Inhibikase Therapeutics, Inc. (IKT) Earnings Call Transcript & Summary

Well, thank you, everyone, for joining the live webcast of Inhibikase Therapeutics 2023 R&D Day. Today's work will be focused on neurodegeneration. Last week, last Wednesday, we put out a press release that discussed our recent updates on our IkT-001Pro program that is focused on an alternate form of delivery of the anticancer agent, imatinib mesylate, a technology development program for us. With us today are myself, Dr. Milton Werner, President and Chief Executive Officer; and Joe Frattaroli, our Chief Financial Officer. Joe, why don't you say hi for a second.

Hi. I want to thank everybody for taking the time today. I know we're all busy, so appreciate everybody out participating.

So we all know that it's a pretty volatile time in the market, Inhibikase has had quite a number of swings in our research programs, and I will hopefully provide a lot of confidence around where we've gone, what we've completed and what's to come, in the coming 12 and 24 months. And all of what we're talking about today is focused on our Neurogen disease programs, which are lead programs in the company. Just as a, an aside, I will be making forward-looking statements. I'll be presenting some unpublished data, in fact, and so you should be paying attention to all of the necessary risk factors on social with our public filings with the Securities and Exchange Commission that are readily available. So we assume, in terms of today's agenda, I want to try to provide some more fundamental understanding of why c-Abl or the Abelson Tyrosine Kinase is an important target in Parkinson's disease. As many of you know, we've been pursuing this for the last couple of years in the clinic, has progressed to Phase II. We've recently published in Science Insulation Medicine, a fundamental paper showing how and why Parkinson's disease have initiated and why c-Abl emerged as probably the most important target in our minds. We'll also provide some better background on IkT-148009 or what I'll call 14809, how it was discovered, what led to its discovery, what novel tools we use to actually determine the appropriate drug substance to use for neural treatments in the brain and outside of the brain, I'll highlight some aspects from the recent publication in Science Translational Medicine about what is therapeutically possible with [indiscernible] based on our work. And then we'll spend a fair amount of time talking about where we are in clinical development in Phase II and beyond including long-term dosing studies. And I'll also introduce now a brand-new information that has not previously been made public, on an orphan indication that is Parkinson-related known as MSA or Multiple System Atrophy, and where that clinical development program will be going, as the IND was recently opened by the FDA. So just in terms of looking at our overall pipeline of activities, this is really encompassing the top half of our publicly disclosed pipeline of activities. With the Phase II program already underway in Parkinson's disease, covering a series of indications and now with the IND opening direct to Phase II, in MSA. So Parkinson's disease is a really large market indication. The recent Lean report, which was contracted by the Michael J. Fox Foundation in 2019 and its recent release, really highlighted the expanding prevalence of Parkinson's disease in the United States. It's now estimated to be as many as 1.2 million patients. The U.S. is the highest, almost prevalent country in the world for Parkinson's disease prevalence, and the average age of onset remains about 60 years of age. It's a chronic disease. It takes decades before it emerges and starts to show symptoms. Typically, once diagnosed, the lifespan of a typical Parkinson patient is about 1/3 of the lifespan, over 25 years. And so it really does have a devastating effect over a long period of time and begs for interventions of the type that we're trying to develop. There are many new cases a year in the United States, about 60,000 new cases and there are 38,000 deaths a year. The other mystery about Parkinson's disease is that it tends to be a disease of men over women, about 2 to 1. We don't know why that is. It's not related to your X or Y chromosomes, which define maleness, excuse me, femaleness or maleness, respectively. And so it remains a mystery why certain neurological diseases have a gender preference. For us, what we worry about is the other illnesses that can emerge as you're aging human being. And as you get into your -- the latter 1/3 of your life. Many people in the United States have joint diseases, psoriasis, arthritis are very common ailments these days. And virtually every U.S. male has cardiovascular disease because we are, after all, a hamburger-based or maybe now today Chick-fil-based society. And so as a consequence, our overconsumption of foods in that class really do lead to significant challenges, because we worry about what other medications you'd be taking and how they may cross react with enabled kinase, but for Parkinson disease. All of the patients in Parkinson's disease will go on significant dementias and many, if not most, will all go on to full-blown Alzheimer's disease. And so for us, what we wanted to do was to provide some background how to enable get identified as a role in Parkinson's. Many people ask us this. We really have not illustrated this in detail in the past. So probably the first thing to understand is what able itself is. So this is sort of like a section plot of the different functional domains that a scientist define about able and closely related isoform we call Arc or AbL-related gene, also known as ABL2. Both of these are called nonreceptor tyrosine kinases. If you look at how these various functional domains in the molecule are configured, the molecule in its normal state is sort of in a closed loop. There are a number of drugs that have been taking advantage of this configuration to prevent ABLE activation, branded cancer treatments, such as the allosteric inhibitors developed by Novartis, GNF and G5. Gen 2 is now a third line medication for a chronic biologics leukemia, that's gleevec resistant. And when you activate ABL, you now unfer at least a portion of the polypeptide and you auto phosphorylate at a specific tyrosine residue. And so when we began in this work, we needed to have a marker for ABL activation, and therefore, having a way of monitoring whether or not a drug that we want to use to prevent activation actually could be measured in a functional context. And so we have an easy way of doing that, and so we monitor ABL activation in this fashion. So we also had to develop different types of animal models in order to make this work successful. This was done with a large number of people predominantly at Johns Hopkins University, but also at the formal Parkinson Institute, now in Arizona separate groups in Arizona State University, at the University of Roberto, at the University of Vienna. And so, through all these collaborations, we developed models for both inherited diseases related to dysfunctional alpha-synuclein. In that case, we were able to express a specific mutation that was found clinically to cause Parkinson's at 100% of cases, and for the more common form of Parkinson's, what we call sporadic or idiopathic disease, we actually were able to develop methods with our collaborators, to prepare these synuclein aggregate proteins in the laboratory, and then we could inject them. And so as we've often talked about is that Parkinson's disease is a slowly progressive disease, dependent on a non-essential protein that becomes aggregated called alpha-synuclein, and we had to be able to place those aggregates both within the brain and within the GI tract, the 2 major organs of disease, in a manner that allows the disease to progress on its own in the animal. And then we would wait, often 12 months to read quantitatively what happens. So let's take a look at what some of those results look like. And these results were some of which were recently published in Science Originational Medicine in January. So one of the first results was, to find out whether or not ABL itself was an essential component of the disease process. So here we've got is a picture of all the different neurons present in the 2 hemispheres of a mouse brain. We have 1 hemisphere, where we do not introduce the defect and another hemisphere will we inject either an expression vector for this form of synuclein or we express protein. And if you just do that and wait, you can see that the density of neurons, all that dark staining goes away. We can count those neurons with specific markers called, missile or TH. You can see that at the 6-month time point, you lose about half the neurons in the space, and that's visibly evident. So what was surprising to us, and this was based on some hypotheses before this work, the importance of ABL was known is that if you genetically delete ABL in these animals, so you can delete it in the brain specifically. And when you do so, now you lose all aspects of neurodegeneration. Here, you can see that visually that when you have an ABL knockout, even though you're expressing the synuclein aggregate protein, there's no difference between the left and right halves of the brain. So what that means is that ABL is absolutely essential for driving the neurodegenerative disease process. That was a transformative moment for us. That work became apparent in 2015, it wasn't published by our collaborators until 2019 in the general brain. And that allowed us to now develop new ways of analyzing what would happen with ABL activation and inhibitors of ABL. And so we used an acute neurotoxin a classic experiment in neurology. It's a [indiscernible] injected drug called MPTP for short, happens to be a component of the agricultural pesticide, paraquat. And what we did is develop a way to pretreat animals or to monitor animals, do our neurotoxic injections and then read out what happens. And so the way we screened drugs in our portfolio that have very equal abilities for inhibiting ABL here called 14809, which is listed here as 09. 148032 is another molecule of very similar activity. 1427, a molecule we're using for non-dopaminergic nerve cell treatments, all equivalent drugs. And yet when we go into this model, when you look at wild-type animals and then you give them an MPTP injection, you can see it as significant ABL activation because what we're measuring here is the relative amount that occurred. If you pretreat the animals with 14809 during a 3-day pre-treatment period, you can see that able activation is totally suppressed to baseline because this is the baseline level on the left. Whereas the other 2 drugs, 14832 or 14827, neither of which really suppressed ABL activation in these neurons. And so quite surprising to us was dopa Metagenic nerves, in the brains are selective. There is some selectivity. We don't know it's origins, so that some, but not all drugs could actually treat inside those neurons to block the effects of this neurotoxin. We also looked at the commercial inhibitors like nilotinib or dasatinib. Many of you know that nilotinib was evaluated in Phase II clinical trials in Parkinson's disease and was completely negative. And that was not unexpected. Nilotinib has very limited activity for suppressing ABL even in this context, whereas the anticancer agent tucatinib, because it's potent inhibitor can do quite a good job, it's just not applicable to Parkinson patients because of its side effects and fortunate or not, is about equally good. So because of the selectivity and because of the potency of 14809 and when given orally through this type of experiment, really had a way of identifying the right inhibitor to pursue more detailed studies. So here's an example of just how compelling the effect is. I'm showing you now 2 videos. These are what mice injected with MPTP alone and not treated with drug look like. They're still, their hair stands on ends, their tails are not curved. They don't have any social interaction. But if you pretreat those animals with 14809 and give them the injection as was predicted from the fact that ABL is not activated, there's no really obvious behavioral effect. These are very striking results. And I want to be clear, it's not as if we took these animals on the left, injected them or fed them 14809 and they became the animals on the right. This is a pretreatment experiment. So that 14809 was able to block the neurological defects of the toxin MPTP in real time. But the contrast in these effects are rather slick. So what we learned from the early work on c-Abl inhibition was, it has a real potential for modifying the course of diseases that could affect dopaminergic neurons or dopamine screening neurons like in Parkinson's, enables essential for initiating disease progression. We know if you delete the gene, you cannot induce neurodegeneration in animals. And if you use innovation as a prophylactic, you can block induction in her generation profoundly in this context. So how do we then go forward with 14809 and bringing forward its therapeutic potential in Parkinson's disease. Well, as some of you know, if you followed our past presentations, we've used a method called RAMP. It's a sort of an artificial intelligence associated learning tool, where we take known information from one or more individual molecules and then we apply to it through a computer-generated process, a number of properties that we wanted. In this case, we wanted to be able to have molecules that can be brain penetrant. They have to overcome the effects of a pump known as PGP as a blood-brain barrier that keeps them out of the brain. We wanted to suppress a number of on dosing side effects, common to drugs in this class that just cause nausea, diarrhea, vomiting in the GI or gastrotestinal track and also can suppress white blood cells. And we wanted to have high potency in a wide therapeutic dosing range. So we knew that many different types of doses could potentially be infected -- could be effective. And 1409 emerged from that process. And so when we asked what was the relative inhibitory potential of drugs such as those I discussed in the MPTP experiment and compare those to 1409, we learned an additional surprise on this process that while many of the commercial inhibitors that are being used for treatment of cancers are panAbl family inhibitors. They inhibit all 5 members of this family, 14 of them was different. It only inhibits ABL1 and ABL2, which I described previously. And it's because of this selective inhibition that you don't have any meaningful organ-specific toxicities, we were able to show in contrast to the commercial inhibitors, we can get very high concentrations in the brain, maybe 10x higher than necessary for full saturated inhibition of ABL in these neurons. And then we had the additional unexpected property that as we lengthen the dosing duration in animals such as rats and in monkeys for toxicology measurements, we actually see improved toxicology profiles, the longer you dose. So that boded very well for a potent inhibitor that could be selective and be given chronically to human beings. So we wanted to now characterize just how good a therapeutic was. And so I'm going to show you a few experimental outcomes, aimed at understanding this with respect to inherited disease models. This work has been published in Science Insulational Medicine. And the way we measure this is, that when we give a defect in 1 hemisphere, these animals really can only run in circles. And so if you stimulate them with lilamphetamine, they tend to run in circles much faster when they have specific defects much slower when they still have both sides of their brain active. So in the wild-type state animals that are performing in this experiment to about, 25 circles in 10 minutes, but if you give them toxic levels of alpha-synuclein and they develop a Parkinson-like disease, they now travel much more quickly, about 100 turns, if you will, in the same period of time. And so that's illustrated here in these 2 treatment measurements. Here are the controls about 20 to 25 turns in 10 minutes for wild-type animals. You give them to the disease. Now 1 hemisphere is defective. They really cannot run straight line, so they run in circles very rapidly, now getting up to about 100 circles in 10 minutes. But if you start treating these animals after 4 weeks and read them out just 3 months later, so that's 4 months of age, you've now gone back almost a full effect of the drug, reversing the functional deficits that the synuclein aggregate introduction introduced. And it's a durable response. You see that same level of 3 months that you do at 6 months. So once you start dosing and if you maintain that dosing for long periods of time, you maintain the functional response. And we can also see that in terms of recovery of dopamine secretion dopamine neurotransmission. Here, you'll lose substantial amounts of dopamine neurotransmission about 3/4 of the total dopamine secretion present in the mass brain in the disease state. You get back about half of the lost dopamine secretion in the recovered state. So these are quite compelling results with respect to the functionality of these animals and what's responsible for driving that functionality. If you look at ABL activation, of course, in this context, you're now seeing very substantial suppression of ABL activation. In fact, it's even below baseline levels. And we have a specific effect on the activation of Abl, which is monitored by this phosphorylation at Cyrus 245, whereas wild-type able remains roughly intact. We can also look at the effect of neuroprotection in these animals, again, looking as we did previously at Enable knockout context. Here's what the normal brand looks like in this mouse. Here's what the lesion side looks like. You can see the substantial loss of all the neural density. Here, it's quantified, you lose about 85% of the neurons of the disease state. But again, if you therapeutically treat beginning 4 weeks after the lesion was established, you get back about 80% of the total neural density. You can see that also in these visible slides. And again, this is just 2 independent measures, measuring it by 2 different markers for this type of neurons. So one other fact that was really quite striking in these things is that we not only see suppression of ABL activation, we see neuro protection, we see recovery function. And when all those things occur, they occur with suppression or clearance or near clearance of the synuclein aggregates that gave rise to those functionality problems in the first place. Here, you can see the ladder of aggregates in different mice. And the animals that have not been treated with drug, here's what happens at the end of 6 months and now that have been treated with drug for 2 independent markers of the synuclein aggregates in the affected neurons, and here is where you can see it's quantified. So what's striking about this is that our goal for treatment in neurodegenerative diseases like Parkinson, has been to do clearance of these aggregate proteins by targeting the treatment to within the in effect of neurons, we can recover most of the loss function and clear the underlying pathology. And so just to summarize all of this underlying basic science, ABL inhibition is neuroprotective in animal models of disease. We, of course, have not shown that yet in human beings. That's what the nature of our Phase II and later programs will attempt to measure. ABL inhibition blocks downstream effector pathways from neurodegeneration animals of disease. I'll illustrate those on the next slide. And ABL inhibition also can reduce or clear the underlying per protein pathology linked alpha-synuclein that correlates with the disease effect. So we've published previously what all of these downstream effective pathways are like. The only point I want to make here is that we can suppress all those downstream events that's illustrated in the -- both in this paper and in Science Translational Nation Medicine paper. And the clearance that we're getting of the synuclein aggregates are through endogenous or natural, normal intracellular processes. So the point of ABL inhibition is to restore the ability for cells to recover from the appearance of toxicity inside of them. And that's why we think we're getting restoration of functional responses. So let's now talk about what's going on in the clinic. As many of you know, we've talked about the 113 patients. They now have been an additional 6. It's 120 patients total that were healthy subjects that have received different doses of IkT-148009, once a day orally in the form of a gelatin capsule. We had 88 healthy subjects in single or multiple doses and a total of now, excuse me, this is down 95 subjects and a total of 25 Parkinson patients, half of whom were on Parkinson-related medications. We really focused on an earlier group in terms of their age, many Parkinson's patients are 80 and 90 years of age. But because this is an unknown drug when we started this 2 years ago, we were reluctant to go into older age groups that could be more fragile or have less availability to respond to anything that might have shown up. Surprisingly, however, very little has shown up in the clinic. Across all of these individual patients and subjects, we only saw 18 total adverse events. Drugs in this class would typically show between 2 and 5 adverse events per patient or per subject per day and dosing at different levels. Here, we saw 18 total and of those, only 7 of them could have had any relationship to the drug. Most importantly, none of the persistent GI problems, nausea, diarrhea, vomiting, that happens at all in half of all patients who take imatinib, nilotinib, tucatinib. For cancer treatment, for example, they don't appear in these patients. No QTC or other cardiovascular abnormalities appear in these NED subjects or patients. No suppression of white blood cells, no hematological adverse events appear in any of these cases. So this was a very promising set of observations. It will let us go into Phase II in the first half of last -- in the middle of last year. And these are what all those adverse events look like, just 3 among healthy subjects, just 5 among Parkinson patients. The palpitations that were emerged in 1 subject at a single dose of 75 milligrams was a complaint that emerged 2 weeks after the subject left the clinic. That was in our observation window. There was no clinical coal that found and when we began the analysis of those patients complaint. All the complaints went away and have been away since then. That's now 2 years later. At the highest dose we evaluated. We had 2 instances of diarrhea, and that was it. Among the Parkinson's patients, we had 1 person with elevated amylase for lipase. This is a known sporadic occurrence among people who take a kind inhibitors for any therapeutic purpose. It was asymptomatic and it's not considered to be clinically meaningful observation because it doesn't persist. We had 1 person who failed to take food with their dose at home. So they got a stomachache and nausea. We have 1 person who was taking Parkinson's-related medications at the same time as our drug, had a rash for a few hours on the first day of a 7-day dosing cycle. They were given Benet once and then continue dosing without any further occurrence. So a really very mild set of adverse events associated with drugs, this drug in this class, even though you're taking it for a very long period of time. So what's going to happen now in the 201 trial. Many of you know that we had a clinical hold initiated at the end of November when we were initiating expansion of the 1409 usage into another indication known as MSA or Multiple System Atrophy. And that hold was lifted at the end of January, about 2 -- under 2 months later. And so we're now in the process of restarting that trial. We expect in the month of April that we'll begin screening again. We'll have a double-blinded period for 3 months that we think will take 12 months to enroll. But at the same time, we plan on overlapping that trial by rolling every completed patient at 12 months into an open-label 12-month safety extension at all 3 doses. And so the first question to answer, of course, is, as many of you know, the FDA asked us to measure a pharmacokinetic profile for the highest dose before implementing in this trial that 200-milligram pharmacokinetic profile has not been measured, and we'll complete and submit the data to the FDA, at the end of March. And then we'll begin the implementation of the 200-milligram dose, along with the other 2 doses in the early days of screening for this trial. In terms of primary and secondary endpoints, the primary endpoints are safety and tolerability over the 3-month period, secondary endpoints a hierarchy cover movement cover quality of life, cover non-motor symptoms, cover sleep, cover GI activity. In the 12-month extension study that will continue to be the process, except everybody will ultimately end up with 15 months of dosing, assuming that at the end of the 3-month period, they continue to be eligible for continuation of the study and that will include the same hierarchy as we had before, measured every 3 months during the extension. What's going to be different between the 3-month period and the 12-month period is that while we'd be doing exploratory endpoints to look at the status of synuclein aggregates in the skin and possibly in the GI, which are organs of disease. We're not looking at the CSF per se because we don't think those represent organs of disease, and the synuclein aggregates there, may not be a reflection of what happens in the brain or GI tract. In the 12-month extension study, we're not just looking at synuclein aggregates. We're also going to looking at time to initiation of Parkinson medication, if needed and the time before initiation of Parkinson's medication, if needed. These are very important observations from an exploratory standpoint because what one would expect in the ideal world is that ABL inhibition will actually lengthen the time it will take before you have a need to go on other supportive therapy. And in a fantasy world, that time could become infinite. And we don't really know whether that's going to be the case. All of the enrolled patients coming into the trial are evaluated by an enrollment authorization committee. Their status as a patient with properly diagnosed Parkinsonism and symptoms of Parkinsonism is part of their enrollment. And so they're constantly going to be balancing their ability to stay off Parkinson meds, stay on 14809 treatment orally once daily and see whether that will be necessary or even sufficient to allow them to continue for as long as a year. In Phase III programs, a year of dosing is a very common way of analyzing the overall effect in support of approval for drugs in this class. So we're going to be adding back that 200-milligram dose because we've completed the data. The required safety study has been done. The PK profile is completed, and we'll submit that data at the end of this month, and then introduce it after 5 patients have been randomized at 1,500 milligrams in placebo. So we have a sort of delayed initiation of the 200-milligram dose because that's the easiest way to maintain our current spate of activities without more IRB approval changes. We can do that work and introduce it at a later day without a statistical penalty. Now the other thing I want to bring up is the concept of vision monitoring, as many of you know from the clinical hold that we overcame in under a 2-month period. We also introduced in the press release related to that, that the FDA asked questions about vision monitoring that was already part of the trial when they first reviewed the trial protocol. And at that time, we had no comments in the first half of 2022. What prompted their interest was that when we go from 3 months to 6 months in our chronic studies in rats, we had an increase in the frequency of minimal or mild changes in the revenue eye. Because we saw that and we didn't know were recurring humans, we were already going to implement that monitoring plan, and we did implement that monitoring plan before the hold it actually was issued. But in the context of the MSA IND submission, the FDA finally seems to have read those chronic toxicology reports. They wanted to review with us before allowing the trial to proceed whether or not our monitoring program was adequate. Fortunately, the program that, we had done and the FDA and other divisions had also approved. There is already to start a standard program for vision monitoring that had been known. There are at least 8 approved kinase inhibitors that are not in the ABL class, for which vision monitoring as part of either the trial work or as a mandate even post market. And so we've adopted the same monitoring program of the eye, all of the tests that were implemented in the monitoring program, our standard test in an ophthalmology office. So other than the inconvenience that the enrolled patients will have in visiting 2 clinical sites instead of 1 periodically, this is really not a burden on the trial. But it does take -- add considerable work to the trial sites. And so that's why it's taking about 2 months to get the trial sites back open. Once the trial sites are back up and there'll be 20 sites open immediately, and 10 more sites that are still completing contracting. And then we've added 5 sites in the last couple of months that are also now in the contracting phases. I just want to also point out that we've seen no vision pathology in the 11 patients that were pulled from the trial and we made those results public at the end of last year. And we had dosed at all 3 doses planned in this trial for up to 11 weeks. So that's an encouraging sign, but it's an insufficient data set to know that this won't become a problem in human beings. And so we'll be monitoring vision throughout both the blinded phase and the extension phase of the study. Let me now say a few words about what's going on in multiple system atrophy. As many of you know, one of the things that we think differentiates in heavy case from every other company that might be working in the space is that we gate all of our clinical efforts by demonstrating therapeutic efficacy in animal models of the human disease, and we strive to get animal models of human disease that are quite robust that really represent what's going on. So we've done that in an MSA and we've been talking about that work that's been ongoing but haven't shown any results from the last year. Well, now there are results that are emerging and so there's something to say about what's going on in that area of the company. Just to give you a sort of high-level overview of what's the difference between Parkinson and Parkinson-like diseases called MSA. Parkinson's is a slow to progressive disease, about 25 years of death. MSA is very rapid. 8 years to death is common, faster time frame to death is also common. You have a lot of inter-patient variation between the rate of progression and disease manifestation among Parkinson's patients. In MSA, people are much more similar to each other, but I'm not trying to imply that they're identical. There are many symptomatic treatments for Parkinson's disease that can improve quality of life for patients suffering from this disease for periods of time. Unfortunately, those treatments are not very helpful at all in MSA. And so there's almost nothing in the market that really could benefit an MSA patient from real time. Diagnosis PD has become quite easy. MSA diagnosis is very difficult to diagnose early. And so that creates challenges to the trial activities. There are many cases in Parkinson's disease, about 1 million U.S. prevalent cases but there are only about 20,000 cases in the U.S. overall and many fewer in other countries, maybe 50,000 total cases worldwide would be the current estimates. Another key difference between them is that while the synuclein aggregates, which we've talked about at length today, are found inside the effect of neurons. That's not where they end up in MSA. In fact, the antifinamibratory cell known as a glial cell. Glial cells play a number of critical roles in the brain. They form the mile and sheath, that sort of insulated around every nerve fiber in the brain and in the periphery. And because these aggregates end up in the glial cells and not in the neurons, we now have to target synuclein aggregate clearance and resolution to different parts of the brain than we previously had done. So about 2 years ago, we published the fact that an MSA, even though these are glial cell derived aggregates, they are present in the chemically modified form, just as they are in Parkinson's disease. We have 2 different markers for these modified forms, the most important, which is the tyrosine phosphonate form, tyrosine phosphorylation arises from c-Abl activation. And so by seeing in post-mortem patient brain in both an area of the brain known as the putamen as well as in the substantial nigra, we can see evidence of the synuclein aggregates that are specific for these forms of phosphorylated synuclein, we know that Abl activation was already taking place as part of the disease, even though it's in a different vibratory cell. Working with Jeff Corner's lab, this paper was published at the end of 2021. We also showed in monkey models that those aggregates also appear. So we can reproduce in model studies. We now can do that in rodents, both rats and mice. We can reproduce the synuclein aggregates, the activation of ABL, all of the salient features that we think should be present in MSA to understand whether an ABL inhibitor could be beneficial. So we've been working for a while. This is one of several different tests that are done. And here, I'm going to illustrate the experiment very briefly. The way you do this is you monitor how well mice traverse a gapped beam. So you monitor how fast they cross and most importantly, how well they can position their hind legs and their front legs so they can go from one step to the next. And what you're measuring is how many errors or slippages that they have. So here, we've broken out what happens with male and female mice. This particular defect is introduced transgenically, which means we introduced the defect genetically and then we breed those mice. And from the moment the brain develops, the defect starts to get introduced. So we began a baseline measurement about 11 weeks of age. That's about the earliest week, that earliest time point where we can begin once a day oral treatment by medication. You can see that wild-type animals have about 5 slips per measurement time. The animals that have the lesion developing have the same number, the cohort of animals that were going to be treated have the same number of male and female. And now if you look at 7 weeks later, well, the lesion animals, are getting worse. They make many more mistakes because they're starting to get neurodegenerative diseases because of the glial cell accumulation of synuclein aggregates but the animals that have been treated with drug do not get worse. And you'll notice there's a difference between male and female mice. That makes a lot of sense to us in rodents but in no other animal that we've worked with drugs like 19 have a higher absorption and distribution in female mice relative to male mice. So this is an effect of dose response between male and female mice. We're following these miles for another 12 weeks. So that means sometime in May, these mice will be sacrificed. And we'll evaluate what's going on in the brain in the manner that I showed previously in Parkinson's. But what we're already seeing is a very clear delineation that treatment of these animals who have this lesion can be rescued from getting the devastating effects of an MSA-like lesion. That's very encouraging. We have also a different test. We've also done this shown the same outcomes. And we have a separate model that's underway, but has not yet started dosing. So we're quite encouraged. We haven't yet lifted the date for the clinical trial. But I can tell you that we know that able activation is a disease that occurs more prominently in many different diseases, not just in the rare disease that's aggressive like MSA, well described in the literature for Alzheimer's disease also is hypothesized to occur broadly in different forms of ALS. And these are future growth areas for inhibit case as we begin to demonstrate that 1409 and other drugs in our portfolio are active inerogogen disease will begin depending on clinical outcomes in Parkinson's exploring whether other diseases like Alzheimer's or ALS and as well as MSA are going to be accessible. So what does the Phase II program in MSA look like? We have not yet initiated this. It's why I don't really indicate what month this is. Again, we're going to have a 6-month double-blinded enrollment period where safety and tolerability in these patients will be the primary endpoint and a different hierarchy of activities, notably looking at orthostatic hypotension. That's a change in -- it's a blood pressure drop and going from a line to a standing position. Looking at different blood markers that are specific for MSA treatment effects, such as what's known as the neurofilament light chain or NF. And we can also use MRI in contrast to what we can do in Parkinson's disease and look for atrophy of the frontal portion of your brain. We know from natural history studies in MSA that degradation of that area of the brain is measurable by MRI. If the drug is having a benefit in MSA patients, we may see that, that rate of progression or degree of progression of atrophy is reduced. And just as we've done in Parkinson's disease, we'll also look at aggregate formation. So let me give you some guidance for what's happening in urge generation, then we'll say a few things about our finances and cap table and open it up to questions. From the Parkinson's perspective, we expect this year to fully enroll it to 1 trial, and we'll start obviously getting information from that and initiate the long-term extension study. We're also going to be preparing for the Phase III program as we begin to progress through the 201 trial, and we will declare a commercial formulation. So we have 2 different tablet forms that are ready for clinical testing. We expect the clinical testing to begin in the second or third quarter depending on availability of clinic time. And we need to also analyze what's known as a food effect, because drugs in this class are very nonpolar or very fat loving, we have to make sure that the -- depending on what you're eating that day, that you're not going to get too high a dose of 1409 because you had a high fat need. In MSA, we're going to complete both prophylactic, so pretreatment as well as therapeutic animal model studies. Both studies are ongoing now. I've shown you some outcomes from part of the prophylactic studies that were going. And we hope to initiate the Phase II program in the U.S. and EU. We've got specialized sites for this. We need to see positive model outcomes and appropriate capital that we have not yet devoted to the MSA trial, but we'll look at that in the future, depending on the outcomes of these studies. So let me now have Joe talk a little bit about our cap table and our finances. Go ahead, Joe.

Thank you, Milton. If you take a look at this slide, you'll see the balance sheet information was derived from our Q3 2022 10-Q filed in November, at which point, we had $25.1 million in working capital. we guided at that time that we had a runway into Q1 of 2024. You can see here, it's a very clean balance sheet, very clean cap structure. We've got a single class of common stock. We have no preferred stock. We have no debt of any kind of the balance sheet. I think principally that is because all of the pre human clinical trial work was funded with non-dilutive dollars, primarily from government grants -- government grant type revenue. That type of grant revenue that we had did not qualify the human clinical trials. So in 2019 and 2020, we began to prepare for an initial public offering to conduct the human trials. When the window opened up, we were able to raise $18 million on the IPO in December 2020. That $18 million was enough -- adequate to accomplish 2 objectives: number one, to uplist to NASDAQ; and number 2 to commence our human Phase I clinical safety trials. Those trials went extremely well and quickly. So in June of 2021, we're back up to the market and raised an additional $45 million straight common stock, very clean deal, and we projected that would be enough to get us through our Phase IIa trial that Milton has just finished describing. And again, we had a runway into beginning of 2024. In January of this year, we had an opportunity to extend that runway. In January, we sold about 11.6 million units to raise $10 million a unit was 1 share of common stock and 1 common warrant. So as you look at that January 30 data on the left, those 22.4 million warrants, about 11.6 million of them are the common warrant at the market price for strike and the other 8-point just prefunded warrants that was a single institutional investor and they took 2.8 million shares and the rest in prefunded warrants. The options you see, they have 4 million options are playing Penella, issued over the years to employees and directors in the ordinary course of business and shares outstanding were 28 million. At the time that we registered those underlying shares. We guided that we extend our runway. This raise would extend our runway into the end of 2024 and again, adequate to accomplish the Phase IIa objectives. So again, pretty clean cap structure, cap table, no debt, no preferred stock. Nothing out of the ordinary.

Thanks, Joe. So now I want to open the floor to questions. We'll have Julie Seidel and Andrew Diamond from Stern IR. We'll be meeting those questions, and we'll be reading them as -- and we'll answer as many as we can for the next 20 minutes or so. Go ahead.

Right now, we are not seeing any questions in the queue, but please feel free to type a question in the chat box, and we will give it a couple of minutes, and we will see where we get.

Great. Well, even if there are turn out to be no questions today, we just want to thank everyone for participating in the R&D Day. We've had a lot of fundamental publication work and advancement of clinical trial work. And in contrast to what many people have experienced with changes in the agency's performance, we managed to look to clinical hold in under 50 days for across 5 different clinical programs. And I think that just reflects our knowledge that 14809 looks to be so far a very promising agent with a good safety and tolerability profile. We do not yet have a full talk -- full safety profile and long-term dosing. It's a state that it's a safe molecule, but it certainly looks promising. It's been associated with no clinically meaningful adverse events.

Great. One question that we have coming through is just about the competitive landscape. Obviously, the Alzheimer's disease space is quite crowded. Just wanted to kind of get your take on your key points of differentiation against what's out there.

Sure. So one of the things that we've come to believe, I think there is a fairly growing consensus, but obviously not complete consensus is that Alzheimer's and Parkinson's or both diseases characterized by a misfolded protein that is non-essential. In Alzheimer's, it's known as amyloid beta and tau and Parkinson's is afienuclein, both form aggregates, both diseases have been pursued for the last 50 years, even to current day as an effort to try to remove the aggregate proteins to overcome the aspects of the disease. In the Alzheimer's space, 10-year prophylaxis studies fail to reduce incidents or prevalence of disease in a genetically at-risk population. Those are results published in the last couple of years from both Roche and from Lilly. We've seen mixed clinical results on the 2 approved drugs, although one, LOKAMBI did reach clinical statistical significance, but a very small effect in a large dynamic range. What the Parkinson's model studies that we've published recently demonstrated is that while the aggregates are necessary for disease initiation, they are not sufficient to actually cause disease. We know that because when we place those aggregates into the brain, in the right area of the brain of an animal, but we believe c-Abl, you can't get disease to initiate at all. So what that tells us in context of all these other studies is that the aggregates play a role, but not the fundamental role in causing disease. What we showed in our study is that we published this now over the last several years in 2 key papers you can get from our website one and moving to orders from '22, 1 from Science Translational Medicine. What those papers say is that these aggregates are internalized. Synuclein aggregates are internalized and modified by ABL, and it's only in the modified state that you start driving the downstream processes. The same thing occurs in Alzheimer's. Amyloid aggregates are associated with tau internalization. Tau phosphorlation occurs at 2 different points, one of which appears to be the pathological form. What we don't understand in Alzheimer as well, because we don't have equivalent models like we have in Parkinson's is what happens downstream. So from a competitive landscape, we think it's wide open. We know of only one other company that's actively pursuing at Phase II related trials in the ABL inhibitor space for Parkinson's disease. Those trials have been trying to enroll for 3 years. Results have not yet known. And in the Alzheimer's space, there remains a prevalence of using antibody therapy that we think ultimately will not be the long-term solution for these diseases. If what we've learned at Parkinson's is right, we should be pursuing these diseases by attacking it within the effective neurons, and we should be using therapies that have the ability to do that and an antibody cannot achieve those goals. There are many other disease-modifying therapies that are being attempted in Parkinson's, trying to affect glial cells, trying to affect aggregates, trying to affect translation of synuclein. And we don't know if any of those will ultimately be effective because they're trying to attack the disease in more of a preventative way to prevent progression then to attack disease that's already present. And so those methods could be complementary to ours. So I think the landscape for success in neurogenesis is just wide open. And right now, at least in our view, and obviously biased is we have demonstrated and highly validated why this form of therapy that we proposed has such validity against the disease itself. We want to do the same thing in every disease indication where we pursue it, and we'll find out whether, in fact, we see those pursuits result in therapeutic benefits in people.

Next question, what is your updated cash runway following the January raise?

Joe, what's the guidance we can give? We're going to put out our earnings report in a week, but go ahead.

Great. When we guided 1st week of February, we filed the resale registration statement guided that we project into the fourth quarter 2024, post the January raise.

So that's just about 2 years cash.

Great. Next question, based on the new RAP data, will the MSA trial focus on female patients preferentially?

No. So that -- those are my state just to be clear. But as I said at the outset is that drugs in this class, all drugs, not just 1409 or all inhibitors, have a differential absorption in male versus female mice. What that means is that the male mice will catch up in terms of activity relative to females, it will take longer because the effect of the drug is not as close to saturation. So that has no reflection on what happens in human beings unlike what happens in rodents, neither monkeys nor human beings show this gender differential for absorption. And so -- and what human being show for 1409 is that absorption in men and women are the same, and they are the same as they are in female rodents. So we have no reason to do a gender preference in the overall study. That's just a corp of how these drugs are absorbed by the -- in the GI tract of mice and rats.

Next question. When and how do you plan to release results from the disease model experiments with 14809 in MSA.

That's a good question. So we have put in an abstract. So we don't know the outcomes other than what I've shown you, there is another experiment that's roughly equivalent measuring it on a different kind of beam to get a little more granularity. But we don't know what the full outcomes are going to be realized. In end of September of this year, we are going to be -- we expect to be presenters at the Movement Disorder Society Congress. I can't actually remember where the congress is being held this here. I think it's in Sweden, like the ADPD meeting is. And we've put in an abstract on our MSA work there. So we do anticipate by September, most of the outcome of these studies will be known. And so that's likely to be the first place where it to be published.

Great. And next question, do you see an opportunity for more NIH funding for human trials?

Well, so far, the NIH is not -- so it's funny. When the pandemic hit, we had 2 trials, smaller aspects of the Phase I work that were favorably reviewed in NIH but the NIH captured the money from the SBIR program where we -- where businesses can apply because they had to provide a full year funding to support every student post-doctoral associate and faculty member who can no longer conduct research in the United States due to the COVID pandemic. Since then, a clinical trial money has been hard to come by. We've put in several grants, they have not succeeded because reviews change every cycle. And now our trial work is too expensive. So because in Phase II programs, it's hard to do that. So we've gone out to both private foundations and we'll go back to NIH to fund some of the things like the commercial tablet formulation because we think the tablets will have a unique advantage, and we want to show that advantage. That's a valid trial effort at a reasonable cost for NIH funding. But trials that cost $10 million, we're not going to get funded by the federal government to a for-profit business. And so -- because they just simply won't provide funds at that level for full profit businesses. We'll have to do that through either strategic partnerships or through equity sales in the future if needed.

Great. Two more questions in the queue so far. Next question, how is the prodrug being developed?

Well, so we talked last week in a press release, and because there was a lot to talk about in neurogeneration, that's why wouldn't include it today -- 001Pro is now about midway through its bioequivalence trial work, what's known as the 501 trial on our website. We've dosed 3 of the 4 escalation cohorts. The outcomes have been outstanding. We've seen 3 adverse events with prodrug that were all insignificant. We've seen 4 adverse events on the standard of care dose. So as we escalate, we're starting to see a separation between the two. We will complete the fourth dose escalation in the month of April, and then we'll have a confirmatory study done conducted between mid-May and mid-June to confirm that we have the equivalent dose. Once the equivalent does is known, there'll be 2 branches that this will take. One is that we'll go first to the FDA, and we'll begin -- we'll open up a discussion with the FDA on the parameters for approval of that drug because it can be approved and what's known under the 505(b)(2) statute, if you have bioequivalence. From a commercial perspective, however, that's not good enough in our opinion. We need to show superiority over standard of care. There are 2 ways to show that. One is to add a fifth dose escalation cohort by comparing 600-milligram imatinib, which is now becoming a more common dose for treatment, and the delivery of 600-milligram imatinib by project. Most people cannot tolerate 600-milligram imatinib mesylate. If the tolerance is significantly better, depending on how it's defined for the prodrugs delivery of that dose, that will be a game changer for the treatment population. And separately from that, we plan to -- we design, but we've not yet implemented a trial in CML patients, where we will cross them over from treatment once a day with prodrug for a period of time and then treatment once a day at standard of care dose for a period of time and see what the adverse event profile and tolerability profile looks like between the 2 different dosing periods. That's an activity we're likely to do with a strategic partner. Once we know what the parameters are for approval, we'll be going out to the marketplace and seeking a strategic partner for the commercial phase. That's not something we would do on our own current resources.

And last question I'm seeing in the queue. In what ways could 14809 punitive effect on intracellular aggregates be demonstrated?

Well, we're doing that. So we've done that in animal models because we can take out the brains and the GI tract, and we can go into the tissues and look exactly where the aggregates are and show they've been reduced or cleared, which is what I showed in the slide deck. In humans, we're doing the same thing. We'd like to do it in the GI because, obviously, you cannot biopsy a human brain while people are living. So the problem in the GI is that this aggregates reside sort of mid wall thickness in your GI tract near the end of the stomach, all the way through the colon, in our esophagus, in your throat. And so because the aggregates are in a place that will require a deep penetration into the tissue, you used to have [indiscernible] as the only option a preparation. So you punch a hole through the tissue but you're not going to do that very easily in people who are 70, 80, 90 years of age, who are all going to be on blood centers most likely. And so -- because that creates a bleeding risk as well as other problems. So under development with a couple of investigators that we work with is to do full thickness biopsy without perforation, but those are still experimental surgical procedures that we cannot yet implement. So instead, at least for the moment, what we're relying on is what happens in the skin. Your skin has all kinds of peripheral nerves, the things that you know when you poke yourself or bumping to something feel pain. Well, it's been known for many years now and highly validated that synuclein aggregates in Parkinson's disease and other diseases like MSA, deposits synuclein aggregates in those peripheral nerves. They're accessible with a standard punch biopsy that would maybe go down 3 millimeters from the surface of your skin. We've validated with a partner 3 different locations in which we can take skin samples and look for synuclein aggregates presence or absence -- it's hard to interpret whether syndicate aggregates are reduced in frequency or density, if you will, because there's no way to calibrate that with regard to progression of disease. But if we're seeing the effects that we saw in the animal studies, meaning we see clinical benefits that correlates with protection of neurons, that correlates with recovery of function then we ought to expect to see that in tissues of disease like the skin where the peripheral nerves reside, we should be able to see reduction or elimination of synuclein aggregates themselves. No one has ever measured how fast they accumulate in the skin. And so -- and no one has ever had an opportunity to remove them from the skin by an oral treatment or by any treatment for that matter. So it's completely experimental science. We started doing skin biopsies in the 201 trial already before the trial was briefly halted and it will be commonly done across most patients. It is an optional activity for most patients, but there was good voluntary participation in that. So I think we'll learn a lot on the 201 trial about how informative it is, and whether we see correlations of benefit with removal of synuclein aggregates over time.

Great. And one more question. Will you make a public announcement when the 1409 PD data for the 200-milligram dose is submitted to the FDA later this month?

Yes, we will. It should be -- we have a meeting scheduled in early -- the first week in April, which is a safety review committee meeting. I probably would not put out a press release until the safety review committee, which is an independent group of physicians has the same view that the company does about the parent safety, but we didn't see anything that was surprising in 200 milligrams. We've explored even higher doses in healthy subjects and in patients and on the 201 trial, we had 3 subjects that were dosed between 2 and 11 weeks at 200 milligrams and had no meaningful adverse events. The missing piece of data, what I've not seen yet is the pharmacokinetic profile itself. That is presently being measured from the blood samples that were drawn. We should know that data next week. So we'll put out an update to the trial once we have that data submitted.

Perfect. At this time, there are no other questions. So I will turn it back over to you.

Great. Well, thank you, everybody, for participating today. Hopefully, you all got a deeper understanding, even though there was some heavy science there that not everyone is familiar with and some use jargon. What I hope what Joe and I have been able to show you is that we are a strong, healthy company. We have robust transformative activities ongoing that are different than every other company on the planet, and there's no guesswork involved in our approach to treatment. We've proven the treatment can be effective. And now we're in the process of trying to improve whether that treatment is effective in human beings. And over the next 24 months, we expect to have really robust outcomes that could be very promising for patients in the future. Thank you all for your attention.