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 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 wanna thank everybody for taking the time today. I know we're all busy, so appreciate everybody participating.
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. 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. All of what we're talking about today is focused on our neurogen disease program, which are our new programs in the company. Just as an aside, I will be making forward-looking statements. I'll be presenting some unpublished data, in fact, you should be paying attention to all the necessary risk factors associated with our public filings with the Securities and Exchange Commission that are readily available.
At least 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. It has progressed to Phase II. We recently published in Science Translational Medicine a fundamental paper showing how and why Parkinson's disease is initiated and why c-Abl will emerge as probably the most important target in our minds. We'll also kind of 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 drug substance to use for oral 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 148009 based on our work. 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. 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. 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.
The Phase II program already underway in Parkinson's disease, covering a series of indications, and now with the IND open direct to Phase II in MSA. Parkinson's disease is a really large market indication. The recent Lewin Group report, which was contracted by The Michael J. Fox Foundation for Parkinson's Research 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 or most 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's patient is about a third of their lifespan or 25 years. It really does have a devastating effect for 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 two to one. We don't know why that is. It's not related to your X or Y chromosomes, which define maleness, femaleness or maleness, respectively. 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 an aging human being and as you get into your, the latter third of your life. Many people in the United States have joint diseases. Psoriasis, arthritis are very common ailments these days. Virtually every US male has cardiovascular disease because we are, after all, a hamburger-based or maybe now today, Chick-fil-A-based society. As a consequence, our overconsumption of foods in that class really do lead to significant challenges because we worry about what other medications you'll be taking and how they may cross-react with an Abl kinase inhibitor for Parkinson's disease. All of the patients with Parkinson's disease will go on to significant dementias, and many, if not most, will all go on to full-blown Alzheimer's disease.
For us, what we wanted to do was to provide some background. How did Abl get identified as a role in Parkinson's? Many people ask us this. We really have not illustrated this in detail in the past. Probably the first thing to understand is what Abl itself is. This is sort of like a section plot of the different functional domains that a scientist defined about Abl and a closely related isoform we call Arg or Abl-related gene, also known as ABL2. Both of these are called non-receptor 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 Abl activation.
For instance, cancer treatments such as the allosteric inhibitors developed by Novartis, GNF-2 and GNF-5. GNF-2 is now a third-line medication for chronic myelogenous leukemia that's Gleevec resistant. When you activate Abl, you now unfurl at least a portion of the polypeptide. You autophosphorylate at a specific tyrosine residue. 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. We have an easy way of doing that. We monitor Abl activation in this fashion. 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 former Parkinson's Institute, now in separate groups at Arizona State University, at the University of Bordeaux, at the University of Vienna. 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. 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.
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. We had to be able to place those aggregates both within the brain and within the GI tract, the two major organs of disease, in a manner that allows the disease to progress on its own in the animal. Then we would wait, often 12 months, to read quantitatively what happens. Let's take a look at some, what some of those results look like. These results were some of which were recently published in Science Translational Medicine in January. One of the first results was to find out whether or not c-Abl itself was an essential component of the disease process.
Here we've got is a picture of all the different neurons present in the two hemispheres of a mouse brain. We have one hemisphere where we do not introduce the defect and another hemisphere where we inject either an expression vector for this form of synuclein or we express protein. 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 Nissl or TH. You can see that at the six-month time point, you lose about half the neurons in the space, and that's visibly evident. What was surprising to us, and this was based on some hypotheses before this work, the importance of c-Abl was known, is that if you genetically delete c-Abl in these animals, you can delete it in the brain specifically.
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. 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 journal Brain. That allowed us to now develop new ways of analyzing what would happen with Abl activation and inhibitors of Abl. We used an acute neurotoxin, a classic experiment in neurology. It's an injected drug called MPTP for short. Happens to be a component of the agricultural pesticide paraquat.
What we did is developed a way to pre-treat animals or to monitor animals, do our neurotoxic injections, and then read out what happens. The way we screened drugs in our portfolio that had very equal abilities for inhibiting c-Abl, here called 148009, which is listed here as 09. 148027 was another molecule of very similar activity. 1427, a molecule we're using for non-dopaminergic nerve, cell, treatments, all equivalent drugs. 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 there's significant c-Abl activation because what we're measuring here is the relative amount that occurred.
If you pre-treat the animals with 1489 during a three-day pre-treatment period, you can see that Abl activation is totally suppressed to baseline because this is the baseline level on the left. Whereas the other two drugs, 14832 or 14827, neither of which really suppressed Abl activation in these neurons. Quite surprising to us was dopaminergic neurons in the brains are selective. There is some selectivity, we don't know its 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 of Parkinson's disease and was completely negative. That was not unexpected. Nilotinib has very limited activity for suppressing Abl, even in this context.
Whereas the anticancer agent dasatinib, because it's a very potent inhibitor, can do quite a good job. It's just not applicable to Parkinson's patients because of its side effects. 148009 is about equally good. Because of the selectivity and because of the potency of 148009 when given orally, through this type of experiment, really had a way of identifying the right inhibitor to pursue more detailed studies. Here's an example of just how compelling the effect is. I'm showing you now two 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.
If you pre-treat those animals with 1489 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. I want to be clear, it's not as if we took these animals on the left, injected them or fed them 1409, and they became the animals on the right. This is a pretreatment experiment. That 1409 was able to block the neurological effects of the toxin MPTP in real time. The contrast in these effects are rather striking. 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-secreting neurons, like in Parkinson's. Abl is essential for initiating disease progression.
We know if you delete the gene, you cannot induce neurodegeneration in animals. If you use inhibition as a prophylactic, you can block induction of neurodegeneration profoundly in this context. How do we then go forward with 1409 and bring forward its therapeutic potential in Parkinson's disease? As some of you know, if you've 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 at the 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 cause nausea, diarrhea, vomiting in the GI or gastrointestinal tract, and also can suppress white blood cells. We wanted to have high potency and a wide therapeutic dosing range, so we knew that many different types of doses could potentially be effective. 1409 emerged from that process. When we asked what was the relative inhibitory potential of drugs such as those I discussed in the MPTP experiment and compared 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 pan-Abl family inhibitors, they inhibit all 5 members of this family. 1409 was different.
It only inhibits ABL1 and ABL2, which I described previously. 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 10 times higher than necessary for full saturated inhibition of c-Abl in these neurons. 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. That boded very well for a potent inhibitor that could be selective and be given chronically to human beings. We wanted to now characterize just how good a therapeutic was.
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 Translational Medicine. The way we measure this is that when we give a defect in one hemisphere, these animals really can only run in circles. If you stimulate them with a little amphetamine, they tend to run in circles, you know, much faster when they have specific defects, much slower when they still have both sides of their brain active. In the wild-type state, animals that are performing in this experiment do about 25 circles in 10 minutes. 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.
That's illustrated here in these two 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 lines, so they run in circles very rapidly. Now getting up to about 100 circles in 10 minutes. If you start treating these animals after four weeks and read them out just three months later, so that's at four months of age, you've now gone back almost to the full effect of the drug, reversing the functional deficits that the synuclein aggregate introduction introduced. It's a durable response. You see that same level at three months that you do at 6 months.
Once you start dosing, and if you maintain that dosing for long periods of time, you maintain the functional response. We can also see that in terms of recovery of dopamine secretion, dopamine neurotransmission. Here you lose substantial amounts of dopamine neurotransmission, about 3/4 of the total dopamine secretion present in the mouse brain in the disease state. You get back about half of the lost dopamine secretion in the recovered state. 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. We have a specific effect on the activation of Abl, which is monitored by this phosphorylation at tyrosine 245, whereas wild-type Abl remains roughly intact.
We can also look at the effect of neuroprotection in these animals. Again, looking as we did previously at a c-Abl knockout context. Here's what the normal brain looks like in this mouse. Here's what the lesion side looks like. You can see there's a substantial loss of all the neural density. Here it's quantified. You lose about 85% of the neurons in the disease state. Again, if you therapeutically treat beginning four 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. Again, this is just two independent measures measuring them by two different markers for this type of neurons. One other fact that was really quite striking in these things is that we not only see suppression of c-Abl activation, we see neuroprotection, we see recovery function.
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 latter aggregates in different mice, in the animals that have not been treated with drug. Here's what happens at the end of 6 months in animals that have been treated with drug for two independent markers of synuclein aggregates in the affected neurons. Here's where you can see it's quantified. What's striking about this is that our goal for treatment in neurodegenerative diseases like Parkinson's has been to do clearance of these aggregate proteins. By targeting the treatment to within the affected neurons, we can recover most of the lost function and clear the underlying pathology.
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 in neurodegeneration animals with disease. I'll illustrate those in the next slide. Abl inhibition also can reduce or clear the underlying pre-protein pathology linked to alpha-synuclein that correlates with the disease effect. We've published previously what all of these downstream effect pathways are like. The only point I want to make here is that we can suppress all those downstream events that's illustrated in both this paper and in the Science Translational Medicine paper. The clearance that we're getting of these synuclein aggregates are through endogenous or natural normal intracellular processes.
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. As many of you know, we've talked about the 113 patients. There 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 now 95 subjects and a total of 25 Parkinson's patients, half of whom were on Parkinson-related medications. We really focused on a earlier group in terms of their age.
Many Parkinson's patients are 80 and 90 years of age. Because this is an unknown drug, when we started this two years ago, we were reluctant to go into older age groups that could be more fragile or have less of an ability 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 two and five adverse events per patient or per subject per day of dosing at different levels. Here we saw 18 total, and of those, only seven of them could have had any relationship to the drug.
Most importantly, none of the persistent GI problems, nausea, diarrhea, vomiting, that happens in all, in half of all patients who take imatinib, nilotinib, or dasatinib. For cancer treatment, for example, they don't appear in these patients. No QTC or other cardiovascular abnormalities appear in these, any of these subjects or patients. No suppression of white blood cells, no hematological adverse events appear in any of these cases. This was a very promising set of observations. It would let us go into Phase II in the middle of last year. These are what all those adverse events look like. Just three among healthy subjects, just five among Parkinson's patients.
The palpitations that were emerged in one subject at a single dose of 75 milligrams was a complaint that emerged two weeks after the subject left the clinic. That was in our observation window. There was no clinical core that found. When we began the analysis of this patient's complaint, all the complaints went away and have been away since then. That's now two years later. At the highest dose we evaluated, we had two instances of diarrhea, and that was it. Among the Parkinson's patients, we had one person with elevated amylase or lipase. This is a known sporadic occurrence among people who take Abl kinase 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 one person who failed to take food with their dose at home, so they got a stomachache and nausea. We had one 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 seven days dosing cycle. They were given BENADRYL once and then continued dosing without any further occurrence. A really, you know, 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. What's gonna 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 148009 usage into another indication known as MSA or multiple system atrophy. That hold was lifted at the end of January, about under two months later. 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 three months that we think will take 12 months to enroll. 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 three doses.
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 now been measured, and we'll complete and submit the data to the FDA at the end of March. We'll begin the implementation of the 200 milligram dose, along with the other two 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 three months period. Secondary endpoints in 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 three months period, they continue to be eligible for continuation of the study. That will include the same hierarchy as we had before, measured every 3 months during the extension. What's gonna be different between the three months period and the 12-month period is that while we'll 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 in the CSF per se, because we don't think those represent organs of disease. 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 gonna looking at time to initiation of Parkinson's 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 c-Abl in addition will actually lengthen the time it'll take before you have a need to go on other supportive therapy. In a fantasy world, that time could become infinite. We don't really know whether that's gonna 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.
They're constantly going to be balancing their ability to stay off Parkinson's meds, stay on IkT-148009 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. 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.
We have a sort of delayed initiation of the 200 milligram dose because that's the easiest way to maintain our current state of activities without more IRB approval changes. We can do that work and introduce it at a later date without a statistical penalty. 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 two months period. We also introduced in the press release related to 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 had no comments in the first half of 2022.
What prompted their interest was that when we go from three months to six months in our chronic studies in rats, we had an increase in the frequency of minimal or mild changes in the retina in the eye. Because we saw that and we didn't know if it would occur in humans, we were already going to implement that monitoring plan, and we did implement monitoring plan before the hold actually was issued. 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 was already a sort of standard program for vision monitoring that had been known.
There are at least eight approved kinase inhibitors that are not in the Abl class for which vision monitoring was part of either the trial work or is a mandate even post-market. We've adopted the same monitoring program of the eye. All of the tests that were implemented in the monitoring program are standard tests in an ophthalmology office. Other than the inconvenience that the enrolled patients will have in visiting two clinical sites instead of one periodically, this is really not a burden on the trial. It does add considerable work to the trial sites. That's why it's taking about two months to get the trial sites back open. Once the trial sites are back open, there'll be 20 sites open immediately and 10 more sites that are still completing contracting.
We've added five 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. We had dosed at all three doses planned in this trial for up to 11 weeks. That's an encouraging sign, but it's an insufficient data set to know that this won't become a problem in human beings. 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 Inhibikase from every other company that might be working in this space is that we gate all of our clinical efforts by demonstrating therapeutic efficacy in animal models of the human disease. We strive to get animal models of human disease that are quite robust, that really represent what's going on. We've done that in an MSA. We've been talking about that work that's been ongoing, haven't shown any results from the last year. Well, now there are results that are emerging, 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, what's the difference between Parkinson's and Parkinson's-like disease is called MSA? Parkinson's is a slow to progressive disease, about 25 years to death.
MSA is very rapid. Eight years to death is common. Faster timeframe to death is also common. You have a lot of interpatient 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 on the market that really could benefit an MSA patient in real time. Diagnosis of PD has become quite easy. MSA diagnosis is very difficult to diagnose early. That creates challenges to the trial activities.
There are many cases in Parkinson's disease, about one million U.S. prevalent cases. There are only about 20,000 cases in the U.S. overall. 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 affected neurons, that's not where they end up in MSA. In fact, they end up in a migratory cell known as a glial cell. Glial cells play a number of critical roles in the brain. They form the myelin sheath, that sort of insulator around every nerve fiber in the brain and in the periphery.
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. About two years ago, we published the fact that in 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 two different markers for these modified forms, the most important of which is the tyrosine phosphorylated form. Tyrosine phosphorylation arises from c-Abl activation. By seeing in postmortem patient brain, in both an area of the brain known as the putamen, as well as in the substantia nigra, that we can see evidence of these 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 migratory cell. Working with Jeff Kordower's lab, with whom this paper was published at the end of 2021, we also showed in monkey models that those aggregates also appear. We can reproduce the 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. We've been working for a while. This is one of several different tests that are done. 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.
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. What you're measuring is how many errors or slippage that they have. Here we've broken out what happens with male and female mice. This particular defect is introduced transgenically, which means we introduce the defect genetically, and then we breed those mice. From the moment the brain develops, the defect starts to get introduced. 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 five slips per measurement time. The animals that have the lesion developing have the same number.
The cohort of animals that were gonna be treated have the same number of male and female. Now if you look seven 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. The animals that have been treated with drug do not get worse. 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 1409 have a higher absorption and distribution in female mice relative to male mice. This is an effect of dose response between male and female mice.
We're following these mice for another 12 weeks. That means sometime in May, these mice will be sacrificed, we'll evaluate what's going on in the brain in the manner that I showed previously in Parkinson's. 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 that's shown the same outcomes, we have a separate model that's underway but has not yet started dosing. We're kind of encouraged. We haven't yet lifted the gate for the clinical trial. I can tell you that we know that Abl activation is a disease that occurs more prominently in many different diseases.
Not just in a 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. These are future growth areas for Inhibikase as we begin to demonstrate that 1409 and other drugs in our portfolio are active in neurodegenerative disease. We'll 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. What does the Phase II program in MSA look like? We have not yet initiated this. This is why I don't really indicate what month this is. Again, we're gonna have a 6-month double-blinded enrollment period, where safety and tolerability in these patients will be the primary endpoint. A different hierarchy of activities, notably looking at orthostatic hypotension.
That's a blood pressure drop in going from a lying to a standing position. looking at different blood markers that are specific for MSA treatment effects, such as the, what's known as the neurofilament light chain or NfL. 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. Just as we've done in Parkinson's disease, we'll also look at aggregate formation.
Let me give you some guidance for what's happening in nerve regeneration, and 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 the 201 trial. 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 our commercial formulation. We have two different tablet forms that are ready for clinical testing. We expect that clinical testing to begin in the second or third quarter, depending on availability of clinic time. We need to also analyze what's known as a food effect, because drugs in this class are very non-polar or very fat loving.
We have to make sure that 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 meal. In MSA, we're going to complete both prophylactic, so pre-treatment 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 we're going. We hope to initiate the Phase II program in the US 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. We'll look at that in the future depending on the outcomes of these studies. 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 Q three of 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 Q one 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 on 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 for human clinical trials. 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 two objectives. Number one, to uplist on Nasdaq, and number two, to commence our human Phase I clinical safety trials. Those trials went extremely well and quickly. In June of 2021, went back out 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.
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 one share of common stock and one common warrant. As you look at that January 30th 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 8.8 just pre-funded warrants. That was a single institutional investor, and they took 2.8 million shares, and the rest in pre-funded warrants.
The options you see there, four million options are plain vanilla, issued over the years to employees and directors, in the ordinary course of business. 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. Again, pretty clean cap structure and cap table. No debt, no preferred stock. Nothing, out of the ordinary.
Thanks, Joe. Now I want to open the floor to questions. We'll have Julie Seidel and Andrew Diamond from Stern IR will be meeting those questions, and we'll be reading them and we'll answer as many as we can for the next 20 minutes or so. Go ahead.
Thanks, Milton. 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 minutes, and we will see what we get.
Great. Well, even if turn out to be no questions today, we 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. In contrast to what many people have experienced with changes in the agency's performance, we managed to lift a clinical hold in under 50 days of cross five different clinical programs. I think that just reflects our knowledge that 1409 looks to be a so far a very promising agent with a good safety and tolerability profile. We do not yet have, you know, a full safety profile and long-term dosing to state that it's a safe molecule, but it certainly looks promising. It's been associated with no clinically meaningful adverse events.
Great. Thank you, Milton. 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. 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 are both diseases characterized by a misfolded protein that is non-essential. In Alzheimer's, it's known as amyloid beta and tau. In Parkinson's, it's alpha-synuclein. 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 failed to reduce incidence 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 two approved drugs.
One, Leqembi, did reach clinical statistical significance, but a very small effect and a large dynamic range. What the Parkinson's model studies that we've published recently demonstrate 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 delete c-Abl, you can't get disease to initiate at all. What that tells us, in the 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 studies, and we published this now over the last several years, in two key papers you can get from our website, one in Movement Disorders from 2022, one from Science Translational Medicine.
What those papers say is that these aggregates are internalized. Synuclein aggregates are internalized and modified by c-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 phosphorylation occurs at two different points, one of which appears to be the pathological form. From a competitive landscape, we think it's wide open. We know of only one other company that's actively pursuing at Phase II or later trials in the c-Abl inhibitor space for Parkinson's disease. Those trials have been trying to enroll for three years. Results have not yet known.
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 in Parkinson's is right, we should be pursuing these diseases by attacking it within the affected 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 than to attack disease that's already present. Those methods could be complementary to ours.
I think the landscape for success in neurodegenerative disease is just wide open. Right now, at least in our view, and obviously biased, is we have demonstrated and highly validated why this form of therapy that we've 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.
Thank you. Next question. What is your updated cash runway following the January raise?
Joe, what's the guidance we can give? We're gonna put out, you know, our earnings report in a week. Go ahead.
Right. When we guided, first week of February, we filed the resale registration statement and guided that we project into the fourth quarter of 2024, post the January raise.
That's just about two years cash.
Great. Next question. Based on the new RAMP data, will the MSA trial focus on female patients preferentially?
No. Those are my data, just to be clear. As I said at the outset, is that drugs in this class, all drugs, not just 1409, but all Abl 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'll take longer because the effect of the drug is not as close to saturation. 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. What human beings show for 1409 is that absorption in men and women are the same, and they are the same as they are in female rodents.
We have no reason to do a gender preference in the overall study. That's just a quirk of how these drugs are absorbed by the GI tract of mice and rats.
Thank you. Next question. When and how do you plan to release results from the disease model experiments with IkT-148009 in MSA?
That's a good question. 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. we don't know what the full outcomes are gonna be realized. In end of September of this year, we expect to be presenters at the Movement Disorder Society Congress. I can't actually remember where the Congress is being held this year. I think it's in Sweden, like the ADPD meeting is. we've put an abstract on our MSA work there.
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'll be published.
Great. Next question, do you see an opportunity for more NIH funding for human trials?
Well, so far, the NIH has not. It's funny. When the pandemic hit, we had two trials, smaller aspects of the phase one work that were favorably reviewed at NIH. The NIH captured the money from the SBIR program where businesses can apply because they had to provide a full year of funding to support every student, postdoctoral associate, and faculty member who could no longer conduct research in the United States due to the COVID pandemic. Since then, clinical trial money has been hard to come by. We've put in several grants that have not succeeded because reviews change every cycle. Now our trial work is too expensive. Because in Phase II programs, it's hard to do that.
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 wanna show that advantage. That's a valid trial effort at a reasonable cost, for NIH funding. Trials that cost $10 million, we're not gonna get funded by the federal government to a for-profit business. Because they just simply won't provide funds at that level for for-profit businesses. We'll have to do that through either strategic partnerships or through equity grants, equity sales in the future if needed.
Okay, two more questions in the queue so far. Next question, how is the prodrug being developed?
We talked last week in a press release, and because there was a lot to talk about in neurodegeneration, that's why we didn't include it today. IkT-001Pro is now about midway through its bioequivalence trial work, what's known as the 501 trial on our website. We've dosed three of the four escalation cohorts. The outcomes have been outstanding. We've seen three adverse events with prodrug that were all insignificant. We've seen three adverse events on the standard of care dose. As we escalate, we're starting to see a separation between the two. We will complete the 4th 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 dose is known, there'll be two branches that this will take. One is that we'll go first to the FDA, and we'll open up a discussion with the FDA on the parameters for approval of that drug because it can be approved 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 two ways to show that. One is to add a fifth dose escalation cohort by comparing 600 milligram amantadine, which is now becoming a more common dose for treatment, and the delivery of 600 milligram amantadine by prodrug. Most people cannot tolerate 600 milligram amantadine mesylate.
If the tolerance is significantly better, depending on how it's defined for the prodrug's delivery of that dose, that will be a game changer for the treatment population. Separately from that, we've designed, 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 two 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.
Great. Thank you. Last question I'm seeing in the queue, in what ways could 1409's putative effect on intracellular aggregates be demonstrated?
We're doing that... we've done that in animal models 'cause we can take out the brains and the GI tracts, 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 on the slide deck. In humans, we're doing the same thing. We'd like to do it in the GI because obviously we cannot biopsy a human brain while people are living. The problem in the GI is that these aggregates reside sort of mid-wall thickness in your GI tract, near the end of the stomach, all the way through the colon, in your esophagus, in your throat. Because the aggregates are in a place that would require a deep penetration into the tissue, you used to have as an only option a perforation.
You'd punch a hole through the tissue, but you're not gonna do that very easily in people who are 70, 80, 90 years of age, who are all gonna be on blood thinners, most likely. Because that creates a bleeding risk as well as other problems. 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. 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 bump into something, and you 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 deposit synuclein aggregates in those peripheral nerves. They're accessible with a standard punch biopsy that would maybe go down three millimeters from the surface of your skin. We've validated with a partner, three different locations in which we can take skin samples and look for synuclein aggregates presence or absence. It's hard to interpret whether synuclein aggregates are reduced in frequency or density, if you will, because there's no way to calibrate that with regard to progression of disease.
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 no one has ever had an opportunity to remove them from the skin by an oral treatment or by any treatment for that matter. 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. I think we'll learn a lot in the 201 trial about how informative it is and whether we see correlations of benefit with removal of synuclein aggregates over time.
Great. One more question. Will you make a public announcement when the 148009 PD data for the 200 milligram dose is submitted to the FDA later this month?
Yes, we will. Should be, We have a meeting scheduled in 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. We didn't see anything that was surprising at 200 milligrams. We've explored even higher doses in healthy subjects and in patients. In the 201 trial, we had three subjects that were dosed between two and 11 weeks at 200 milligrams and had no meaningful adverse events. The missing piece of data, what I have 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. 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 usage of some jargon. 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. 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 prove whether that treatment is effective in human beings. 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.