Cortexyme ($CRTX) and GAIN Clinical Trial: Is Alzheimer's Disease Solved?

This is the decade of neuroscience. Everyone in biotech knows it. Everyone at the FDA knows it. Bob Nelsen knows it ("Really Big Neuroscience Company"). Biogen knows it. If you didn't know, now you do. Alzheimer's Disease is the crown jewel. Why? The potential patient population is absolutely massive, it's a years-long progressive disease with a treatment duration that provides serious recurring revenue, and it has been a near-impossible scientific puzzle to solve. Biogen got a controversial win with the seemingly do-nothing biologic Aduhelm. Congrats BIIB. You set any stock Alzheimer-related on absolute fire. $ABOS, $ANVS, $AVXL, $CRTX, $DNLI, and $SAVA all have the market primed to sprint on even a whiff of good news in the coming months. I'm focused on one, Cortexyme (CRTX). ​ TL;DR Cortexyme (CRTX) presents a causative mechanism for Alzheimer's Disease (bacterial infection of the brain) that explains amyloid beta 1-42 accumulation, pTau production, and APOE4 genetic risk factors -- all hallmarks of disease. CRTX is testing a patent-protected, orally-administered, first-in-class small molecule in a clinical trial to evaluate improvements in actual cognition (ADAS-Cog11) not just biomarkers like amyloid. This is significant because small molecules are cheaper and easier to manufacture than biologics like Biogen's Aduhelm and cognition is the gold standard for an effective therapy. CRTX is running a phase 2/3 clinical trial with expected readout in Q4 2021. Fun fact: Peter Thiel was a seed investor in Cortexyme. That's probably enough for most of you. ​ UPCOMING PRESENTATIONS July 23, 2021 (10:00am ET): KOL Webinar Series on Atuzaginstat, "Part 1: Innovation in Periodontal Disease - A Major Unmet Medical Need" July 26-30, 2021: AAIC conference, Cortexyme presenting new baseline data for GAIN trial July 30, 2021 (10:00am ET): KOL Webinar Series on Atuzaginstat, "Part 2: Innovation in Alzheimer's Disease - Getting to the Root Cause of Neurodegeneration" November 11, 2021 (1:00-2:30pm ET): CTAD conference, oral communication, " An update and baseline data from the Phase 2/3 GAIN trial of COR388 (Atuzaginstat) a novel bacterial virulence factor inhibitor for the treatment of Alzheimer's disease." ​ THE SCIENCE: GINGIPAIN HYPOTHESIS AND ALZHEIMER'S DISEASE Initial Observation Scientists noticed that individuals with gum disease (chronic periodontitis) were at high risk for developing dementia (Ref 1,2). Porphyromonas gingivalis (Pg) is the bacteria that causes gum disease. Big deal, a bunch of people with oral hygiene problems developed Alzheimer's Disease, so what? Just give them broad spectrum antibiotics and problem solved. Well, no. Broad spectrum antibiotics have been shown ineffective against Pg. Pg releases molecules called gingipains (virulence factors) that are essential to Pg survival in a host organism. These molecules make the host environment suitable for the survival of Pg by aiding in nutrient acquisition and disable certain immune defenses. There are several types of gingipains (Ref 3): lysine (Kgp) and arginine (RgpA and RgpB). Instead of targeting Pg itself, Cortexyme (CRTX) developed a small molecule (COR388) that targets the gingipains essential to Pg survival in human brain and gum tissue (Ref 4). ​ COR388: Mouse Study Scientists infected the mouths of mice with Pg (oral infection). After 6 weeks, they took brain tissue from the mice and found migrating Pg had infected the brain (Ref 4). More importantly, amyloid beta 1-42 (AB1-42) production increased significantly after infection (Ref 4). AB1-42 is the hallmark protein aggregate (amyloid plaque) that amyloid theory is based upon -- including Biogen's Aduhelm. Remarkably, Dominy's and Lynch's work (co-founders of Cortexyme) shows that AB1-42 has antimicrobial effects that attempt to disrupt the membrane of Pg to kill it. Most work on amyloid theory hasn't presented a causative reason for the accumulation of AB1-42 in the brain. Cortexyme presents (1) an ability for oral Pg to infect the brain, (2) how Pg can induce AB1-42 production, (3) a rationale for why the brain would increase production of antimicrobial AB1-42, and (4) *most importantly* that inhibitors of Pg virulence factors can prevent death of the Gad67+ interneurons of the hippocampus (the part of the brain responsible for memory!) after Pg infection (Ref 4). Cool story bro, but this is one group publishing some outlandish theory. Not quite! Dominy and Lynch were pioneers, but there have since been many peer-reviewed publications from independent groups that validate these findings (Ref 5). ​ COR388: Human Study Presence in the Alzheimer's brain An analysis of post-mortem brain tissue of Alzheimer's Disease patients shows the presence of gingipains in the hippocampus (region for learning and memory processing) and cerebral cortex gray matter (Ref 4). Further, the DNA of Pg was found in the cerebrospinal fluid of Alzheimer's Disease patients. Electron microscopy images show that gingipains are even present within neuron cells (see here: https://www.cortexyme.com/wp-content/uploads/2021/03/ADPD2021ePoster131DominyFINAL.pdf). AB1-42 Amyloid beta (AB) is a protein well-known as a hallmark of Alzheimer's Disease. The precursor protein APP can be cut multiple ways to generate various forms of AB. AB1-42 is the hallmark "plaque" forming variety commonly associated with Alzheimer's Disease. An experiment where Pg was mixed with AB1-42 showed higher levels of Pg death relative to Pg mixed with other forms of AB like AB1-40 (Ref 4). In the brain tissue of Alzheimer's Disease patients, fluorescent microscopy showed that intracellular amyloid aggregates and gingipains (RgpB) often are found in the same location (Ref 4). This suggests that AB1-42 is being produced by the brain in an effort to kill invading Pg and that the build-up of amyloid plaques is a potential consequence of this anti-microbial response. Tau and pTau The fragmentation of Tau protein and phosphorylation of Tau (pTau) is a hallmark of Alzheimer's Disease. Tau protein incubated with purified gingipains was subjected to mass spectrometry. This showed that gingipains cut Tau at multiple sites. The cells in the brain hyperphosphorylate Tau (making pTau) to try to prevent these cuts from occurring, but the phosphorylation negatively affects Tau function. Importantly, there is a significant correlation between the amount of gingipains in the brain and amount of Tau (Ref 4). This is an elegant causative explanation for the presence, fragmentation, and phosphorylation of Tau in Alzheimer's Disease progression. APOE We all carry the APOE gene. There are three main types of this gene: APOE2, APOE3, and APOE4. It has been repeatedly shown that people with APOE4 are at significantly higher risk for developing Alzheimer's Disease than people with APOE2. This perplexing finding has been difficult to reconcile with the other seemingly disparate hallmarks of Alzheimer's Disease like AB1-42 and pTau. In an absolutely incredible experiment, Cortexyme demonstrated that the gingipains released by Pg are able to cut apart ApoE4 protein much more efficiently than ApoE2 or ApoE3 (Ref 6). ApoE protein is critical to many cellular functions in neurons such as lipid transport, inflammation, and even AB1-42 removal. Even more incredibly, Alzheimer's Disease patients treated with gingipain-inhibitor COR388 (see Phase 1 clinical trial below) showed significant reduction of ApoE fragments in cerebrospinal fluid compared to control! In my opinion, this is an incredible finding that for the first time presents a causative hypothesis to explain both the inherent genetic risk of APOE4 carriers, as well as, accumulation of the hallmark biomarkers AB and pTau. Poster from 2020 AAIC conference highlighting these experiments: https://ir.cortexyme.com/static-files/012eb6ac-c726-4bff-986a-508311b329a4 COR388 Protection As a teaser before the clinical trial design and data below, Cortexyme has demonstrated protection of human neurons in culture by COR388 following Pg infection, as well as, COR388's ability to prevent synaptic spine loss (spines are essential to the cell-to-cell communication that neurons perform). Summary Here is a comprehensive poster from the 2020 AAIC conference with experiments demonstrating Pg localization, loss of neuron synaptic density, degradation of Tau, increased inflammatory signaling, and protection by COR388: https://ir.cortexyme.com/static-files/51bfb586-2343-46bd-a0f8-125eb3257f47 References 1: Kaye 2010, Tooth loss and periodontal disease predict poor cognitive function in older men. 2: Kamer 2015, Periodontal disease associates with higher brain amyloid load in normal elderly. 3: Guo 2010, Dichotomy of gingipains action as virulence factors: from cleaving substrates with the precision of a surgeon's knife to a meat chopper-like brutal degradation of proteins. 4: Dominy 2019, Porphyromonas gingivalis in Alzheimer's disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. 5: Díaz-Zúñiga 2020, Alzheimer's Disease-like pathology triggered by Porphyromonas gingivalis in wild type rats is serotype dependent. 6: Raha 2021: Gingipains identified in Alzheimer's disease brains differentially fragment ApoE proteins. ​ THE CLINICAL TRIAL COR388 Phase 1 January 4, 2018: Announced first cohort dosed with COR388 May 31, 2018: Completion of COR388 ascending dose studies October 24, 2018: Phase 1 clinical trial data presented at CTAD COR388 was considered safe and well tolerated over multiple doses for 28 days Not powered for statistical significance, but a positive trend in cognition was observed for the Alzheimer's Disease afflicted group December 7, 2019: Phase 1 clinical trial data presented at CTAD Oral presentation on reduction of ApoE fragmentation in cerebrospinal fluid of Alzheimer's Disease afflicted patients ​ Study 1: Healthy volunteers (55-80 years old, randomized, double-blind, placebo-controlled) Cohort 1 (six volunteers): 25mg COR388 (each 12 hours for 10 days) Cohort 2 (six volunteers): 50mg COR388 (each 12 hours for 10 days) Cohort 3 (six volunteers): 100mg COR388 (each 12 hours for 10 days) Cohort 4 (six volunteers): Placebo Result: 23 of 24 volunteers completed the trial with no drug-related adverse events or dose-limiting toxicities. ​ Study 2: Alzheimer's Disease afflicted volunteers (55-85 years old, randomized, double-blind, placebo-controlled) Cohort 5 (six volunteers): COR388 (each 12 hours for 10 days) Cohort 6 (three volunteers): Placebo Result: No drug-related adverse events or dose-limiting toxicities. Reduction of inflammation markers in the blood and reduction of ApoE fragments in cerebrospinal fluid. Although not powered for statistical interpretation, MMSE (mini-mental state exam) and CANTAB (Cambridge Neuropsychological Test Automated Battery) showed trends to improvement in measures of memory and reaction time. Statistically-significant improvement in three measures of Winterlight's cognitive test. ​ Clinical Trial Design (Single Ascending Dose): https://clinicaltrials.gov/ct2/show/NCT03331900?term=COR388&draw=2&rank=2 Clinical Trial Design (Multiple Ascending Dose): https://clinicaltrials.gov/ct2/show/NCT03418688?term=COR388&draw=2&rank=1 ​ COR388 Phase 2/3 April 2019: GAIN (GingipAIN Inhibitor for Treatment of Alzheimer's Disease) trial begins enrollment of mild to moderate Alzheimer's Disease patients in the United States July 17, 2019: GAIN trial study design (P4-663) and speech-based digital biomarkers of Alzheimer's Disease (Winterlight Cognitive Assessment) presented at AAIC September 26, 2019: European volunteer screening for GAIN trial begins (US enrollment initiated in Q2 2019) August 14, 2020: GAIN trial enrollment reaches 500 volunteers August 17, 2020: GAIN trial on-track for Q4 2021 readout September 24, 2020: GAIN trial exceeds 570 volunteer enrollment target November 6, 2020: GAIN trial study design and biomarker updates presented at CTAD Human radio-labeled mass balance study complete (Note: C14 mass balance required for NDA submission to FDA) A high proportion of patient samples analyzed to that point had biomarker profiles consistent with Alzheimer's Disease and evidence of immune response to systemic Pg infection: https://ir.cortexyme.com/static-files/67504b27-4509-44be-9f9a-a9d8a4ae80b3 November 12, 2020: Press release describing possible outcomes of pending interim data analysis Cortexyme management remains blinded to clinical trial data An independent data monitoring committee (DMC) evaluate the clinical trial results and recommend one of four potential outcomes: End study for overwhelming futility (p<0.05) Increase sample size by up to 100 participants per arm based on favorable trends Continue as planned End study for overwhelming efficacy (p<0.05) on co-primary endpoints December 4, 2020: GAIN trial interim analysis by independent DMC shows that GAIN has passed the futility analysis and will continue without modification to 1-year endpoint. January 26, 2021: Press release indicating >90% of patients in the trial voluntarily elected to remain on COR388 after participation in the trial ended (open-label extension, OLE) February 15, 2021: Partial clinical hold placed on the open-label extension portion of the GAIN clinical trial No new OLE enrollment and current patients discontinued Hold resulted from reversible hepatic adverse event without long-term effects ​ Study: Alzheimer's Disease afflicted volunteers (randomized, double-blind, placebo-controlled) Clinical trial sites: Approximately 90 sites across the United States and Europe Total enrollment: 643 patients Cohort 1: 40mg COR388 (twice per day) Cohort 2: 80mg COR388 (twice per day) Cohort 3: Placebo ​ Patient Profiles (November 5, 2020, ~40% of enrolled patients) 100% show Pg-specific IgG reactivity at baseline (despite not being an enrollment criteria!) 89% show total Tau protein above assay cutoff for Alzheimer's Disease 86% show pTau181 consistent with Alzheimer's Disease 88% show AB42/40 ratio associated with AB positivity on PET imaging scans 75% show AB42/40 ratio below assay cutoff for Alzheimer's Disease 65% have at least one genetic allele of APOE4 ​ Clinical Trial Endpoints Co-Primary Endpoint #1: Mean change in ADAS-Cog11 (Alzheimer's Disease Assessment Scale - Cognitive Subscale 11). The FDA has previously supported this test during review of drugs for Alzheimer's Disease. Co-Primary Endpoint #2: ADCS-ADL (Alzheimer's Disease Cooperative Study Group - Activities of Daily Living) Secondary Endpoint: CDR-SB (Clinical Dementia Rating - Sum of Boxes) Additional Endpoints: Biomarker analysis of saliva, blood, and cerebrospinal fluid for Pg DNA. Winterlight Speech Assessment. MRI volumetric brain measures. ​ GAIN Interim Analysis An analysis of 300 patients after 24 weeks of treatment using co-primary cognitive and functional endpoints. On December 4, 2020 Cortexyme announced that COR388 had passed the futility analysis and no modifications to the clinical trial were necessary. ​ Open-label extension study After 48 weeks of participation in the trial, open-label extension enables voluntary continuation of COR388 (40mg or 80mg) for an additional 48 weeks. This was discontinued on February 15, 2021 due to reversible hepatic adverse event in one or more participants, but did not affect the ongoing GAIN clinical trial. ​ Phase 2/3 Clinical Trial Design (GAIN Trial): https://clinicaltrials.gov/ct2/show/NCT03823404?term=COR388&draw=2&rank=3 Phase 2/3 Clinical Trial Recruitment: https://gaintrial.com/en/ ​ THE PIPELINE (NON-ALZHEIMER'S DISEASE TARGETS) Alzheimer's Disease is obviously the main indication for Cortexyme (the company has 'cortex' in its name). However, it is important to keep in mind that COR388 and the other gingipain inhibitors (COR588, COR788, COR822, etc.) in Cortexyme's portfolio were developed out of the observation that most Alzheimer's Disease patients have gum disease. COR388 seems like a good bet in the billion dollar periodontitis market and Cortexyme was clever enough to include a sub-study for peritonitis in the GAIN clinical trial. In my opinion, this was a deft move by company's management to mitigate risk and build in a safety net for the company to fall back on if the GAIN clinical trial flops for Alzheimer's Disease. Here's a very brief glimpse of what else Cortexyme has announced so far: ​ Periodontal Disease (Phase 2) REPAIR (REduction of P gingivAlis to ImpRove pocket depth) is a sub-study of the GAIN clinical trial 233 patient sub-group Anticipated readout in Q4 2021 COR588 (lysine gingipain inhibitor with improved pharmacokinetic profile) is planned to enter clinical trials in Q3 2021 COR788 and COR822 (arginine gingipain inhibitors) are both entering IND-enabling studies ​ Parkinson's Disease (Phase 2) January 26, 2021: Announced initiation of Phase 2, placebo-controlled, multi-center PEAK clinical trial to evaluate gingipain inhibitors in Parkinson's Disease. March 8, 2021: Partnership with Parkinson Study Group as PEAK advisory board ​ Oncology (Research Presentation) November 9, 2020: Gingipain inhibitors (COR388 and COR613) reduce expression of immune checkpoint ligand PD-L1 induced by Pg infection in an esophageal cell line. Poster from STIC: https://ir.cortexyme.com/static-files/9bd894e8-f332-42ed-a569-fd4716e65f51 ​ Cardiovascular Disease (Research Presentation) August 17, 2020: In collaboration with the Forsyth Institute, Cortexyme shows roles for Pg in co-morbid cardiovascular disease. Poster from AAIC: https://ir.cortexyme.com/static-files/d19b5fdf-e100-430b-94cf-5ef2c6ed5a21 ​ THE FINANCIALS Corporate Overview May 2021: https://ir.cortexyme.com/static-files/7eaeaf98-b255-4686-966f-a2290bd0540b ​ Capital Raises Seed: Peter Thiel, Breakout Labs (2014) Series A: $15 million (January 6, 2016) Series B: $76 million (May 31, 2018) IPO: $78 million (May 8, 2019) Stock Issuance: $89 million (April 7, 2020) S-1 (April 12, 2019): https://www.sec.gov/Archives/edgar/data/1662774/000119312519105299/d703513ds1.htm S-1 (April 7, 2020): https://ir.cortexyme.com/static-files/c9acd392-980f-4d80-becc-1d75f6df64db ​ Stock Float (Yahoo Finance on July 10, 2021) Shares Outstanding: 29.59 million shares Float: 17.81 million Percent of float held by insiders: 33.2% Percent of float held by institutions: 62.92% Percent of float held by public: 3.88% Percent of float held short: 20.9% (3.55 million shares) ​ THE PATENTS 9,758,473: Inhibitors of Lysine Gingipain Granted September 12, 2017 Expiration December 28, 2035 https://patentimages.storage.googleapis.com/1b/ca/75/af46b28860a886/US9758473.pdf 9,988,375: Inhibitors of Lysine Gingipain Granted June 5, 2018 Expiration October 5, 2035 https://patentimages.storage.googleapis.com/c8/61/50/59f559b521fc36/US9988375.pdf 10,301,301: Inhibitors of Lysine Gingipain Granted May 28, 2019 Expiration October 5, 2035 https://patentimages.storage.googleapis.com/43/c9/6e/d9294417ed8252/US10301301.pdf 10,676,470: Inhibitors of Lysine Gingipain Granted June 9, 2020 Expiration October 5, 2035 https://patentimages.storage.googleapis.com/db/12/71/1575e39221c687/US10676470.pdf 10,730,826: Ketone Inhibitors of Lysine Gingipain Granted August 4, 2020 Expiration September 15, 2037 https://patentimages.storage.googleapis.com/d0/bb/42/6d40fc1c0135c6/US10730826.pdf 10,906,881: Inhibitors of Arginine Gingipain Granted February 2, 2021 Expiration November 9, 2036 https://patentimages.storage.googleapis.com/de/15/92/428944b63598d8/US10906881.pdf ​ Disclaimer I currently own both stock and options in CRTX. I wrote this for my own enjoyment so do your own diligence. Good luck to all Alzheimer's Disease patients, I hope this is the therapy you need!