Data from trials testing the safety, pharmacokinetics (PK), biomarker and cognitive readouts of a Phase Ib study of Cortexyme’s COR388, were presented at the 2019 International Congress on Alzheimer’s disease (AD) and Parkinson’s disease (PD) in Lisbon, Portugal.
Alzheimer’s disease treatment
The drug is a small molecule, orally available inhibitor of gingipains that is the cysteine proteases of the periodontal pathogen Porphyromonas gingivalis (Pg).
Chronic periodontitis (CP) has been identified as significant risk factors for AD and in mouse studies indicated Pg can translocate to the brain after oral infection in mice.
In a key publication from the University of Illinois, they showed that oral infection of Pg in wild mice results in brain infection and AD pathology, namely, Pg brain infection increased APP/Bace1 gene expression, Abeta42 production and plaques, tau phosphorylation and tangle formation.
COR388 is an optimised new chemical entity that is first-in-class and orally administered, in the Phase Ia SAD study the drug showed that was well tolerated in healthy volunteers with infrequent adverse events (AEs) and no subcortical arteriosclerotic encephalopathy(SAE’s), no dose-limiting toxicity (DLT) was identified and no clinically relevant changes in laboratory tests, electrocardiogram (ECG) or vital signs.
The Phase Ib trial was a randomised, placebo-controlled, repeat dose that enrolled 33 subjects in four cohorts, cohorts 1-3 enrolled healthy volunteers with no dementia and received 25, 50, and 100 mg of COR388 or placebo every 12 hours for ten consecutive days while cohort 4 enrolled subjects with AD and received 50 mg of COR388 or placebo every 12 hours for 28 days as outpatients.
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Results showed that COR388 was safe and well tolerated in all 4 cohort and drug-related treatment-emergent AE was mild and transient and no dose-limiting toxicities or serious adverse events reported. The PK profile of COR388 was consistent with twice daily dosing and CSF levels of the drug were detected at levels similar to that seen in nonclinical studies that are associated with high brain penetration.
Alzheimer’s disease treatment: GAIN trial
After these positive results data, Cortexyme is planned to do a Phase II/III study called GAIN (GingipAIN Inhibitor for treatment of AD) that will start in Q2 2019 and topline results are expected at the end of 2021. The GAIN study will be a randomized, double-blind, placebo-controlled, parallel groups that will recruit 570 patients with mild to moderate AD and it will last 48 weeks with 6 weeks safety follow up.
The primary endpoint will be AD Assessment Scale-Cognitive subscale (ADAS-Cog 11), 90% powered to detect 2.5 points/year change in slope and the study will be conducted in the US and in 8 countries in European Union.
The AD pipeline has been characterised by big failures, and the latest discontinuation of Roche’s crenezumab and mainly Biogen/Eisai aducanumab have cast doubts about the amyloid hypothesis.
The amyloid hypothesis has been the major explanation for the pathogenesis of AD for more than 20 years, but after Aβ-targeting drugs for the treatment of AD ended in failure, researchers are exploring other potential treatment options such as tau proteins, vaccines and now also with a bacterial pathogen.