Quince Therapeutics, Inc. (QNCX) Earnings Call Transcript & Summary

Good morning, and welcome to Part 1 of the Cortexyme KOL Webinar series, Innovations in Periodontal Disease: A Major Unmet Market. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the Cortexyme website following the conclusion of the event. I'd now like to turn the call over to your host, Casey Lynch, Co-Founder and Chief Executive Officer of Cortexyme. Please go ahead, Casey.

Thank you, Tara, and welcome to everyone joining us today. We're excited to kick off the first and a 2-part KOL webinar series about the promising applications and near-term clinical readouts of atuzaginstat. I'm very happy to introduce Dr. Mark Ryder. Next slide, please, who is -- next slide, please, who is a Professor and former Chair of Periodontology at UCSF, where he's been a faculty member for the past 41 years. Mark received his dental training from Harvard and is the author of over 190 articles, abstracts and book chapters. He has lectured extensively on a variety of research topics, including the connections between periodontal disease and Alzheimer's disease, the links between oral and systemic health in HIV patients and basic research and clinical trials on novel periodontal therapies. Mark also sits on Cortexyme's Clinical Advisory Board and was instrumental in early research towards understanding the role of P. gingivalis in Alzheimer's disease. Also joining us today is Cortexyme's Chief Scientific Officer and Co-Founder, Steve Dominy; and Leslie Holsinger, Cortexyme's Executive Vice President of Research and Development. Steve's tenaciousness and unwavering commitment to identifying P. gingivalis as the root cause of Alzheimer's and Leslie's exceptional leadership and research experience in driving our drug discovery efforts are at the heart of Cortexyme's success to date, and I'm so glad you'll have the opportunity to hear from them directly today. You can see our agenda on the right side of the slide. I'll give a very brief overview of the company, followed by remarks from Mark Ryder, presentation of new data we released this week at IADR and followed by an outline of the clinical program and upcoming data announcements. Next slide, please. We're very excited to be approaching data in a few short months during Q4 for 2 major studies: a pivotal study in Alzheimer's disease and a robust sub-study in periodontal disease. As you will hear from Mark, and you can see on the right side of the slide, periodontal disease is a massive market impacting 65 million people in the U.S. alone. We're continuing to expand into new indications and recently announced a new study we're working on with the Parkinson's study group in Parkinson's disease as well as the program we announced in more detail this morning targeting coronaviruses. Our pipeline is based on our own unique medicinal chemistry expertise in protease inhibition. We have potent orally available brain penetrant small molecules that you'll learn more about today. And our goal is always to treat upstream, getting at the root cause of disease rather than just the symptoms or some small aspect of the downstream pathology. The evidence base for our approach, as you'll hear over these KOL calls the next week, continues to expand with our own studies and third-party research, and we're well funded to execute on all of these milestones. Next slide, please. With that, I'll turn it over to Mark to tell us more about periodontal disease.

Well, thank you, Casey, for that introduction. And before we get into some of the recent work in the relationship of a key bacteria in the periodontal disease and how it relates to Alzheimer's disease, I'd like to give just a little background on the nature of periodontal disease and what that potential connection between periodontal disease and Alzheimer's might be particularly through the plaque biofilm that accumulates on our teeth and even more particularly from, again, a key bacteria Porphyromonas gingivalis and its key enzyme gingipain in this whole possible connection between periodontal disease and Alzheimer's disease. Now what is periodontitis. Of course, you're probably all familiar that it is a chronic inflammatory disease of the teeth perhaps the most common of all chronic inflammatory diseases from infection somebody would encounter in their life. It's caused by a biofilm that accumulates on the tooth surface resulting in an inflammatory reaction that results in the loss of the supporting tissues, and eventual loss of the teeth themselves. And there's been extensive research, particularly in the last 20 or 25 years that have linked periodontitis and particularly the biofilms of periodontitis and the inflammatory reaction to those biofilms to a variety of systemic conditions, including cardiovascular diseases, certain cancers, preterm birth, rheumatoid arthritis and, of course, the topic for today, dementia and Alzheimer's disease. This is a quite prevalent disease, as you know, with about, let's say, 20% to 50% of the world population having some form of mild, moderate or severe periodontitis with a smaller but significant percentage having what we might call a severe form. And this is a condition just in the United States, as Casey just mentioned, that really presents a major unmet medical need where only a portion of patients who have periodontal disease or as the lay say gum disease are actually seeking any type of treatment whatsoever. And there's at least a $2 billion market in unmet need for those patients who are not seeking treatment at this point. Well, what is the periodontal disease and how can it possibly link to conditions such as Alzheimer's? Here's healthy tissue. This is without the accumulation of a plaque biofilm. The tissue was nice and pink, and the tissue is nice and firm. Now let's say this patient stops brushing these teeth for 2 weeks. What happens is, of course, the tissue changes dramatically in appearance. It becomes swollen, it becomes erythematous or red along the margins. It is -- well, we lose the pattern of what we call stippling, it's shiny now. And the reason for that is if we now take a special stain to look at that biofilm, what we see is that there has been a plaque biofilm that is accumulated both above the gum line and is spreading below the gum line. Now at this point, we can actually look at this inflammatory reaction in the gum tissue and make some measurements to measure the extent of inflammation in this early part of periodontal disease where the tissue is just inflamed. One of the things we can do is take a probe. Many of you are familiar with what a probe does. It measures the depth of the gum pockets themselves or cuff around the tooth. And as the tissue swells, those gum pockets get deeper. And in addition, as those gum pockets get deeper, they tend to bleed much more easily on probings, which we can see here. Now in earlier periodontal disease conditions that just affected the soft tissues, the swelling results in a deeper gum pocket, which we can measure. But gradually, that swelling, which is really due to that underlying inflammation will spread to the deeper tissues and we start to lose the support around the tooth, which is shown here in the right-hand panel. Where now the gum has receded because the attachment to the gum, we call clinical attachment, has receded. And in addition, if we now look at the x-rays, let's say, comparing health in this left-hand panel to disease in this right-hand panel, we see that, that inflammation has spread into the deeper tissues causing destruction of both the attachment of the tooth to the gum and also the loss of bone. Now the culprit again for all of this is that biofilm that we just talked about. So let's talk about that biofilm and why it's so important and why conventional treatment is often so difficult in eliminating this biofilm completely. If we look at a cartoon view, let's say, of the dental biofilm here, sitting up against the tooth it is attached to the tooth here. And right next to the biofilm itself, we have the lining of the gum pocket itself. And in inflammation, we should point out a couple of things. One is that with inflammation, the pocket lining that protects us from whatever is coming from the biofilm becomes ulcerated. It becomes an open door where bacteria can penetrate not only into the tissue but into the bloodstream and to other parts of the body. Well, you might say, well, why don't we just simply remove the biofilm. Easier said than done. The reason for that is 2 reasons really. One, as the biofilm moves deeper and deeper under the gum line, it's much, much harder to remove. As a matter of fact, just in routine procedures, some of that biofilm will be left. And even if we flat the gum tissue away to try to get better access to that biofilm to mechanically remove it, studies have shown that some of that biofilm will still remain. Why is that important? Well, that biofilm itself consists of cells of bacteria. Hundreds, sometimes thousands of cells stick. And harmful bacteria, particularly Porphyromonas gingivalis or P. gingivalis, which we'll talk about, can be hidden deep in these biofilms within these layers of bacteria, and getting at those residual biofilms with antibiotics systemically or with let's say some irrigation may not be that effective and often is not effective. For the simple reason that you can't penetrate deep into the biofilm for a long period of time or a long enough period of time to kill off those most harmful bacteria. And certainly, the most widely studied in periodontal disease of the harmful bacteria is P. gingivalis. We call this a key pathogen in the plaque biofilm. And why P. gingivalis is so critical not only in periodontal disease but has been studied very extensively in other systemic conditions, including Alzheimer's disease, which we'll talk about, is it, again, can readily penetrate into this inflamed tissue, into the tissue itself and into the bloodstream. In addition, this bacteria, P. gingivalis, has a host of enzymes, in particular, a key enzyme called the gingipains, which are essential for the survival of the bacteria itself. Now these gingipains have a well-established role in periodontal disease and progression. As I mentioned before, it's a key bacteria and has been detected in 70% to 80% of chronic periodontitis patients within the plaque itself. I should also mention that even in patients that have been treated for periodontal disease, P. gingivalis still may have penetrated into the bloodstream and into other parts of the body, including the brain. So a past history of periodontal disease may also involve penetration of P. gingivalis into the bloodstream. The key enzyme -- one of the key hot family of enzymes, of course, of the gingipains, which are virulence factors that help break down the tissue and also have direct toxicity to the cells of the periodontal tissue can cause dysbiosis of the oral microbiome and can actually inhibit your -- the body's own defense system in neutralizing or killing the P. gingivalis itself. So as we mentioned before, the limitations of current treatments are that, again, the conventional therapy, which involves scaling and root planing can't completely remove the biofilm. Now the treatment, which involves surgery to reduce pocket depths, which can use antibiotics, using just antibiotics alone or even with some local other antimicrobials often cannot penetrate into the biofilm itself. And so the -- and also, the other important thing to keep in mind in this third box here is that even if we can almost completely remove the biofilm, we're still faced with the issue of patients keeping that biofilm off on a daily basis with efficient home care. And it's almost impossible for most patients to do that, especially in harder-to-reach areas. Biofilms just continue to accumulate. And of course, this really opens up a potential for oral treatments that can hopefully be covered by health insurance that address both controlling this oral biofilm and killing the most important bacteria as for -- and which would be quite valuable for patients because what we're again trying to avoid is this spread of bacteria from the biofilm in the mouth, particularly bacteria such as Porphyromonas gingivalis with gingipains into other parts of the body where both the bacteria itself and the enzymes have been implicated in a variety of systemic conditions. With that, I'd like to turn this over to Dr. Leslie Holsinger, who will now talk about how we can overcome some of these problems with the biofilm and periodontal disease, specifically Porphyromonas gingivalis and its key enzyme, the gingipains. So, Dr. Holsinger, please proceed.

Great. Thank you very much, Dr. Ryder. If I could have the next slide. So Cortexyme had a goal to screen for small molecule therapeutics that were particularly effective in treating Porphyromonas gingivalis biofilms. In addition to the development of resistance to antibiotics, these biofilms are a major reason for the lack of efficacy of systemic treatments targeted to P. gingivalis and periodontal disease, as Dr. Ryder just eloquently described for us. So identifying therapeutics that can penetrate these biofilms is critical not only to treat the oral disease but also to destroy this oral reservoir of P. gingivalis that can contribute to ongoing systemic disease, including brain disease and neurodegeneration. And as Dr. Ryder mentioned, the lysine gingipain protease known as Kgp, and you will see that as Kgp on my slides, is critical to disease pathology caused by Porphyromonas gingivalis but it's also essential for bacterial growth and survival. Cortexyme's proprietary lysine gingipain inhibitor analogs were screened for their ability to penetrate and inhibit Kgp with an intact biofilms in vitro. If I could have the next slide, please. So in collaboration with the contract research laboratory iFyber, Cortexyme scientists generated a method to develop robust biofilms of Porphyromonas gingivalis in vitro. What you see on the left-hand panel is a live bacterial viability staining and confocal laser scanning microscopy of Z image stacking or 1 micrometer images over a total of 20 micrometers measuring the viability and 3-dimensional structure of these biofilms formed for 48 hours on a surface in vitro. A key hallmark of biofilms is indeed this not flat but 3-dimensional structure that I will actually show you some scanning electron micrograph images of later. In addition, a hallmark of these biofilms, as Dr. Ryder mentioned, is that they are less sensitive to broad-spectrum antibiotics. And on the right side of this slide, you can see that an enumeration, a way of measuring the difference in growth of P. gingivalis bacteria in biofilms, versus growth in liquid culture, also known as planktonic growth, the biofilms are significantly resistant to the standard broad-spectrum antibiotic of amoxicillin and grow more like vehicle-treated cultures, whereas the platonic or liquid growth cultures that do not form biofilms are more sensitive to this amoxicillin. So we knew we had the hallmarks of the generation of in vitro 3-dimensional robust and viable biofilms. If I could have the next slide, please. So next, we tested to see atuzaginstat and other proprietary Kgp small molecule inhibitors penetrated these mature formed surface-attached biofilms. And indeed, COR388, atuzaginstat penetrates these biofilms that have grown for 48 hours and then also engages and inhibits the gingipain target throughout this biofilm. In the left panel, biofilms that are formed on these solid surfaces for 48 hours were treated with either a vehicle control or atuzaginstat for 1 hour. Kgp within activity within the biofilms is measured using a substrate cleavage assay over 90 minutes. And as you can see, the biofilms themselves in the vehicle-treated samples quickly show a high level of Kgp protease activity and cleavage of this fluorescent substrate. Biofilms treated with atuzaginstat have little to no Kgp activity within the biofilm. Consistent with this in the right-hand panel, we can also see this biochemically. So we utilize an activity-based probe which is an irreversible Kgp inhibitor that binds to the active site of the gingipain proteases. This has a chemical linker attached, which also attaches it to Cy5, a fluorescent molecule that we can use as a probe to visualize the presence of the active site biochemically. These cultures, as you can see on the right, either treated with vehicle or biofilms treated with atuzaginstat for 1 hour and up to 24 hours contain Kgp protein as visualized in the bottom part of this panel with an anti-Kgp-specific antibody. However, only the vehicle-treated biofilms have the ability to visualize an active open site for lysine gingipain, but biofilms treated with atuzaginstat at 1 hour and maintained for 24 hours do not have any remaining lysine gingipain active sites for this probe to be able to engage because it's already -- those active sites are already engaged with atuzaginstat. If I could have the next slide, please. Cortexyme has developed a second-generation inhibitor, COR588 and similar to COR388, there is robust and potent inhibition of Kgp within these already formed surface-attached Porphyromonas gingivalis biofilms by COR588, as shown on this slide. And on the next slide -- if I can have the next slide, please, there are actually unique properties of our gingipain inhibitors that contribute to differential biofilm penetration. COR388 and COR588 are particularly potent and selected as clinical compounds because of their potency, not only in inhibiting Kgp, but in penetrating these -- unique structure in penetrating these biofilms. Shown here are 5 proprietary Kgp inhibitors all irreversible with a picomolar IC50 level of inhibition on lysine gingipain, as shown in the table. So all potent. However, the level of inhibition of Kgp relative to the vehicle control due to differences in penetrating this biofilm is shown on the left-hand panel with COR388 and 588, particularly potent and inhibiting the vast majority of Kgp. Well, compared to other inhibitors following an hour of treatment of these existing biofilms, they have lesser ability and a differing level of ability of inhibiting these biofilms. So these 2 molecules are potent in penetrating biofilms and unique compared to structurally different but potent Kgp enzyme inhibitors. If I could have the next slide, please. So in -- the biofilms are formed, first, if you can see on the left, as an attachment on to a solid surface that then make micro colonies, which over 48 hours develop into mature characteristic 3-dimensional mushroom like structures. Part of the 3-dimensional structure is formed from the polysaccharide that is secreted from the bacteria to form this 3-dimensional structure or matrix. In collaboration with the laboratory of Dr. Yvonne Kapila at UCSF, we performed scanning electron microscopy images of these biofilms, again, to demonstrate the presence of robust biofilms that atuzaginstat was penetrating. At 48 hours, in panels B and E, you can see, if you hover over these biofilms, this 3-dimensional mushroom like structure. These cultures treated for 24 hours rather than vehicle but with atuzaginstat in panel C and F, you can see collapse a compromise of the structural characteristics of the biofilm and posits collapse. And what you see, particularly in panel F at the highest level of magnification is simply individual colonies of bacteria flat on the surface of this disk, no longer maintaining this robust 3-dimensional biofilm structure. So we also believe that COR388 has the potential to compromise robust biofilms and their structural integrity as well as robust penetration to inhibit the gingipains within the biofilm structure. If I could have the next slide, please. Atuzaginstat -- these data are consistent with some previous work published in the article listed below in this slide, that atuzaginstat targets a natural infection of Porphyromonas gingivalis growth in a natural dog model of periodontal disease, also known to contain bacterial biofilms. So when atuzaginstat is dosed for 28 days, we see a robust reduction of Kgp activity in the oral cavity, including gingival crevicular fluid and bacterial load reduction in buckle cells. If this dosing is stopped at 28 days and the buckle cells collected on or after a cessation of dosing, there is still some suppression of bacterial growth. But again, the bacteria, as Dr. Ryder mentioned to us, it is very difficult to penetrate all biofilm and eliminate it and therefore, the disease begins to come back, supportive of the use of chronic dosing. When these animals are, for 90 days, given a minimal efficacious concentration, we do actually see efficacy in reducing periodontal disease as measured by a decrease in inflammation and a decrease in the pocket depth of periodontal pockets, greater than 3 millimeters in size over these 90 days. Can I have the last slide, please. So in conclusion, these robust biofilms of P. gingivalis were used to characterize the biofilm penetration of lysine- gingipain inhibitors and atuzaginstat and COR588 quickly penetrated these biofilms to inhibit Kgp specifically at concentrations relevant for therapeutic efficacy in periodontal disease and atuzaginstat also compromises the structural integrity of these biofilms. Biofilm penetration and gingipain target engagement in subgingival plaque, we have shown this previously in a natural dog model of periodontal disease, resulting in efficacy in reducing inflammation and pocket up, and the data support the ability of these virulence factor inhibitors to reduce P. gingivalis bacterial growth in human periodontal disease, including the growth of bacterial biofilms, so critical to the disease. With that, I would like to turn the discussion over to my colleague, Dr. Stephen Dominy, Chief Scientific Officer and Co-Founder of Cortexyme.

Thank you, Dr. Holsinger. I will not present in vivo data entitled Novel lysine gingipain inhibitor atuzaginstat is efficacious in a mouse model periodontal disease. Next slide, please. Kgp inhibitors are efficacious in the mouse periodontitis model. And this is a good model because number one, mouse periodontitis models demonstrate P. gingivalis acts as a keystone pathogen. Number two, the P. gingivalis mouse periodontitis model is considered a highly translatable mouse model consistent with human disease. And number three, Kgp dysregulates the mouse immune response to favor a polymicrobial biofilm, disrupting homeostasis to cause dysbiosis and disease. Next slide, please. So on our first mouse model, Kgp inhibitor COR271 reverses alveolar bone loss. COR271 was an early Kgp inhibitor of Cortexyme. In Study 1, we showed that: number one, P. gingivalis infection increased alveolar bone loss at 5 in 10 weeks; and number two, COR271 enabled recovery of bone versus loss at 10 weeks; and number three, moxifloxacin was not significantly effective in this model. In the upper left, is a schematic showing the infection and dosing protocol. Mice were infected orally 3 times per week with P. gingivalis for a total of 6 weeks to establish infection. At week 5 of infection, mice were administered COR271 10 milligrams per kilogram orally twice per day for 5 weeks or a high dose of the broad-spectrum antibiotic moxifloxacin twice daily by subcutaneous injection. In the lower left are images of micro CT scans used to determine alveolar bone loss. As measured by the distance from alveolar bone crest to the cementoenamel junction, these are abbreviated ABC and CEJ in the figure, respectively. And the lower right is a graph showing alveolar bone loss with oral PG infection and the effect of treatment of COR271 or moxifloxacin. So I'll step you through this somewhat complicated graph. So we'll start on the left-hand side and showing you the first bar on the left is a mock infection control. The second bar shows a significant increase in bone loss after 5 weeks of PG infection and the third bar shows bone loss remains significantly elevated at week 10 equivalent to the bone loss seen at week 5. The fourth bar shows a significant effect of COR271 in reducing bone loss and allowing recovery of bone. And the fifth bar shows an addition of moxifloxacin added to COR271 does not provide any additional benefit to COR271 alone. And the sixth bar shows that moxifloxacin given alone was not significantly effective in reducing bone loss. Next slide, please. Now we'll move to mouse model 2. Kgp inhibitors atuzaginstat is efficacious in treating P. gingivalis alveolar bone loss. Here, we showed the P. gingivalis infection-induced alveolar bone loss in the second mouse model at 5 and 10 weeks. Bone losses reversed by 5 and 10 milligrams per kilogram of COR388 with twice or once daily dosing, and exposures from this and other studies were used to select doses in the GAIN/REPAIR trial that you will see in a minute. At the upper left is a schematic showing a PG infection and dosing protocols. Again, as in model 1, mice were infected orally 3 times per week with P. gingivalis for a total of 6 weeks to establish infection. At week 5 of infection, mice were administered either COR388 5 milligrams per kilogram or 10 milligrams per kilogram orally twice daily for 5 weeks. In addition, mice were administered COR388 10 milligrams per kilogram just once daily for 5 weeks starting at week 5 of infection. So below the infection and dosing schematic is the alveolar bone loss graph showing the effect of the different COR388 treatments. And again, I'll step you through this graph. The first bar on the left is a mock infection control. The second bar shows a significant increase in bone loss after 5 weeks of PG infection. The third bar shows bone loss at week 10 with no effect from vehicle. The fourth bar shows the significant effect of atuzaginstat 5 milligrams per kilogram twice daily on reversing bone loss. The fifth bar shows a significant effect of atuzaginstat 10 milligrams per kilogram twice daily on reversing bone loss. And the sixth bar shows that atuzaginstat 10 milligrams per kilogram dose just once daily has a significant effect on reversing bone loss equivalent to twice daily dosing. Next slide, please. Benefits of virulence factor inhibition. Broad-spectrum antibiotics induce resistance, but Kgp inhibitor atuzaginstat does not. What we show here is that specifically targeting at P. gingivalis virulence factor does not lead to the development of resistance in vitro because it works by a selective mechanism unique from broad-spectrum antibiotics. The graph you can see on the right shows PG resistance rapidly developing to moxifloxacin after only about 6 serial passages and culture, as evidenced by an increase in the minimum inhibitory concentration. In contrast, PG did not develop resistance to atuzaginstat during the study. Next slide, please. Now this is a very exciting data that we published in 2019 showing that atuzaginstat also acts upstream in the brain to block P. gingivalis-induced Alzheimer's disease pathology. Using the same PG infection protocol as used in the previous periodontal studies, mouse brains were analyzed for Alzheimer's disease pathology. This study showed the oral P. gingivalis infection infects the brain resulting in Alzheimer's disease pathology. Cortexyme's gingipain inhibitors blocked bacterial infection and disease pathology. As can be seen in the first graph on the lower left, atuzaginstat significantly decreased the brain PG load as measured by qPCR. In the second graph, atuzaginstat significantly decreased the level of Abeta 1 and 42 in the brain. In the third graph, atuzaginstat significantly decreased the level of TNF alpha, a major neuroinflammatory cytokine. In the final graph, atuzaginstat significantly protected hippocampal interneurons from neurodegeneration after Porphyromonas gingivalis brain infection. Next slide, please. So in conclusion, oral treatment with atuzaginstat can reverse alveolar bone loss induced by repeated oral infection with P. gingivalis in mice. Oral treatment with atuzaginstat can block P. gingivalis-induced Alzheimer's ease pathology in the mouse brain. The efficacy of atuzaginstat in reducing both periodontal disease and Alzheimer's disease pathology in P. gingivalis infected mice provided the rationale for designing a periodontal-disease substudy, REPAIR, in the large Phase II/III GAIN trial of atuzaginstat in mild-to-moderate Alzheimer's disease. At this point, I would like to turn the presentation back over to Dr. Ryder. Next slide, please.

Great. Thank you, Dr. Dominy and Dr. Holsinger. And as we can see from their presentations, in dealing with the problems of biofilms, Porphyromonas gingivalis is the key bacteria and the possible clinical benefits in improving the clinical signs of periodontal disease, we've been able to demonstrate this both in the laboratory and in various animal models. During the course of these presentations, we received several questions already through our chat and also some prior to the presentation. And I think I'll be able to answer some of these questions just in the last few slides I'll present here in discussing both the overall Phase II, Phase III FDA trial using the specific inhibitor, atuzaginstat. And then the substudy. So let's first, talk about the broad FDA study, the Phase II, Phase III of the GAIN trial, which is a study which has enrolled 643 patients who have shown signs of moderate -- mild-to-moderate cognitive impairment and received either 1 of 3 treatments, either placebo or 2 different doses of the atuzaginstat. And the primary outcome of this study as an Alzheimer's disease study is improvements in cognitive function or changes in declining cognitive function, stabilization of cognitive function, et cetera. However, in addition, because many of these centers of this Phase II, Phase III trial were associated with dental clinics, we had the opportunity to look at the periodontal condition of these patients in a sub-study, which we call the REPAIR trial, which enrolled a total of 233 subjects. And in this study for these patients who are -- do have -- show signs of mild-to-moderate cognitive impairment, we are measuring the signs of periodontal disease at the beginning of the study. And these include, as you can see from the box on the right-hand side, pocket depths at baseline, 6 and 12 months, the clinical attachment levels we talked about, bleeding on probing. And in addition, what we're also doing is looking at the saliva. We're collecting plaque samples too and as well as cells from the buckle tissue where we can determine the presence of Porphyromonas gingivalis in these various areas as well as other markers of inflammation in the mouth. Now because this is a secondary outcome that we're looking at and the primary outcome and the primary criteria for enrollment was the actual presence of early-to-moderate Alzheimer's disease, the question is, well, of these 233 subjects, what percentage or what proportion actually do initially present with periodontal disease? Well, as it turns out, using the Centers for Disease Control American Academy classification system for disease, it turns out that a considerable proportion, over 90% of these subjects, do show -- did show a baseline moderate -- well, moderate-to-severe periodontal disease. The other question you may ask is, well, what percent of these patients, let's say, had Porphyromonas gingivalis either in the mouth or let's say, were exposed to Porphyromonas gingivalis sometime during their lifetime? For that, we can look at the antibody levels to Porphyromonas gingivalis in all of these patients. And what we found here is that, again, a sizable portion of these patients had elevated levels of antibody to Porphyromonas gingivalis using a cutoff point here that's been used in previous studies to indicate the correspondence of higher antibodies levels to Porphyromonas gingivalis and severe or moderate periodontal disease, we can see, again, a sizable portion at this higher level. Now, if, of course, the trend shows that this gingipain inhibitor, the atuzaginstat, does also improve the periodontal condition as measured by pocket depths, clinical attachment level, bleeding on probing, then of course, there is a need for doing a separate trial just looking at the effects of these specific engineered gingipain inhibitors on periodontal disease itself, which would involve a study that would involve patients who present with periodontal disease. And let's say, they were either treated with just cleaning, scaling as we would say, to remove the deposits mechanically, scaling plus using the enzyme inhibitor such as the atuzaginstat or just using the atuzaginstat alone. We will know what the effects of this enzyme inhibitor are once the top line data is released. And that is something that Casey will now discuss with you.

Thank you, Mark. Next slide, please. In conclusion, as you've heard today, P. gingivalis is an important driver of periodontal disease, which is an important unmet market and one in which we intend to address with our small molecules not only COR388, but also moving 588 into the clinic to separate the markets from Alzheimer's disease. Atuzaginstat has unique properties as well as 588 required for treatment of P. gingivalis in biofilm penetration as well as disruption. Atuzaginstat efficacy in treating periodontitis has been established in mouse and dog models of disease. Also, we heard today, P. gingivalis translocates from the oral cavity and is associated with systemic disease and causal evidence meeting coke postulate in Alzheimer's disease has been published and replicated by third parties. We're very excited for top line results coming from both the GAIN and REPAIR trial in a few short months in Q4 of 2021. And now we can proceed to questions.

Thanks, Casey. I'm Corey Davis with LifeSci Advisors, and I'll be moderating the Q&A as most of you listening -- no, we're going to be taking written questions, so just punch them in I will ask anonymously, if you'd like. But we have a number of questions already, and we're going to start with Dave Sherman of LifeSci Capital. And he asks Dr. Ryder, can you give us some context as to how meaningful a change in pocket depth is in that dog data that were shown? And what is typical possible with normal periodontal care?

It's a good question. In normal periodontal care, we're really dealing with monitoring 2 things. One is how we reduce the inflammation in our treatment. And secondly, have we actually been able to stop the progression of loss of attachment, loss of bone around the teeth and maybe even more optimistically gain some attachment and gain some bone. With periodontal treatment when we're talking about reduction of inflammation, the 2 things we're looking at are, is there a reduction in the bleeding on probing? That's a very objective way of looking at it. And also, is there a shrinkage of the pocket depth. We should see those effects somewhere between 4 to 6 weeks after we do our treatment of cleaning the areas, teaching the patient how to control the plaque as best as possible. If the treatment has been effective, we should -- again, should see reduction in bleeding on probing, and we should see some reduction in pocket depths. When we're talking about gaining some attachment or maybe even gaining some bone, there we might see some results that are clinically evident maybe somewhere between 6 months and a year, perhaps 2 years out.

Thanks, Dr. Ryder. Next question, also for you, from Jason Butler from JMP Securities. How do you envisage a drug like 388 being incorporated into clinical practice, both your own and others? Are there patients that would be better suited to treatment with a drug versus scaling and when in the course of the disease do you think the treatment should be started?

I would say -- again, an excellent question. Excellent questions because these are questions we deal with all the time with clinical periodontal research. Regard to the second question first, as a substitute for scaling. I think the general agreement -- the consensus, which I certainly go along with is that what you try to do, of course, is -- as part of your initial treatment is remove as much of this biofilm mechanically, understanding that you're never going to get it completely removed. And the patient is never again going to get it completely removed with what they can do at home on a daily basis. Keeping that in mind, using something like an enzyme inhibitor such as atuzaginstat or something similar to that can be used as an adjunct particularly in those types of areas where the patient can't reach or the clinician can't reach. Where you might want to use this initially, of course, would be patients, let's say, who can't take care of their teeth as well. Patients who are more likely to break down. They include patients such as your smokers, your uncontrolled diabetics. If it works -- if it's effective in these patients, perhaps you can expand this to your general patient population who presents with moderate-to-severe periodontal disease, even some mild forms because as you know, treating periodontal disease is not like treating a root canal or just putting a filling in, in the tooth that's decayed. It's something that you need to follow and maintain throughout the patient's life with some initial treatment as well as follow-ups and maintenance treatment to keep those biofilms off as best as possible. So an adjunct as we say, such as atuzaginstat or something like that, could be quite valuable in the periodontal treatment strategy.

Again, for Dr. Ryder. Can you discuss P. gingivalis colonization in the oral cavity?

As I mentioned before, in the actual GAIN study and the REPAIR substudy, we are taking samples in the mouth. And they include saliva. They include using paper points to collect the biofilms in subgingival sites and also the buckle cells. So there are ways that we can detect Porphyromonas gingivalis in all 3 of these different types of samples taken from the mouth, in particular from the subgingival plaque.

Can this bacteria be controlled by probiotics? And do you ever use antibiotics for patients with an infection?

Okay. Well, let me answer -- that's 2 good questions, again, because this is an area that's received extensive investigation in the field of periodontal clinical research. As far as probiotics are concerned, let's just say right now the jury is still out how effective they are. But what has been shown in most studies is that use of probiotics, you can get a very transient or very short-term change in the flora or shift, which you're not going to eliminate the most harmful bacteria like Porphyromonas gingivalis for the simple reason that probiotics taken orally wash out or go down pretty quickly. They go right through the oral cavity into your GI tract where they may last a little bit longer. So their effect will be very, very short lived. The second question is what about let's say -- well, what was -- the second part of the question was what? I apologize. The first part was the effect of probiotics...

Do you ever use a standard antibiotics?

Do we ever use standard antibiotics? Yes. In some cases, it's shown to be effective at least over the short term. And these are really in extreme examples where we're getting patients who are really deteriorating at a very rapid rate. I would say that the use of antibiotics is -- systemic antibiotics, in particular, is well, is declining in practice for 2 reasons. One, is that, again, it's limited use of maybe only a few types or a few types of patients. And secondly, because of just the concerns on basically using systemic antibiotics over and over and over again, the dangers of resistance, the emergence of resistant strains of bacteria.

Great. Next question comes from Neena Bitritto-Garg from Citigroup asking about the REPAIR study and what you would see as a win on it? What sort of improvement would you want to see on the key clinical endpoints? How much of an improvement in pocket depth, clinical attachment and some of the other endpoints? So maybe Dr. Ryder if you can start first and then perhaps an answer from someone from Cortexyme, but we'll let you go first.

Okay. Well, basically, we are going to get the data, the baseline data for all of these bleeding on probing, pocket depths, clinical attachment level, and we're going to see what the results look like after 1 year. There are various ways of analyzing this. One is you can look at just the average gain or average reduction in pocket depths. The percent of sites in the mouth where there is a reduction of bleeding on probing and see if that is statistically significant. If not even statistically significant, is there a trend that merits a further clinical study where we're specifically focusing on periodontal disease treatment. With that, I'd like to turn this over perhaps to Casey, who can maybe give a little more detail on what else might be followed in a focused study just on periodontal disease.

Thanks, Mark. Yes, we're planning to leverage the data from GAIN, which will tell us both exposure, we have 2 doses, a low dose and a high dose as well as the time line to see benefit over placebo. We have a 6-month endpoint and a 1-year endpoint. So that will really inform the design of the pivotal study, both the dose and the length of time. So as Mark said, I think we're looking for a benefit over placebo. There's, as he's been describing, a big unmet need to improve the standard of care. So that's what we're looking for.

Great. As you can imagine, we've got a lot of questions coming in on ADUHELM. So I wanted to get a bunch of the other ones in first. But next one from Tazeen Ahmad from Bank of America. Following the approval of ADUHELM, how do you feel about the possibility of still applying for approval for atuzaginstat if GAIN, overall, this is the primary endpoint, but shows efficacy in specific subgroups?

Yes. So I think that ADUHELM approval is unequivocally good for Cortexyme, good for the field, where the regulatory bar has changed, and we intend to engage with the FDA around any positive data. We're really excited to be reaching the gold standard, which is really a change on cognition and function. And we have the gold standard co-primary endpoints. We have a well-powered study that's very strong from a statistical perspective. So that's what we're looking for. But as you're saying, there's now many paths to approval, including this accelerated approval pathway, which might be applicable to different types of data sets. So we intend to engage with the FDA absolutely very rapidly following the results.

Next question is a follow-up from Jason Butler at JMP and probably best for Casey. Assuming success in the periodontal sub study, can you give us some thoughts on the next steps towards approval? Would you need 1 or 2 more trials, changes in the trial design you would consider including items such as endpoints, population and expanding beyond just Alzheimer's patients?

Yes. So again, in future studies on periodontal disease, it will be enrollment criteria based on periodontal disease. Again in our Alzheimer's study, we actually didn't use periodontal disease as part of our screening criteria. So the comorbidity, the rate of -- the high rate of moderate-to-severe periodontal disease, I think, says a lot about the hypothesis and that we're enrolling the right patient population. But in the future, we will do a typical pivotal design in periodontal disease. And we'll be engaging with that division more. We obviously will have a strong supportive study with the REPAIR trial and potentially one pivotal along with that supportive study would be sufficient, but we need to engage further with the agency once we have the data from this study.

Next 2 questions I'll combine and probably best for Leslie. What properties does 388 have that allow it to penetrate the biofilms and why don't other antibacterials penetrate the same way. It's a separate question, but I'll ask it now is, how difficult is it to create an inhibitor for these similar properties, obviously, getting it barriers to entry?

Sure. So I can say from what we have seen on our molecules, it's key that's small molecular size as well as very specific substituents on the structure outside of the binding area of the active site do make a difference in penetration in the biofilms on our structure. They all do penetrate but ones with specific substitutions and again, this small molecular size seem to make a large difference on our structure. And I think those key features were not present in other antibiotics. As to how easy it is, for the second question, that's a good question. Knowing some of those specific substituents and maintaining small molecular size, I would say we could generate additional gingipain inhibitors to do that, but it's also a matter of keeping those features while analoging and screening for the other right properties that we need, including selectivity, potency, oral bioavailability, CNS penetration as well. And so that's a testament to a good medicinal chemistry team to preserve those properties while also finding these specific substitutions that seem to add penetration into the biofilms.

Next question is, what's the best way to measure or monitor PG gingipain levels or activity in a patient? It seems that antibody levels are somewhat dependent on a functional immune system, but PG tends to sabotage that. Whoever wants to take that one.

Yes. I can take that. We're -- as Mark -- Dr. Ryder mentioned to you, we are looking at Porphyromonas gingivalis presence in a number of oral bio fluids. We've been able to measure these ex vivo and in our Phase I study. So we know we can measure these. Which one is the best one yet, I think will come from our data from GAIN, but we can easily detect P. gingivalis using simple molecular biology and qPCR techniques and we have a quantitative method of qPCR for the measurement of the presence of bacterial load within saliva. We have that same method in biofilm plaque, in subgingival plaque that Mark mentioned. So we have to disrupt that plaque, but then we can subject that to the same qPCR detection of Porphyromonas gingivalis within the plaque and the same with the buckle cells. We also have an ability to use this activity-based probe. So we are measuring Kgp, the protein itself and our level of target engagement within subgingival plaque within the GAIN II study. So those are 2 keyways that you can measure that both bacterial load and inhibition of the target within oral bio fluids?

I would just like to also just follow up very quickly with what Leslie said that one of the questions we got was, when you would actually maybe institute using an enzyme inhibitor in periodontal treatment itself? And certainly, what Leslie has talked about is these detection methods for detecting P. gingivalis would be a way that you could determine whether there is P. gingivalis present. And should we use this inhibitor too, either systemically or locally, and in which case, you can probably do this at the beginning of your treatment.

Next question is an interesting one asking about the length of treatment whether or not you would consider 388 as chronic therapy. It's obvious that it would probably be chronic therapy for Alzheimer's disease, but for periodontitis and start with you, Dr. Ryder, would you envision this as something patients would have to be on for the rest of their life? Or what would be an ideal length of therapy thinking about the potential for resistance to develop as well?

Well, as Dr. Dominy presented, at least the results from the in vitro test, which show that the core compounds don't give -- don't result in resistance versus a use of an antibiotic, at this point, it appears safe to use over a longer period of time, which again, I think in a really focused study on the treatment of periodontal disease, this would be something we would need to determine. But if there is no evidence of resistance from the studies that are ongoing, then I would envision this as a more long-term type of therapy as opposed to, let's say, over a couple of days, perhaps over months or years, the analogy being the studies with low-dose doxycycline, which has shown to be safe over long periods of time.

And I'll just follow up with that. As Leslie showed in her slide related to our dog study, we found that this really -- we do think this is a chronic treatment potentially rest of life based on the data that when you withdraw it, even though the bacteria load has come way down in these dogs, when you withdraw it that bacteria does start to creep back. So this is consistent with the mechanism of action of really keeping the pathogen in check versus an antibiotic, which might only be a 7-day treatment. We really think this is chronic. And also, you can get reinfected by your spouse, for example. So we want to keep people on therapy.

We still have a number of really good questions coming in. So we're going to go a little bit past our 11:00 Eastern Time, if that's okay. So please bear with us. Next question is, please detail exactly how COR388 is administered?

388 is an oral pill, twice a day pill.

I think the nature of the question gets to kind of the differentiation from other products that maybe out there in Alzheimer's.

It's really important not only for periodontal disease to have this twice-a-day pill versus these appointments, which can be painful and expensive but also in Alzheimer's disease, it's a real differentiator for these patients who might have difficulty with hospital visits and IV infusions to have a twice-a-day pill is a big improvement.

Next question is probably for Dr. Ryder. Is there a diagnostic that you're aware of or would envision as a prerequisite for using this to treat periodontitis?

Well, certainly, as an answer to that previous question that Leslie gave, if there is Porphyromonas gingivalis detected in the mouth, this would be a diagnostic. Currently, there are some commercial laboratories. There are some chairside kits that can detect Porphyromonas gingivalis. You can envision other rapid chairside diagnostic kits being developed to detect Porphyromonas gingivalis. And this would be an indication for using this type of approach at the time of initial treatment and through the patient's lifetime. The -- or at least over a longer period of time. Other than that, if it's shown to be effective in PG positive patients, it could be expanded really to any patient who comes in with periodontal disease, with plaque accumulation keeping in mind that all of these sampling techniques may not detect Porphyromonas gingivalis at the time that they do the sampling or not at the right site that's being sampled. And it also may not take into account, again, the prior exposure of the patient to Porphyromonas gingivalis at some other time in the person's life.

We have a follow-up question from Tazeen Ahmad from Bank of America. And if you choose a different molecule than 388 to pursue for the periodontal indication, do you think that one study would be sufficient or do you likely need 2? For Casey.

Thank you, Tazeen. Again, I think we can leverage the data we're getting from 388 for exposure information and really the target engagement is the same. And so we can leverage that data. Again, we'll just need to engage with the agency once we have the data to negotiate the NDA package.

So I think with that, we will wrap up the Q&A section, and I will turn it back to Casey for some encouraging and closing remarks.

Yes. Thank you, everyone, for joining today. Thank you to our speakers, Mark, Steve and Leslie. That was really informative, and I hope all of you learned a lot about our programs, about the good science going on at Cortexyme and about the really exciting unmet market for periodontal disease and related systemic conditions driven by P. gingivalis.