Good afternoon and welcome to the Grace Therapeutics KOL event. At this time, all attendees are in a listen-only mode. A question-and-answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player. As a reminder, this call is being recorded, and a replay will be made available on the Grace Therapeutics website following the conclusion of the event. I'd now like to turn the call over to Prashant Kohli, CEO of Grace Therapeutics. Please go ahead, Prashant.
Thank you. Hello everyone, and welcome to the Grace Therapeutics KOL event on GTx- 104. GTx- 104 is a novel injectable formulation of nimodipine that is in late-stage clinical development. We will be making forward-looking statements. Please review our SEC filings for details on risk factors. A quick overview: I would like to remind everyone that the company recently rebranded from Acasti to Grace Therapeutics. Our pivotal Phase III trial for GTx- 104 , called STRIVE-ON, was fully enrolled this past September and is on track for data readout in the first quarter of 2025. Our agenda for today: key objectives. Start by describing the life-threatening disease aneurysmal subarachnoid hemorrhage, or aSAH, which is the target indication for GTx- 104 . Second, outline the challenges associated with the only FDA-approved drug in aSAH, a calcium channel blocker called nimodipine.
Lastly, to discuss the market opportunity for GTx- 104 , which is the first-ever aqueous peripherally injectable formulation of nimodipine, to help address the large unmet needs with the oral capsule and liquid solution that are on the market in the U.S. It is important to note that there is no FDA-approved parenteral dosage form of nimodipine. We will begin with each of the panelists today presenting their prepared remarks and then transition to the Q&A session. We have an exciting panel of two thought leaders from the field of neurosurgery and neurocritical care. I'm honored to introduce our two panelists: Dr. Abhishek Ray, M.D., practicing neurosurgeon at University Hospitals and holds a faculty position at Case Western Reserve; Dr. Andrew Webb, Ph.D. in neurocritical care, pharmacist at MGH with research interest in acute brain injury and works extensively with the hospital P&T Committee on drug formularies.
We will next start off with Dr. Ray's prepared remarks.
Hi everyone. My name's Abhi. I'm a neurosurgeon here at University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine. I do open cerebrovascular and endovascular surgery for aneurysms. And I just wanted to give you kind of a quick introduction to the disease process that nimodipine is targeted towards. Just very quickly, the layman's term of stroke is kind of a big umbrella. There's ischemic stroke, which is what we usually use the word stroke for. There's intracerebral hemorrhage, and then there is subarachnoid hemorrhage, which is usually related to aneurysm when it's spontaneous subarachnoid hemorrhage. And aneurysms occur usually at branch points. This is a Circle of Willis where our blood vessels and the brain supply the brain, and they can occur at these different locations. The prevalence is about probably 2-8% of patients in the population have aneurysms.
The rupture risk depends on size, location of the aneurysm, morphology, smoking history, family history of ruptured aneurysm. There's a lot of factors, but in general, it's probably about only 0.5%-1% per year. This can cause subarachnoid hemorrhage, but sometimes intracerebral hemorrhage. This is kind of a classic when we teach the medical students. This is like we call this the dead chicken sign of subarachnoid blood in the cisterns of our brain. That is the bright areas that represent subarachnoid blood. It does have a significant global public health impact, and it's severely morbid and often deadly. Overall, worldwide incidence of aneurysmal subarachnoid hemorrhage is around 6 per 100,000 person-years. Incidence of death is very high when an aneurysm ruptures.
So it's important to note that even though the risk of an aneurysm rupturing on a day-to-day or year-to-year basis is relatively small, when it does rupture, it's extremely morbid and often fatal. Pre-hospital mortality for aneurysm rupture for patients that aren't even getting to the hospital is somewhere between 22%-26%, and an additional up to 20% of patients who do end up getting to the hospital still succumb to the disease. As our population ages, aneurysmal subarachnoid hemorrhage may be an even more significant public health burden. The incidence of aneurysm rupture increases with age, particularly in women over 55. To diagnose the cause of subarachnoid hemorrhage and where the aneurysm is and its morphology and how we're going to treat it, we usually start off with CT scans and CT angiograms, and sometimes we'll get formal catheter-based angiography.
Here's an aneurysm of the right middle cerebral artery that has ruptured and caused a bleed on the right side of the brain that's causing mass effect and will need surgery. There's a couple of different treatment options for aneurysm rupture. You can do craniotomy. Here's a case that we did where we did a right-sided craniotomy where you can see the optic nerve and the carotid artery next to it, and there's an aneurysm that has ruptured, and we put a clip across the neck of the aneurysm, and this is the temporal lobe on the right side, and the frontal lobe is being retracted away, and that will basically make the risk of this aneurysm bleeding again very unlikely, and we like to treat ruptured aneurysms preferably within the first 24 hours of presentation. Here's an aneurysm that we coiled.
We had to use a couple of different balloons to get the coil to stay in the aneurysm and not into the parent vessels so the parent vessels would stay open, and this is coil embolization of ruptured aneurysms. There are multiple complications that can happen with aneurysm rupture. Even when a patient comes in and you treat the aneurysm, whether it's by coiling or by microsurgical clipping, and they're doing great, you can sometimes have patients that are on their cell phone or on their tablet in the neurocritical care unit doing really well, and then they can deteriorate from vasospasm and delayed cerebral ischemia a week later, but yes, aneurysm rupture can cause hydrocephalus or high fluid pressures in the brain, vasospasm, cardiac ischemia, neurogenic pulmonary edema. We neurosurgeons love grading scales.
Here's one of many of them, but this is the Hunt and Hess scale that tries to predict mortality and how serious the aneurysm rupture is. As you can see, the survival rate goes down very quickly for high-grade subarachnoid hemorrhages. Here's another couple of scales, modified Fisher and Fisher scales, basically representing the thickness of the blood matters, and the thicker the blood and the basal cisterns where our blood vessels run, the more risk of vasospasm and delayed cerebral ischemia, so the narrowing of the arteries that happens with aneurysm rupture is associated with DCI and infarction. It occurs in about 30% of patients, mostly between days 4 and 14.
This is why even a very good, healthy patient that has had aneurysm rupture that is overall neurologically doing very well, again, on their phone, talking normally, wouldn't even know that this patient had an aneurysm rupture, are kept in the neurocritical care unit for an extended period because this can happen and they can go down quickly, and our goal is to prevent that as much as we can, and we know that DCI is associated with the worst outcomes when it does happen in the setting of aneurysmal subarachnoid hemorrhage. Nimodipine is, we know, beneficial in preventing delayed cerebral ischemia and improving functional outcomes. It's the only drug approved by the FDA for neuroprotection of patients with this disease. Here's kind of a typical case. I thought it would be illustrative to just show this is a case I did.
29-year-old woman, no significant past medical history, teaching her second-grade class, suddenly felt the worst headache of her life, noticed to be confused by staff and had nausea and vomiting, left-sided weakness by the EMS staff, but this resolved by the time she got to the ED. On exam, the patient was somnolent but arousable and oriented, following commands. Cranial nerves were intact. CT scan was done, which shows blood in the subarachnoid spaces. This is the Sylvian fissure on the right side where the middle cerebral artery sits, so we can kind of tell this is likely going to be a middle cerebral artery aneurysm rupture. Got a CT angiogram that shows this aneurysm sitting there on the left side of the screen. That's the right side of the patient with blood surrounding it.
We decided to do a craniotomy and microsurgical clipping of the aneurysm and also try to get rid of some of the blood clot. Her brain was very full, and we actually decided to leave the bone off temporarily and put it back on at a later time via cranioplasty just because of the amount of swelling there was. She did extremely well right after surgery. It was following commands, full strength, eating full meals. But then on day three, had acute onset of left-sided weakness. A CT head was done stat. This didn't show any changes. Her transcranial Doppler studies, which tries to predict vasospasm, was a little bit elevated. We took her down urgently to angiography, and sure enough, she did have narrowing of her blood vessels or cerebral vasospasm with delayed flow. This was treated endovascularly, and she got better. She had hypoxic.
She became hypoxic, tachypneic, tachycardic. She had bilateral crackles in her lung bases, and she eventually was intubated for hypoxic respiratory failure, which is not uncommon in the setting of aneurysm rupture, and developed Takotsubo cardiomyopathy, which is reduced ejection fraction of the heart, which can also be seen with aneurysm rupture that does resolve with time, and the patient was treated with pressors and treated again intra-arterially for additional vasospasm that she continued to have on that right side. She eventually did actually very well and was discharged home, actually with just home healthcare and a completely neurologically intact state on day 21 after she came in, and then she eventually went on to have her bone flap replaced, but with her own bone graft a month later and went back to work and teaching her second-grade class.
That was a good win, but it kind of illustrates the problems with aneurysm rupture. There is nothing more frustrating to a cerebrovascular surgeon than treating an aneurysm, the patient's doing great, and on day seven or day eight, the patient has some sort of severe vasospasm, DCI event, and has a big stroke. And this patient did very well, but I have a patient right now in the neurocritical care unit who didn't. We did a clip to her aneurysm, was doing well, and didn't get to the vasospasm in time, has a large stroke. She will likely never be functionally independent. And it's a horrible, horrible disease. And anything we can do to move the needle with vasospasm, I think that's what I've been studying and have been involved in multiple trials even since really training. So yeah, I hope that was informative and helpful.
Great. Thank you so much for that fantastic introduction to aneurysmal subarachnoid hemorrhage. So as Prashant introduced, my name is Andy Webb. I'm a clinical pharmacy specialist in neurocritical care here at Massachusetts General Hospital. I have a bit of a unique role as a clinical pharmacist in that I have patient care responsibilities where I'm integrated as a pharmacist on the medical team in the Neuro- ICU, rounding with the medical team and helping to make decisions about the plans for our patients, including aneurysmal subarachnoid hemorrhage patients on a day-to-day basis. But as a pharmacist, I also have, of course, an important role in medication delivery and the medication use process where part of my role is helping to ensure the medications that are important for our patients get to the bedside, they're being used safely and effectively.
We're monitoring our patients for side effects, toxicities, drug interactions, and ensuring that our patients are prescribed the right medications. And lastly, I also, as a critical care specialist, have an administrative role in ensuring that we have the most appropriate and effective therapies available for our patients as well. And as a clinical specialist, I help liaise with our Pharmacy and Therapeutics Committee with bringing new therapeutics onto our formulary so that they can be available to our patients. And as a neurocritical care clinical pharmacist, aneurysmal subarachnoid hemorrhage, as Dr. Ray spoke to, is one of the most challenging disease states that we face on a day-to-day basis. It's a disease state that has a very poor prognosis in certain patients and very excellent prognosis in other patients. But unfortunately, we're still limited in the therapeutic options that we have for these patients.
As we've talked about, nimodipine is currently the only FDA-approved medication for aneurysmal subarachnoid hemorrhage, and desperately, we're looking for new therapeutics to help advance and improve the outcomes of our patients, and so for the next few minutes, what I'm going to do is really talk about the challenges as well as opportunities for nimodipine, particularly with our patients admitted with aneurysmal subarachnoid hemorrhage in the Neuro- ICU, so to start, as we've mentioned, nimodipine is the standard of care medication therapy for patients with aneurysmal subarachnoid hemorrhage. Nimodipine, which is an oral dihydropyridine calcium channel blocker, has been found in multiple randomized controlled trials to improve functional outcomes in patients with aneurysmal subarachnoid hemorrhage, reduce the rates of strokes, as Dr. Ray mentioned, and hopefully improve functional outcomes long term.
What's been found is that patients who have ruptured aneurysms who are prescribed nimodipine tend to have a higher likelihood of achieving functional independence or at least have better functional outcomes when they're given a full 21-day course of nimodipine after their aneurysm rupture. Because of the quality of these data, nimodipine is supported by multiple, really all major national treatment guidelines for aneurysmal subarachnoid hemorrhage. So here on the left is a snippet from the 2023 American Heart Association aSAH treatment guidelines with the highest level of evidence and highest level of support, saying that patients with aneurysmal subarachnoid hemorrhage should be given enteral nimodipine to prevent delayed cerebral ischemia and improve functional outcomes. Additionally, the 2023 Neurocritical Care Society aneurysmal subarachnoid hemorrhage guidelines on the neurocritical care management of subarachnoid hemorrhage conclude additionally that nimodipine should be administered to all patients with aneurysmal subarachnoid hemorrhage.
Now, you'll notice that enteral nimodipine or oral nimodipine is mentioned here simply because that is the only formulation that's currently available for our patients. But despite that, nimodipine through the oral formulation is actually a quality metric to be accredited as a Comprehensive Stroke Center. So the Joint Commission or other accrediting bodies which accredit hospitals to rate the quality of the care that they provide aneurysmal subarachnoid hemorrhage patients say that initiating nimodipine within 96 hours is essentially a required metric to demonstrate that you're providing quality care to your patients. However, oral nimodipine as the only available FDA-approved agent for aneurysmal subarachnoid hemorrhage has multiple challenges, particularly in the ICU. The ICU is a dynamic place. Patients come in in a variety of clinical states. Things change rapidly.
We respond to changes in vital signs, changes in neurologic exam, and many other factors of the patients on a minute-to-minute basis. And having only an oral medication available as the standard of care is a big challenge to our patients in the ICU for a number of reasons. So first, nimodipine is a bit of a challenging medication from a pharmacokinetics perspective, which as a pharmacist is something I think about quite a lot. And because it's a relatively short-acting medication, it requires very frequent administration from bedside nursing. The standard dosing algorithm for nimodipine is giving a 60-milligram capsule or a 60-milligram oral solution dose every four hours.
So you can imagine a bedside nurse having to give a dose of the medication every four hours for 21 days, which is oftentimes the duration of time the patients are in the ICU, and that is the studied duration of time that nimodipine is given for these patients. However, as we'll talk about in a moment, nimodipine is not always well tolerated at that dose of 60 milligrams every four hours. But because it's so important that patients get that dose, we'll oftentimes even give lower doses more often simply so that we can ensure the patient is getting the medication that we know is effective in this disease state.
And so while 60 milligrams every four hours is the standard administration, sometimes we'll also give 30 milligrams every two hours to our patients, meaning up to 12 administrations a day for nursing to have to give that either via the oral route or down a nasogastric or orogastric tube. And importantly, the reason that we oftentimes fractionate those doses is those oral doses being given every four hours will frequently affect hemodynamics. So as I mentioned, nimodipine is a calcium channel blocker. Calcium channel blockers is a large group of medications, class of medications, which is classically used to treat high blood pressure. So medications like amlodipine and other medications in a similar class are used in the outpatient setting for patients with hypertension.
But nimodipine is quite unique in that it tends to have a higher likelihood of dilating the blood vessels in the brain, which is why it's specifically used for aneurysmal subarachnoid hemorrhage. However, it still has that class effect of lowering blood pressure. And because our patients with aneurysmal subarachnoid hemorrhage can be quite sick and quite dynamic, sometimes the decrease in blood pressure that we do see with nimodipine can be unacceptable and borderline dangerous. And what we've seen is that up to 25% of patients who receive, maybe even more than 25% of patients who receive nimodipine, will experience significant hypotension with the oral dosing. Hypotension significantly enough that it requires intervention with IV fluids, IV vasopressors, or other measures to support those patients' blood pressures.
Oftentimes when that's happening with the 60 milligrams every four hours dosing, those are the patients that we end up fractionating the dosing or potentially even having to stop giving it entirely because it may be unsafe to continue it in those specific patients. Additionally, as you might assume, the exclusive availability of nimodipine as an oral product is itself a large challenge. At least 30% of patients with aneurysmal subarachnoid hemorrhage present to the hospital with some degree of dysphagia or difficulty swallowing; it may not be able to swallow the standard of care gel capsules that nimodipine comes formulated in. Many of these patients will inevitably require either a nasogastric tube placed, which is a soft tube that's placed through the nose down into the stomach for medication and nutrition administration, or if they're sick enough to require intubation, as Dr.
Ray mentioned, they may have a tube put through their mouth called an orogastric tube, and so the capsules are not able to be put down those tubes, and they may need the oral solution prescribed, which can have its own set of complications and side effects. However, some patients may not have any enteral access at all, a smaller portion of these patients, of course, but may not have the ability to have medications put down into their gastrointestinal tract, and thus giving nimodipine is not an option at all. An additional complication that's more frequently seen with the oral solution is gastrointestinal intolerance, so nimodipine is a difficult-to-solubilize medication, and so the oral solution is basically co-formulated with what's effectively a laxative to make it stay in solution and able to be absorbed through the GI tract.
And so because of that, up to 80% of patients who receive the oral solution product experience significant gastric intolerance, including diarrhea, which could include placement of invasive devices to manage the diarrhea and is additional work for nursing as well. And lastly, and perhaps most importantly to me as a pharmacist, the formulation of nimodipine itself can lead to extensive variation in how much of that medication the patient is exposed to, whether it's because the medication is actually sticking to the feeding tubes it's being administered to, or the patient is on vasopressor agents, which may affect the ability of the medication to be absorbed through the GI tract, or they're on concomitant medications, which may cause drug interactions that may increase or decrease the exposure of the medication.
It's very difficult to predict just how much of that medication is actually being exposed or actually being absorbed and how much the patient is actually being exposed to the medication. And so we know from the randomized controlled trials, which have shown that nimodipine is effective in aneurysmal subarachnoid hemorrhage, that that full exposure to 21 days is most important. But currently, the exclusive availability of an oral formulation does provide a significant limitation in our confidence in patients actually being exposed to that full course. And because of this, when you look at a population of patients with aneurysmal subarachnoid hemorrhage, less than half of patients actually receive that studied 60 milligrams every four hours, 21-day course of nimodipine. And that is quite problematic because what's been shown in retrospective literature is that patients who do not get exposed to that full course may have worse outcomes overall.
Now, these studies are sometimes confounded by multiple factors, including sicker patients may not be able to get the full course, but in this figure that I have here on the slide, in blue in this bar chart, are the % of patients who experience a secondary stroke, kind of secondary to that delayed cerebral ischemia that Dr. Ray mentioned. This is one of the feared complications that we want to avoid as much as possible in our patients who present with aneurysmal subarachnoid hemorrhage, where the orange bar here represents the patients who survive their admission without an infarction, and on the Y-axis, basically, this is broken up in the first two bars are patients who have relatively lower severity aneurysmal subarachnoid hemorrhage characterized by a Hunt and Hess score of one to three.
And the bottom two bars are what we call high-grade subarachnoid hemorrhages or patients who have a Hunt and Hess score of four or five. And basically, the top bar are patients who have received a reduction in their nimodipine course, meaning they do not receive that full 21-day course of 60 milligrams every four hours compared to patients who do receive that full exposure. And in lower-grade patients, full exposure to the full 21 days is associated with a significant reduction in infarction, which would constitute a very good outcome in our patients. And in the higher-grade subarachnoid hemorrhage patients, while the difference was not statistically significant, there's a large numerical difference in so far as patients who received that full course, even when they were high-grade, tended to have a much lower likelihood of being discharged with an infarction.
When they kind of pooled all of these data together to try to see what's the association of receiving that full course with having a good outcome as measured by the modified Rankin score, which is a standard scale used to measure functional independence or disability levels in patients with strokes, having a reduced dose or reduced exposure to nimodipine over that full 21 days was significantly associated with having a poor functional outcome after discharge, really just highlighting the importance of consistent and continued exposure to nimodipine in our subarachnoid hemorrhage patients. The availability of an intravenous product could address many of these notable limitations of oral nimodipine in our critically ill patients. First and foremost, nimodipine is already accepted as the standard of care for aneurysmal subarachnoid hemorrhage patients.
The new availability of intravenous formulations of commonly used medications is common practice in the ICU. So in other patient populations, I frequently take care of our patients with severe seizures known as status epilepticus. And many of the seizure medications that we use for those patients, we have both oral and IV medication formulations that we use interchangeably. And particularly in our sickest patients, we often will preferentially use the IV formulation because of its guaranteed exposure to that drug. Next is the titratability. And so in the ICU, we love flexibility and titratability. We like to be able to respond to what's going on with the patient on a minute-by-minute basis. And because nimodipine has fixed dosing at 60 milligrams every four hours or 30 milligrams every two hours, it doesn't allow us to really titrate exposure to what's going on at the bedside.
And the IV formulation may give that ability to really make sure we're tuning the medication to that patient as much as possible. In the same vein, the IV formulation provides flexibility, both from a hemodynamics perspective, being able to adjust doses but try to maintain as much exposure as possible, or being able to really use the medication at the bedside, especially in patients who may not be able to either take or tolerate the oral formulation. And then lastly, consistency is one of the next most important things about an IV formulation. Any medication given intravenously is 100% absorbed into the bloodstream. And so we know that dose that we're giving that patient is getting into the patient, getting to where we need it to be to try to have that good clinical outcome.
It's much less liable to absorption issues with nasogastric or orogastric tubes or gastric motility problems that we oftentimes see in our subarachnoid hemorrhage patients. And so suppose this medication were to be successful in its clinical trials and would be approved, kind of what would be the next steps for this to actually make it to the bedside so we might be able to use it for our patients? And so any new medication that's approved by the Food and Drug Administration needs to undergo a pharmacy and therapeutics or P&T review process. And so after a drug is approved by the FDA, a physician champion would request formulary addition, basically seeing the benefits of this particular medication in a patient population that they treat.
That data supporting that medication would then be presented to the committee, which is made up of a multidisciplinary team of physicians, pharmacists, nurses, really all of the kind of contributors to patient care that involve medication use. That presentation tries to weigh the cost-to-benefit ratio, the clinical benefits, seeing whether or not it's something that makes sense in the population that institution treats. The committee then votes for approval, and so the committee, again, is made up of a multidisciplinary group, not just neurology or neurosurgery physicians or clinicians, and if approved, it's then operationalized and used at bedside. Now, oftentimes, new therapies, particularly that are kind of changing some other standard of care, will be added to formulary with what's called a restriction criteria. Essentially, what this means is this is going to be added to formulary for use in appropriate or specific clinical circumstances.
And so you can imagine an IV formulation of nimodipine might be added to formulary for patients who can't get the oral capsule or have some intolerance or inability to absorb the oral formulation. And so this is something that's oftentimes addressed or added to formulary addition requests in order to make sure that it's not being used for extraneous uses or not kind of straying from what's been studied in specific clinical circumstances. And so really, in conclusion, nimodipine is already the gold standard treatment for aneurysmal subarachnoid hemorrhage. And timely initiation in all aSAH patients is a quality metric for Comprehensive Stroke Center s. So the introduction of a new nimodipine formulation that allows more flexible and titratable use in our patients would expand the therapeutic arsenal for a critical population that we're really trying to find new avenues to improve their outcomes.
Next, oral nimodipine has multiple limitations, which are well known to neurocritical care clinicians. Administration access, tolerability, inflexibility, and pharmacokinetic variability are hallmark characteristics of the only drug that we have available for our patient population. And lastly, the adoption of a potentially new intravenous formulation of nimodipine would require hospital P&T approval, which involves vetting the published research, assessing the cost-benefit ratio of the medication itself, and potentially applying appropriate restriction criteria to limit inappropriate or unsupported use. So hopefully, this gives you a little bit of context about what the real role of oral nimodipine in the ICU is and what our major limitations of that agent is and what kind of the path forward for a potential IV formulation might look like in some of our sickest patients.
Thank you. So at this time, we'll be conducting a question-and-answer session with our speakers. As a reminder to the audience watching on the webcast, if you'd like to submit a question, please use the Q&A text box at the bottom of the webcast player. So please hold for a moment while we pull for questions.
Thank you, Tiana. I'd like to request Dr. Ray and Dr. Webb to come back online. Thank you, Doctors Ray and Webb, for your insightful remarks. I would like to start by asking a few questions to the both of you before we turn to the audience. So let's start with Dr. Ray. First off, congratulations on being the highest recruiting hospital site in the STRIVE-ON trial. We greatly appreciate the diligence there. How was your overall experience participating in the STRIVE-ON trial? Any general observations or remarks that you would have?
Yeah, I think it's mostly just having really good study coordinators and having a hospital that's been recognized for stroke care and good aneurysmal subarachnoid hemorrhage care. I think all of that kind of put together led to this high enrollment. We treat about 50-ish, maybe more, ruptured aneurysms a year. And we have gone through multiple clinical trials in aneurysmal subarachnoid hemorrhage. Most recently, before this was the REACT study.
But yeah, I think just a combination of good study coordinators and a well-recognized hospital for treating this disease process is helpful. And it's a horrible disease. And when you go to patient families that we may have something that we don't know is better or not, but we're doing a trial, and it's the one standardized, one FDA-approved drug, but in an IV formulation, we may have better success with it.
We may be able to continue it and have less palatability of the medication, and the only way you would be able to get this potentially is by enrolling in the trial. A lot of families, I think, are hopeful and want to enroll, so we had very few patients overall that met all inclusion criteria and whatnot that just said, "No, we don't want to enroll in a study for whatever beliefs they may have." We had very few of that, so.
Yeah, you had some of the lowest drop-off rates, so really, it speaks to volunteer commitment to research. Now, as Dr. Webb laid out, a very elegant case challenges issues with the oral potential fit for an IV. As you fast forward upon potential approval of GTx- 104 , as a neurosurgeon, how do you see its place in the clinical care continuum?
Yeah, I mean, I think that, like Dr. Webb said, about 30% of patients have dysphagia. I think that in my experience, that percentage is even higher for some reason or another. Someone may come in swallowing and eating fine, like this patient that I presented, which was a real case. Even after the aneurysm was treated with open surgery, she was eating full meals and everything like that, but then had some of the typical complications of aneurysm rupture, flash pulmonary edema, takotsubo cardiomyopathy, things like that, where it ended up getting intubated. And then that patient now needs either enteral or peripheral intravenous medications. And so I would say that percent of patients that will not get the classic oral q6-hour dosing of nimodipine is at least 50% at some point in their hospital course, a lot of times throughout their entire hospital course.
So those are the potential patients that this is really going to, I think, take off in the sense that this is a, it's an efficacy study. It's not comparative. And I think comparative studies will be done down the road. And so, but from a neurosurgical neurointensivist standpoint, it's going to be something that I think the majority of centers will want in their formulary because a lot of the things that Andy pointed out about just how the bioavailability and everything like that and how titratable it is, there's a reason why the majority of medications used in the neurocritical care setting in patients who have aneurysm rupture are IV, right? If we're controlling blood pressures preoperatively before the aneurysm is secured because we want their blood pressures very low, we don't want the aneurysm to re-rupture until it's secured with either coils or clips.
We're not giving them oral blood pressure medications, right? We're controlling it with IV titratable stuff, like usually IV nicardipine or something like that to keep their blood pressures down until the aneurysm is secured. There's a reason for that, right? Because it's more titratable and it's more controlled. And I think that's naturally the direction things are going to go when this does become available in IV form.
Thank you for that. Really appreciate the level of complexity with these patients. Unfortunately, very high mortality and morbidity, as you highlighted. Clearly, there is a fit here for IV, given there are other analogs. You mentioned acute antihypertensive therapy as one that the surgeons and physicians are very comfortable working with and to have that level of flexibility.
So I'd like to bring Dr. Webb into the discussion. You touched upon a lot of different aspects of the challenges with the oral and enteral formulation of nimodipine. You also touched upon pharmacokinetic variability. Maybe you can touch upon that a little bit more. Oftentimes, pharmacokinetics doesn't quite get the level of visibility at a clinical level. But given your expertise as a pharmacist and as a key influencer into the P&T decision-making process, how do you view the very high PK variability? And we saw that in our multiple Phase I trials of GTx- 104 , the bioavailability less than 10% with very high inter- and intra-subject variability of plasma concentration. So I would love to kind of have you provide more thoughts or comments around the clinical ramifications of a high PK variability and low bioavailability, potentially via the enteral route in particular.
Yeah. And so I think the real principle here is that a patient can only respond to a medication if they're exposed to it. And with the oral formulation, to your point, I mean, A, the oral bioavailability in the best of circumstances, healthy volunteers who are taking this is very poor. It's less than 10% oftentimes. And so of that oral formulation, only a very small percent is even going to be absorbed. And of that amount that's absorbed, as you pointed out, there's quite a bit of variability due to either changes in gastric motility, drug interactions, concomitant medications the patient might be on. And subarachnoid hemorrhage patients themselves are quite variable. There's so many things that go into the likelihood of them experiencing vasospasm, of them experiencing delayed cerebral ischemia, of them experiencing hemodynamic alterations.
And the variation in nimodipine, be that because of underlying organ dysfunction or drug interactions, the things that I've already mentioned, likely plays a role, is one of those variables that may influence the likelihood of a patient doing well or not doing well. And so I think consistency in kind of removing one of those variables is just a really important factor for us to try to take the best care that we can of our patients. And so I think one of the main advantages of IV medications is that we know that the patient is getting the drug that we're prescribing and we're administering to that patient. And we know at a population level that nimodipine is beneficial, improves outcomes in our aneurysmal subarachnoid hemorrhage patients. But we know that some of our patients still do poorly.
And if we can just remove one of those variables of not really knowing whether the patient's actually seeing the maximum effect of a drug by ensuring that they're getting an IV dose of that, I mean, that's a win for our patients, for sure. And I think, as Dr. Ray mentioned, there are many examples of us in critical care being very comfortable, potentially more comfortable using intravenous medications because we can titrate them. They're flexible. In the ICU, we respond to changes minute to minute. And when you give an oral dose of a medication, you may not see the effect for 30 to 60 minutes. And if the effect is too much, say they're getting overexposed to the medication, you're really stuck with that decision for hours.
And the advantage to this particular IV formulation is that you would have the ability to respond to something that's happening or changing on a minute-to-minute basis, which likely has significant clinical ramifications to the positives for our patients with aneurysmal subarachnoid hemorrhage.
Great. Thank you for that. In the interest of managing time, I'd like to bring some audience questions into the mix. Tiana, do we have anyone online?
Yes. Thank you, Prashant. So our first question will come from Chase Knickerbocker at Craig-Hallum. Please go ahead, Chase.
Oh, good afternoon. And thanks, everybody, for doing this. Maybe just first to kind of put a finer point to it and kind of question, I guess, both Dr. Ray and Dr. Webb , kind of a little bit more detail on kind of how you specifically kind of think about the potential clinical value with the IV formulation here with GTx- 104 . How do you kind of think about kind of the biggest benefit, the biggest kind of game changer for you guys from a standpoint of bypassing the oral route versus not having to worry about incomplete doses on the NG tubes versus convenience for staff?
And then also on the side of kind of the fact that, again, dose-limiting side effect of hypotension, being able to modulate the IV real-time, kind of how do you weigh kind of all those benefits and what's kind of most important to you?
Thanks. So I'm happy to start, and Dr. Ray can come in. I think from my perspective, it would be extremely beneficial to have the IV formulation. I mean, I think solely just to start off, patients not actually being able to get the oral formulation for a variety of reasons, be that through our enteral access or they're not tolerating the PO formulation, just having an extra option to be able to give the med, period. It would be extremely helpful in a pretty large percentage of our patients.
I think Dr. Ray mentioned my clinical experience as well, is that over the course of the patient's 21-day stay, easily over 50% of the patients either can't get a dose because of dose-limiting hypotension or they lose enteral access or some other reason, and being able to put them on the IV formulation and just know that they're going to be getting the drug would be amazing.
I think as clinical experience evolves, particularly if we see dose-limiting hypotension being less common with the IV formulation, I would not be surprised if this is something that is kind of started and then potentially as the patient stabilizes, particularly our sicker patients, maybe get de-escalated to an oral formulation. And I think so I can see a clear role immediately once this gets added to the market. Yeah, I do too. I think that you have to remember that what was actually studied was this 60 milligrams every six hours. And that is often not what happens because of dose reduction and things like that. And a lot of patients, because they have hypotension from 60 milligrams, will go to 30 q2. And that's actually not even really been proven or to show that this actually improves outcomes like the original dosing that the FDA approved.
So I think that, and in fact, there's some evidence that dose reduction does change outcomes for the worse. So I think, yeah, having something that will be utilized right away for these patients. Yeah. Sorry, go ahead, Chase. I'd like to.
Yep, got it. And maybe just also kind of paging through studies, we see hypotension rear its head very frequently. And it seems to rear its head even more so in kind of the more severe clinically presenting patients. Can you just kind of talk about that, Dr. Ray, in your kind of clinical practice?
Yeah.
So, I'm going to see that as well. And then also to Dr. Webb and Dr. Ray , just on the back P&T Committees, would this be something where very, very arduous advocacy on your parts to get this added to your formulary and kind of which patients in particular, kind of broad spectrum across the patient set, their specific patients, just kind of talk through that color as well. Thanks.
Yeah. I think to answer your first question, the hypotension and it being more associated with higher-grade subarachnoid hemorrhage patients, that I think is multifactorial. A big factor of that is because patients with high-grade subarachnoid hemorrhage, we're talking Hunt and Hess grade or if you want to use World Health Organization grading, that's fine too.
The higher the grade and also higher the Fisher grade, which is the thickness of the clot in the basal cisterns where the blood vessels are, the more likely the patient is to have vasospasm, the more likely they are to have DCI and infarction. So those are the patients where you are often. It's relative hypotension, right? It's not just hypotension. These are patients that once they have vasospasm, we are often adding pressors to keep their blood pressures 160, 180 systolic, well above normal. So when we're talking about hypotension, and this was in the trial too, we're talking about holding nimodipine because nimodipine is dropping their new target systolic blood pressure.
That's why a lot of times patients with higher-grade subarachnoid hemorrhage will have dose reduction or halting the dose of nimodipine altogether. This is because we're having to keep their blood pressures for brain perfusion purposes at such a high level that we're kind of chasing our tail. We're giving a medication that's dropping their blood pressures, and then we're giving pressors to augment their blood pressures. I think because of that, something IV that's titratable one-to-one, like along with the vasopressors we're giving to keep their blood pressures up, is going to be that much better. It's very difficult to titrate that in oral form, right? Those are the patients I think that it's even more important than the low-grade subarachnoid hemorrhage patients.
Yeah. I think just to briefly expand on that point, the blood pressure effect, particularly when a patient is in spasm and we're pressing them to higher blood pressures, hypotension from nimodipine is classically a peak effect, meaning that you get the most deleterious drop in their blood pressure when the oral formulation absorption peaks, and then it will gradually get better as the medication is eliminated, and so the availability of an IV formulation would hopefully allow us to modulate that peak and be able to not have the patient exposed to such a high concentration for a brief amount of time, but over the course of the day, what we would call the area under the curve would be consistent, so we know the patient is still getting exposed to the medication and less likely to develop hypotension from that peak effect, so to speak.
So that's another really big advantage of an IV formulation where we can kind of have it in the background and still manage the vasospasm as we typically would either with IV vasopressors or sending them to the angio suite for intra-arterial verapamil or something along those lines.
Let's bring on Oren Livnat. I see he has a question into the mix as well. Go ahead, Oren.
Hello. Thanks for taking my questions. I have a few. You guys have made pretty clear and obvious the theoretical benefits of this product. And I do want to follow up on how that translates into a real-world adoption in the institution. But first, maybe for Dr. Webb, if you're allowed to even comment on this, and maybe you're not, but given this is an open-label study with very different treatment modalities, I know the data themselves are certainly blinded. But with regards to just your experience and the ICU staff, intensivists, and your experience with this product, do you have any early feedback just in terms of ease of training, incorporating into ICU recovery care, just any feedback in general with your experience with the product? Or is that not something you can speak to?
No, I can. I mean, I think this is the neurocritical care space. There's patients that are in the ICU. There's just a wide variability for aneurysmal subarachnoid hemorrhage. You may have the patient that is ordering lunch and on their laptop doing work while they're in the ICU, and they feel like they're being kept hostage. And then there's the patient who has high-grade subarachnoid hemorrhage intubated with probably six, seven different drips going.
And so the aneurysmal subarachnoid hemorrhage patient in the neurocritical care unit may be the healthiest, most awake person in the unit and doesn't even look like they belong in the neurocritical care unit. And the only reason they're there is so that we can closely watch them neurologically in case they do go downhill from a vasospasm standpoint, and we can act early on that endovascularly. Or they are the absolute sickest patient in the unit with tubes and lines all over the place, maybe the sickest person in the hospital. And so the critical care unit where this drug would be administered is very used to a patient with IV dose titration of multiple different medications, whether it be anti-epileptics, blood pressure medications, antihypertensives, or vasopressors to increase, augment their blood pressure, whatever it may be, so many different things, sedating medications.
So yeah, I think that analgesic medications, fentanyl, propofol, blah, blah, all of this stuff. So I think that from an ease of adaptability for this medication into the ICU, it's like a nothing, right? It's like adding another IV blood pressure medication into the onslaught of stuff that you already have. So I think adaptability is not even an issue.
Okay. And I guess without beating around the bush, obviously, certainly when I and investors think about these products, which is different maybe than how you would look at the physicians and in the institution, we've all experienced how difficult it is to get new therapies into hospitals and onto formulary, regardless of what on paper is the value proposition. So I'm really just curious what you can tell us in this particular setting, in this for a life-saving drugs and setting, pretty rare.
How does cost factor into these decisions versus parenteral generics, which are obviously less optimal? How challenging is it to get it through formulary, the P&T process? And then if it does, Mr. Ray, you mentioned it might be first restricted, but I'm just curious, what does it take? What do you need to see from a data perspective or real-world evidence before you can say, "Guys, let's take the reins off of this and let people use this better drug"?
Yeah. I mean, it's a great question. And that's the elephant in the room, right? Is this actually going to get into the hospital for patients to be able to use? And I think hopefully this will answer Chase's question that we didn't have time to answer as well. And so I think this is unique where I think I'll give you kind of a corollary example.
I'll give two corollary examples that kind of went one direction, one in the other direction. And so a recent P&T decision that I was involved with was adding medication ravulizumab to our formulary. So ravulizumab is a monoclonal antibody that is used for a variety of autoimmune conditions. And it is exorbitantly expensive. It is notoriously a very costly medication. And that decision was very important. That aspect was very important for us to decide whether to add the medication to formulary. But the key caveat is that the administration or the consideration of using that medication was really strictly for outpatient use. So this would be for patients, let's say, myasthenia gravis or some other autoimmune condition where the use or the consideration for using that medication would only be for an infusion clinic.
And so the decision for P&T was to restrict, basically not allow the use of that medication in the inpatient setting and only consider it for the outpatient use after insurance approval and all these sorts of things. So oftentimes for those sorts of medications, payer availability or payer acceptance, and whether it's available in the local insurance formularies is a large driver of whether the medication or therapy will be available for use. An opposite corollary example would be a medication, intravenous brivaracetam. So this is an anti-seizure medication that has an oral option. It's used both inpatient and outpatient. And the intravenous formulation of that is really exclusively positioned to be used in the inpatient setting, be used for critically ill patients who can't get their oral formulation. And this is a replacement for a very important medication that we want to continue the patients on.
And so I think for that medication, also a relatively costly product, was, to your point, sometimes difficult to get through the P&T committee because there are "cheaper alternatives," but still got approved with reasonable restriction criteria, patients on the medication at baseline or has failed other therapies and can't take the oral formulation. And I think nimodipine is closer to that camp and even further where essentially the exclusive use of nimodipine is in the inpatient setting. It's also essentially a requirement to have some form of nimodipine available to be a Comprehensive Stroke Center . And we all know that oral nimodipine is poorly tolerated in a large portion of our patients. And so I think most, if not all, Comprehensive Stroke Center s, basically all Comprehensive Stroke Center s are going to have to at least consider it simply because it's the only medication that's available for subarachnoid hemorrhage patients.
It's well known how poorly tolerated the oral formulation is. So I think the data in the stratified trial will be very informative as to exactly how we would make that cost-benefit analysis because that will certainly be a part of the P&T decision. But I think that it will be relatively straightforward if the data kind of reveal themselves in the way we expect them to, that this is a beneficial product that should be added to formulary. I think kind of the threat, so to speak, from a SWOT analysis perspective is exactly what those restriction criteria would be. I think most centers are going to have reasonable ones, if I were to guess. Speaking from my own experience of looking at these sorts of medications, you would probably restrict it to the disease state that it's been studied in.
So it would be restricted to the use in aneurysmal subarachnoid hemorrhage patients and likely be restricted to patient populations that either can't take or are intolerant of the current standard of care, the oral formulation. And as we've discussed, that's a large percent of the patients that we treat. A large percent of our patients experience significant, potentially life-threatening hypotension. A large percent of patients either can't swallow the tablets or have uncontrollable GI intolerance. And I think hopefully the IV formulation will be positioned to really be the preferred alternative for those drugs. And because that medication is exclusively administered in the inpatient setting and is already the standard of care, I don't think we're going to really hit many of the same roadblocks that we see with much more expensive outpatient use-only kinds of medications that are oftentimes rejected from P&T committees.
Okay. You did mention data, right? This is a little bit unusual that there's quite a streamlined pathway here, hopefully, with, I guess, a pivotal safety trial. We're not doing relative efficacy now. So you know what to expect, hopefully, here. In your experience, given this context you've described thoroughly already, barring pricing that's just totally unacceptable, do you think that non-inferior or no statistically different rate of hypo specifically and just sort of, I guess, implied advantages or obvious advantages across the other attributes you've described is enough to get this into use across the P&T formulary finish line?
I think it might change how those restriction criteria are approached. And so, I think if it's the sort of thing where this just simply provides a convenience, the restriction criteria could be more stringent in that you wouldn't want as widespread adoption to every single patient if it's not abundantly clear that there's XYZ clinical benefit. But I still think that the simple operational advantages of the intravenous formulation would be compelling to get it through P&T Committees with restriction criteria for whatever makes the most sense based on the data that's available. That being said, I think as clinical experience evolves, those restriction criteria oftentimes become loosened as individual institutional experiences kind of become more comfortable with the medication.
So there are many examples of medications that get initially added to P&T under very stringent restriction criteria for either cost containment reasons or there's just simply not enough data to support in a certain population or a certain clinical circumstance. But I mean, these patients, as Dr. Webb has mentioned, they may be talking to you, eating their lunch, or they could be very much so the sickest patient on the unit. And so extenuating circumstances oftentimes drive us to use medications against or instead of the restriction criteria, considering what's going on with the patient. And as that's happened, I can very clearly envision a patient who's sick, can't get the oral formulation, so the P&T Committee has locked down the IV formulation to very stringent criteria. But it just makes sense clinically to use the IV that those restriction criteria are kind of lifted for that patient.
And as those experiences accrue, that P&T Committee may reevaluate the restriction criteria and change what's available. That's obviously sort of a looking glass sort of prediction, but that happens often with expensive medications that may not have the clearest path through the P&T. But as clinicians get experience with them and see that they work, it's kind of hard to argue against clinical experience. And I think most institutions will successfully weigh a cost-benefit analysis rather than just simply a cost analysis. And so if this is the sort of thing where it is X price, but it has clear clinical benefit, that cost becomes a little bit less important.
Oh, thank you.
Go ahead.
Well, you segued just into my last question, really, which is just assuming this is used and it sounds like there will be certainly receptivity there, assuming it's approved. Given your experience in this setting and how it's very guideline-driven and it's pretty rare and centers of excellence for the most part, how likely is use of this to perhaps just be protocolized top-down rather than physicians' choice and depending on the nurse, the ICU staff involved, and which shift it's involved? Do you think that if this gets in for appropriate patients, whether that's restricted to the sickest or whether it's ultimately all patients available, is it possible it will get a top-down either that says, "Hey, there's no reason to even take an oral here," and it's less likely to be successful than an IV?
I think that's certainly possible. I think that this is something that clinical experience will help dictate. I think every center approaches these sorts of patients differently, be that it's very individual to the patient or whether there's a protocol. It's certainly a likelihood that if clinical experience is clear that there is better tolerability, it's just simply easier, it's more flexible, that this is the default start, and then the oral formulation comes down the line or something along those lines. But I think that that will come with time.
Okay. Thank you.
Thank you. We are top of the hour here. Appreciate the questions. Sorry I couldn't get to all the audience questions here, but that was a great discussion. This concludes our KOL event. I would like to thank Doctors Ray and Webb for the insightful comments and discussion and the audience for participating. Goodbye for now and have a great day. Thank you, everyone.