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

Great. Thanks so much. Happy to be hosting Cortexyme for this discussion. And with me is Casey Lynch, and it's a pleasure to give you another band with you, Casey. So thanks so much for taking the time. Maybe with that, can you just kind of give a quick overview of the company, the status of the GAIN Trial and then we can get into some Q&A?

Sure, happy to. Good morning, everyone. I'm happy to be here to talk about Cortexyme. The company was founded based on the seminal discovery by my co-founder, Steve Domini, when he was at UCSF. The bacteria called porphyromonas gingivalis in the brain of Alzheimer's patients. And this discovery was made based on a lot of epidemiology showing that periodontal disease is a risk factor for Alzheimer's disease. So people with periodontal disease early in life and are more likely to get Alzheimer's later and this bacteria, called porphyromonas gingivalis is in deals causes periodontal disease as a Keystone bacteria and the development of periodontal disease. And in addition to finding it in the right areas of the human brain with the right timeline, a very important next step was to show causation. And that's been done now by not only our lab, but number of labs around the world have shown a few -- in fact, rodents in their mouth with this bacteria, it gets into their brain and triggers all the characteristic pathology of Alzheimer's disease, including a beta plaques, tau tangles, hyperphosphorylated tau, this chronic low-grade inflammation that you see in the Alzheimer's brain, a lot of pathogens, if they got in the brain would trigger a big immune response like meningitis or encephalitis. But this bacteria has a signature of this low-grade inflammation in the mouth, a little bit of redness and bleeding of the gums, which eventually results in tooth loss. So it creates a chronic degenerative disease in the mouth, which in and of itself is also a big market opportunity we can talk about later. So we developed a drug called, Atuzaginstat to target this bacteria and can very effectively treat it in these mouse models, which we think are not only establish causation in a really beautiful way that's been difficult to do in Alzheimer's disease, but also create a really translatable model for screening drugs. So this bacteria is difficult to treat. It's known in the periodontal field, you can't just throw broad-spectrum antibiotics at it and clear it. So we developed what's called a virulence factor inhibitor. Our drug blocks proteases secreted by the bacteria called gingipains. And the bacteria relies on these gingipains for survival, and they're also responsible for the toxicity of the bacteria. So we're -- have kind of a 2 for 1 approach where we're not only blocking the damage being caused as well as the inflammation, but we're also reducing the bacterial load in the brain, which has a lot of downstream benefits. So the drug is acting upstream of multiple aspects of the pathology and most importantly, of the neurodegeneration. So as you mentioned, we're now in the midst of a pivotal study. Towards the end of this pivotal study, in fact, we're looking forward to the data in Q4, the top line data. It's a large study of 643 Alzheimer's patients with mild to moderate disease. And additionally, we'll be getting a readout on 233 patients on the periodontal endpoints as well.

Great. Awesome. Well, with that, I do want to get into this recent safety update. And I guess, what else can you kind of say there? And how confident are you that if successful in Alzheimer's, of course, and then in periodontal disease as well, that if you show efficacy, you can still have a favorable risk benefit?

Yes. Absolutely. So as you know, we had an open-label extension on the GAIN Trial, and the FDA asked us to put a pause on that due to some liver adverse events, which were affecting -- affected a small number of patients. And we feel that certainly, the risk-benefit profile is there. People are really waiting for a breakthrough in this disease and this drug and this trial are really designed to do that. The GAIN Trial was not affected. That's, of course, really the critical study for understanding the efficacy and that study, again, is going to report in Q4 unaffected. So we're looking forward to unblinding the data at the end of the year to really do all the analyses. But what I can tell you is the events so far have been reversible and without long-term adverse effects for the participants. We're looking into all the possibilities, and we've never seen liver tox in our chronic tox studies in our preclinical studies with this drug. So actually, one of our leading hypotheses that we're looking into is that liver events could be caused by clearance of the pathogen this infection is known to be in the mouth, but also known to go to other organs. And as I've said, we know it goes to the brain. We also know it can go to the liver. And hepatitis B drugs, for example, lamivudine, can cause liver enzyme flares as the virus is being cleared. So that's something that we're looking into. And we do think that we're learning a lot about this and that it can most likely be controlled with the dose regimen.

Okay. Okay. Got it. If it turns out to be idiosyncratic, do you have other molecules that you could pursue? Should you see proof of efficacy here?

Well, as you know, we have a pipeline of small molecules entering the clinic. And again, we think 388 -- that we can understand this, understand who may be at risk and work with the dose regimen. And we also have other gingipain inhibitors, notably 588 is moving into the clinic in Q3. And we have been planning for 588 to be positioned in periodontal disease in order to separate these 2 markets, separate the 2 programs, create different pricing structures when the time comes.

Yes. Okay. Okay. That's great. I'm sure the folks listening in here know some of the basic scientific background, but maybe just for context, can you talk about some of the more recent literature that's been emerging and supporting your mechanistic approach, right? I mean there was the foundational paper that was at the autopsy work and -- but then beyond that, what else has emerged more recently? And how has that kind of impacted your confidence in what you're working on?

Yes. It's been great. We started the company in 2013. We were really in Stealth mode for a long time. We had funding from Pfizer indicated to move the drug program along and then we published the science advances paper in collaboration with collaborators around the world, which really laid out this hypothesis. And already, there was emerging literature where we were essentially getting scooped identifying this bacteria in the brain, showing these causation of brain findings after the oral infection. But there continues to be more and more studies. I mean, not only in the Alzheimer's field, right, that the evolution of the literature there's been this huge focus around beta amyloid, but more recently, people have been asking what is beta amyloid? Why is it being overproduced? And what they found is that it behaves like part of the immune system. So after infection, A beta 42 levels go up and it behaves like other antimicrobial peptides, which are produced in response to infection. And have these properties, a lot of people call it -- people say that A beta is being misfolded and creating these oligomers. But in the antimicrobial world, this is known as self assembly. Actually, these oligomers are formed in order to create pores in the membrane of bacteria and become toxic to bacteria. So additionally, we know now inflammation is important Alzheimer's. We know that microglia are important. So there's a whole line of evidence and then as well as the replication of our data. And even at ADPD just this month, 1 of the more skeptical thought leaders in the field announced that he's going to be publishing a paper where they looked for viruses and bacteria in the brain. And the only pathogen where they saw a difference between controls and Alzheimer's patients was in periodontal bacteria. So it's definitely more and more is emerging.

That's interesting. Who did that come from? That comment?

That's Rudy Tanzi.

Yes, yes. Okay. Very good. How should we think about window for intervention? Yes. I mean, look, in every neurological disease, right, there's this kind of essential question of how early do you need to go, but if the science is on point here, it would seem like this issue precedes amyloid buildup where misfile and amyloid buildup is something that might proceed Alzheimer's by a decade or 2. And so how do you kind of think about the context here where you're intervening at this stage and the issuing question may have been present for a very long time.

Yes. And that is what we see in our human studies. The infiltration seems is happening prior to symptoms. Around that 10 years prior to symptoms mark, it correlates to the buildup of tau pathology even prior to development of symptoms. So we do think -- and similarly, in the mice, of course, the bacteria gets in and then this pathology builds up. So a lot of people think, well, that means you have to treat at the beginning. But this is a chronic infection. And the damage to the neurons, we really think is being driven by the ongoing infection, but the ongoing secretion of these gingers, which are proteases. We can see the bacteria in the ginger pains inside neuron. So they're essentially sitting inside neurons, just like they do in the mouse cells and the Gingiva cells, digesting them from the inside out. Very slowly chopping up the human proteins like tau, like APOE, causing lysosomal dysfunction. So it's a very slowly progressing infection and disease. And when we block the gin Japans, we can't bring back -- we're not going to bring back the dead neurons, of course, but we do see that we stop further neurodegeneration. And some other aspects of the disease do seem to be reversible. The inflammation comes back down to normal, some people think, well, once there's inflammation, the brand it can't come back to normal. But what we see is when we treat this infection, the inflammation comes down, the A beta overproduction comes down, and we do believe you can level off disease. Would we like to -- would it be best to treat prodromally eventually? Certainly. But the best clinical trial design for a new drug, we firmly believe is in symptomatic patients. That's where you're going to see the best risk-benefit profile that's where people are declining mild to moderate disease. People are reliably declining in the placebo group and therefore, you can show a leveling more easily, more efficiently than testing in prodromal patients first. Once you show a signal there, you start moving earlier and earlier. And eventually, we would love to be able to treat people just based on a simple saliva test. You have this pathogen in your mouth that causes not only periodontal disease, but puts you at risk for other systemic diseases on Alzheimer's, you really should be treated sooner.

Yes, yes. okay. Okay. One interesting question, by the way, from someone who's listening that I think is a good scientific question, and that is really -- your drug works by inhibiting gingipains. Do we expect PG to starve off and die off -- and I guess, maybe just a broader context there, what actually happens to P gingivalis with this drug?

Yes. It's a really unique situation that's an asaccharolytic bacteria, it's a saccharolytic bacteria, rely on sugar for their -- as part of their metabolism. They're usually beneficial. asaccharolytic bacteria are using proteins, are using peptides, broken up proteins as part of their metabolic pathway. So that's not the rare part. But the rare part is that it's very dependent on these gingipaints. So when we block them, and this was published in our science advances paper, the bacteria load comes down by about 80% within the first 5 weeks and probably longer, more with longer treatment. Now we do think people should stay on the drug, chronic rest of life treatment. It's a very lance factor inhibitor. It's not an antibiotic that kills off every last bacteria. This is keeping the bacteria load low, keeping the bacteria in check. But we -- and people might be able to take a drug holiday, compliance isn't going to be critical every single pill once that bacteria load is down. But if you went off -- when we've done withdrawal studies in aged dogs, for example, we can see the bacteria creeping back up, you maybe get reinfected by your spice, for example. So we want people to stay on the drug.

Got it. Got it. Okay. All right. That's helpful. And then another question that I just received, too, is should we expect you to publish more on the prospects of this approach in Parkinson's like you did in Alzheimer's?

Yes, definitely. So we have been keeping an eye on other neurodegenerative diseases, and we've been doing some studies with the University of Auckland, Brain Bank, looking at Parkinson's disease brains, and we can see the gingipains in the motor areas in basal ganglia of those Parkinson's patients. So we'll be publishing that data. Other people have been publishing, showing that we know the bacteria is swallowed. And it's interesting on Alzheimer's. It's known that symptoms often start in the nose. So olfactory symptoms, loss of smell, olfactory, nerve damage. That pathway goes back to the interrenal cortex and the hippocampus of these memory areas. In Parkinson's, symptoms are known to start in the gut often. So GI changes. And Brock, the famous pathologist. Brock who did the staging of these diseases, showed that in Parkinson's, the pathology, again, the alpha-synuclein production this protein peptide overproduction starts in the gut travels through the vagus nerve to the motor areas of the brain. So there's already been other publications showing that this oral infection in or 2 mutant mice. This is a risk factor for Parkinson's can result in these GI changes, obviously nuclein overproduction and changes in those motor areas, neurodegeneration in those motor areas. So we are learning about which risk factors might predispose people are which strains, or where the bacteria is might predispose people to one neurodegenerative disease over the other. And certainly, we'll be publishing our own data as well around that.

Yes. Okay. All right. That's really interesting. I guess maybe taking a step back, there's been always talk of genetics drivers of risk in Alzheimer's, Parkinson's, et cetera. Like how would you -- as the literature has emerged on gingipains as a risk factor or maybe even a cause of 88, how should we think about the hazard ratio or I guess, odds ratio for this versus APOE4 or TREM2 or some of the things that I think investors are used to hearing about on that side of things.

Yes. So also in Parkinson's are primarily sporadic diseases. There's a lot of talk about genetically validated targets, but these are sporadic diseases with genetic risk factors for the most part. There is a small number of families who really have familial disease. So the comparison, there was a seminal publication by Pam Stein at University of Kentucky, called the Nun Study where they looked at this group of nuns and what risk factors of these nuns, who progressed to dementia, who didn't. And they found that nuns with 90th or less, had a much higher risk and this loss of teeth is representative of periodontal disease, much higher risk of progressing to dementia and the risk factor is similar to having an a APOE for genotype. So we're not saying having periodontal disease, you're definitely going to get Alzheimer's, 65 million people have periodontal disease, so it's a risk factor. But you need additional risk factors for that bacteria to get into the brain. And that may be TREM2, TLR4. 22 of the last 25 genetic risk factors are immune system proteins. Why would immune system proteins be putting you at risk? Well, you're probably less able to defend against this infection, systemically, and/or in the brain or your blood-brain barrier perhaps has a defect. You don't need a blood-brain barrier defect for this bacteria to get into the brain, but we know that stroke, TBI, microhemorrhage, those kind of things that cause the blood-brain barrier defect certainly put you at risk for Alzheimer's as well.

Yes. Yes. Okay. Okay. Very good. So maybe let's talk just a little bit about the game study, the primary endpoint of the powering dynamics. Any context there would be great. And then how this recent interim analysis is interpreted in light of all that work you did prospectively, I think would be great as well?

Yes. So we powered the study. The study is 90% powered to detect a 50% slowing of disease, which we believe is conservative based on the small study we did, the Phase Ib study that we did. And the animal data that we've seen. So the interim analysis was really designed. The main goal of that was to look to have a potential sample size adjustment, which was even more important during COVID. I mean it was really impressive. Our team, we enrolled 643 patients in 18 months, which I think is really a testament to the interest in the mechanism and the great job of the team and the investigators even during COVID. So we overenrolled the study in that period of time. And the interim is unmitigated good news in that we did not have to increase the sample size, which would have implied to us that the effect size was smaller than we were hoping for, but still perhaps interesting. Whereas the continue as planned is exactly what we were hoping to hear. We didn't have to go back and restart enrollment. We didn't have a futility signal, which was great. The DMC at the time, reviewed the safety, gave us the go ahead. So we felt great about that readout, and we're right where we want to be going into Q4.

Yes. Yes. How is futility set up? Was that a really high bar? Or...

We did have a high bar because this was all in the context of Biogen declaring futility and then later, finding a signal. So we certainly wanted to end it if the futility was clear, but if there was any question, we want to continue the study and analyze the data at the end. This is the first study of this mechanism, so we want to learn as much as we can.

Yes, yes. Okay. Okay. Great. One other question I got in, which is really just what engagement have you had with FDA since the emergence of the liver safety signal? And do you see the path towards chronic dosing, again, is something that could reemerge before the game data? Or would it have to be after having good data.

Yes. FDA is being very collaborative with us, as everyone's seen across the industry. They have an interest and again, especially for breakthrough treatments, but any treatments that can help these patients as we all do. So they're working closely with us on, again, discussing dose regimen, and certainly, we feel chronic studies in the future are -- will be allowed.

Yes. Okay. Okay. And then for Parkinson's, how are you thinking about patient selection and I think when we went back and forth on this, some of the literature you've sent to me, supporting Parkinson's centered around these different genetic subsets where there's this defect in lysosomal function, which makes sense. I guess when you think about this approach, does it make the most sense to go towards the Idiopathic Parkinson's or enrich for LRRK2 or GK or some of these other issues that -- I don't know, might even more aligned with kind of your broader thesis here.

Yes. We don't want to focus on a small group of genetic risk factors. I think that could not only unnecessarily pigeonhole us, but it's -- again, this is sporadic disease and any number of different risk factors could predispose people to the brain infiltration that results in Parkinson's disease. So we want a much broader group of patients. And what's important to us, again, is the PG infection. So we've been learning a lot about the different -- we have lots of different biomarkers that we've been tracking in gain from saliva to antibody level in the blood. So we feel good about those markers and bringing those to bear in the Parkinson's study.

Yes. Okay. Okay. Maybe lastly, can you just kind of walk through the design on the periodontal disease trial? And I think many folks who may have invested in Cortexyme have been following it for an Alzheimer's thesis have a harder time sizing that market opportunity, like thinking about pricing, thinking about how it being marketed. Maybe you could kind of -- I'd be the mechanistic rationale certainly intuitive, but what will the study endpoints? And if it does succeed, how you think about this spring again?

Yes. We think periodontal disease is a very important indication. Again, 65 million people in the U.S. alone. It's currently treated with root scaling and planning. These are manual procedures where people go to the dentist or periodontist once a quarter approximately, usually out-of-pocket costs, painful procedure. It's not fun to have to do that. So the providers and the patients are very excited about a potential once or twice a day pill. That could either substitute or at least delay, but we think it could really substitute in our aged dog study, those dogs didn't get any dental care. And we had a really robust improvement in the periodontal endpoints. So we've done an external market survey, and we found north of $2 billion annual revenue opportunity through our interviews with payers and providers. So to answer your question about endpoints, period ologies is measured by pocket debt. So that when you go to the dentist and they put that probe between your tooth and your gum and they read out 2, 3, 4, that's measure of the depth of that pocket. And so that's the regulatory endpoint is an improvement in that pocket depth, and that's what we're using in the game trial in a subset of participants who are part of the periodontal sub study.

Great. Awesome. All right. Well, do you want to kind of finish it off by just kind of relaying out the timing of these different catalysts as it relates to data in these 2 indications and then your PD trial?

Yes. So we have a lot of catalysts this year in addition to cite more scientific publications and presentations. We're looking forward to the pivotal Alzheimer's top line data in 640 patients in our Phase II parental data in 233 patients also in Q4, and we're planning to start the Parkinson's disease Phase II study. We've been working with Parkinson's study group. On that study design is anticipated in Q3.

Awesome. Great. And so when do you expect more literature to emerge out of this year or different presentations? I mean, are AAIC and things like that events? Or is it just kind of any time?

Yes. We'll be presenting at AAIC as well as CTAD, all the major events. We tend to have new data to share both on the study and on more mechanistic notes. And then we do have a publication and process as well.

Okay. Okay. Great. Awesome. Well, thank you, Casey. It's always great to see you. Appreciate your time.

All right. You, too.

All right. Thanks, everyone, for listening.