacific Research Network, San Diego, CA COR388 is a novel bacterial protease, (ie: gingipain) inhibitor being developed for the treatment of Alzheimer’s disease (AD). The mechanism of action is based on the discovery of Porphyromonas gingivalis (Pg) in the brain and cerebral spinal fluid of AD patients. The levels of toxic proteases called gingipains from the bacterium correlates with tau and ubiquitin pathology in the brain. Oral infection of mice with Pg results in brain colonization, increased production of Aβ1-42, inflammation, and loss of hippocampal neurons (Ilievski et al, 2018). These effects were blocked by COR388, a small-molecule irreversible gingipain inhibitor (Dominy et al, 2019). COR388 was selected to progress to human trials. BACKGROUND METHODS For AD subjects, Major inclusion criteria included having probable mild to moderate AD, baseline MMSE between 14 and 25, screening MRI compatible with AD, and no other cause of dementia. Subjects received 50 mg of COR388 or placebo q12 hr for 28 days as outpatients and returned to the clinic for weekly safety assessments. CSF was collected at baseline and day 28. A cognitive test battery (CANTAB, Cambridge Cognition Ltd., UK) was designed to provide a broad evaluation of cognition. Winterlight’s software (Winterlight Labs, Toronto, CA) was used to generate speech and cognitive scores using acoustic and linguistic variables from participant's description of standard pictures. BACKGROUND CONCLUSIONS The gingipain hypothesis of Alzheimer’s disease, with P. gingivalis as an etiologic agent, is supported by scientific literature from multiple disciplines and several independent labs. COR388 is a promising drug for the treatment of AD with a novel mechanism of action. COR388 inhibits the Kgp gingipain protease secreted by P. gingivalis, essential for pathogen survival and virulence. COR388 is readily bioavailable after oral administration with a favorable PK profile and CNS penetration in humans, with target plasma concentrations for efficacy reached. COR388 was well tolerated and AD patients treated with COR388 for 28 days demonstrated significant reduction in several pharmacodynamic biomarkers including plasma RANTES and pathological ApoE fragments in CSF. There was also a trend of improvement in some cognitive tests in AD patients treated with COR388, in contrast to subjects receiving placebo. Cortexyme is currently enrolling a 570 patient Phase 2/3 study of COR388 assessing the efficacy, safety, and tolerability of two dose levels of COR388 for a 48-week treatment period in subjects with mild to moderate Alzheimer’s disease. This potentially pivotal study is now ongoing. CONCLUSIONS EXPLORATORY COGNITIVE TESTING • MMSE scores showed a trend of improvement from baseline and compared to placebo; the difference was not statistically significant (A); • CANTAB memory composite of cognitive function showed a trend to benefit of COR388 treatment compared to baseline and compared to placebo (B); the difference was not statistically significant • Winterlight speech and cognitive battery was used to assess the change from baseline in 35 speech variables. Improvement in the level of detail provided during the picture description was seen in the treatment group but not in the placebo group. Three speech measures significantly increased in the treatment group including use of prepositions and subordinating conjunctions (C) in which COR388 vs. placebo remained significant after Bonferroni correction. Cohorts 1-3: Older Healthy Volunteers • 24 subjects, mean age of 60 years (55-70) •18 subjects received COR388 and 6 received placebo. Cohort 4: AD patients • 9 enrolled, 5 male and 4 female • 6 received COR388 50 mg (mean MMSE = 19.5, age 72); 3 received placebo (Mean MMSE 17, age 72) PHASE 2/3 GAIN TRIAL: GingipAIN inhibitor for treatment of AD BIOMARKERS in AD subjects • ApoE is proteolytically cleaved by gingipains and a similar ApoE cleavage product of approx. 15kD is detected in AD brain and CSF (unpublished data). ApoE fragmentation was reduced in COR388-treated subjects. • RANTES, a chemokine associated with chronic inflammation, is reduced in plasma of COR388- treated subjects. Cognitive Testing and Speech Variable Changes Using Winterlight Cognitive Battery Cohorts 1-3: Older Healthy Volunteers; Treatment duration = 10 days Dose Subjects dosed Placebo N=6 25 mg N=6 50 mg N=6 100 mg N=6 Dizziness 1 0 0 1 (17%) 1 (17%) Dysgeusia 1 1 (17%) 0 0 0 Nausea 1 0 0 0 1 (17%) Presyncope 2 1 (17%) 0 0 0 Restlessness 1 0 0 0 1 (17%) 0 Tachycardia 1, 3 0 0 1 (17%) Cohort 4: Patients with AD; Treatment duration = 28 days Dose Subjects dosed Placebo N=3 50 mg N=6 Bradycardia 1 1 (17%) 0 Elevated Liver Enzyme 2 0 1 (17%) Elevated pancreatic enzymes 1 0 1 (17%) Orthostasis 1 1 (17%) 0 1 (17%) 1 (17%) Subjects with any drug related TEAE 4 (44%) 0 (0%) 4 (33%) 3 (50%) 1 Mild AE severity, 2 Moderate AE severity. 3 AE consisted of 6 beats of SVT that occurred again 72 hours after stopping study drug. Table 1: Drug Related Treatment Emergent Adverse Events Prolonged QT 1 P4-663 • Study began Q2 2019 and is currently enrolling; www.gaintrial.com ; Top-line data are expected Q4 201 COR388 was well tolerated in a SAD study in healthy volunteers, a 10-day MAD study in healthy older subjects, and a 28-day study in mild to moderate AD subjects age 55-85. • This trial involves extensive collection of biomarkers of P. gingivalis infection as well as biomarkers of neuroinflammation and AD for responder analyses and exploratory efficacy. All biomarkers are collected at prior to dosing and at appropriately scheduled collections throughout the dosing period. PHASE 2/3 GAIN TRIAL: Biomarkers Saliva Oral Bacterial Microbiome Analysis P. gingivalis bacterial burden CSF Subject 004 Subgingival plaque Subject 004 RgpB activity: substrate cleavage assay Kgp activity: active site probe binding and total protein levels Phase 1b COR388-002 All Cohort 4 AD subjects Detection of P. gingivalis PCR product (HmuY gene) and sequence confirmation, confirming presence of infection in AD subjects Subject 004 O.D. SAFETY • COR388 was safe and well tolerated after dosing up to 28 days in older healthy volunteers and patients with AD. • Adverse events were infrequent, transient, and mild to moderate (Table 1), with no serious adverse events reported and no patients withdrew from the study because of adverse events. • No clinically significant trends were seen in laboratory values or ECGs. PK • Rapidly absorbed, Tmax = 0.5-1.5h, with therapeutic target exposure as predicted from animal models achieved • Half-life of 4.5-5 hours at steady state, detected in CSF RANTES (CCL5) in Plasma is reduced in COR388-treated subjects ApoE fragment found in CSF is reduced in COR388-treated subjects Days of Treatment Days of Treatment *p< 0.05, **p< 0.05 PHASE 1 RESULTS • P. gingivalis-specific biomarker examples: p=0.052 vs baseline p=0..17 p=0.001 vs baseline
