Okay. Well, thanks to everyone for joining our 46th Annual Healthcare Conference. I'm Stacy Ku, part of the biotech team, with my colleague, Vish Shah, we'd like to welcome Prashant Kohli, CEO of Grace Therapeutics. Very exciting times for the company as Grace is fast approaching the April 23rd PDUFA date for GTx-104 and the treatment of aneurysm, subarachnoid hemorrhage, which we'll refer to as aSAH for short from now on, show the company is very much focused on the preparation ahead of commercialization. Before we dig into launch, maybe very quickly, could you provide some background on GTx-104, and really, have that interplay with the current standard of care to currently treat aneurysms and the value proposition, of course.
Thank you, Stacy. Thank you for hosting us today. Just start off with aSAH. The disease is a acute critical care disease. It strikes out of the blue in patients, unfortunately, has high mortality and morbidity. A third of the patients eventually do not survive, and a third end up with long-term morbidity. Typically, an aneurysm builds deep inside the brain unbeknownst to the patient, and it ruptures all of a sudden, creating a life-threatening condition. Ideally, the patients are taken to an academic medical center or a comprehensive stroke center where upon CT angiogram confirmation, a neurosurgeon would go in and physically secure the bleed. The patient is put on calcium channel blocker called nimodipine. It's the only FDA-approved drug known to improve outcomes in aSAH.
Nimodipine therapy is indicated for up to 21 days, has a heavy dosing burden administered every four hours, for up to 21 days. In the U.S., it's only available in the oral dosage form, either as a capsule or liquid solution, and both of them have significant clinical liabilities. This is where our innovation with GTx-104 comes into play. Bayer brought the drug to market in the late 1980s. They recognized back then this best delivered, administered via intravenous infusion, but the molecule is extremely hydrophobic, challenging to solubilize. The closest they came to solubilizing it was by using a lot of ethanol. That formulation was never approved in the U.S., is available ex-U.S. Because of the liability, you never took on as a standard of care.
Our team in New Jersey cracked the chemistry code and solubilized nimodipine, first-ever aqueous formulation that can be given as an infusion therapy, addressing a lot of the challenges associated with the oral formulation.
As you talk also about the oral formulation, the liquid Nymalize, what happens when a patient experiences significant hypotension? And when it comes to getting the full dose, what percentage are limited by that AE?
We'll start off with the three core issues related to the oral formulation of nimodipine. The first one you talk about was hypotension. It's a calcium channel blocker, class effect, blood pressure drop is common. In subarachnoid hemorrhage patients, they end up developing refractory hypotension, and what that typically leads to is frequent dose interruption of nimodipine therapy. In fact, over 90% of the patients do not receive the full therapeutic dose that they're eligible for during the course of treatment. It has a very high percentage of patients, majority of the patients that do not end up receiving the full nimodipine therapy. Only FDA-approved drug known to improve outcomes in this terrible condition, patients are not receiving the full therapeutic dose.
That's problem number one with hypotension. The second issue with oral has to do with poor pharmacokinetics, drug exposure. Nimodipine has high first pass metabolism. It has cytochrome P450 liability. The drug, especially in patients that are unconscious, majority of the patients are presented unconscious, they have ileus gut motility issues. The drug, when it's administered to the feeding tube for most of these patients that are unconscious, it's barely detectable in the blood, and it suffers from very high pharmacokinetic variability. In our head-to-head PK work, with IV and oral, the coefficient of variation was 2x-3x, IV versus oral, significant variability, not only across subjects, but even for the same patient. There is this diurnal variation effect that we identified for the first time with nimodipine.
Depending on the time of the day the patient receives nimodipine therapy, it's absorbed, its absorption rate is variable. Having an erratic, unpredictable absorption is a significant issue as well or challenge with oral. The third problem has to do with ICU workload management, nursing. As you can imagine, when patients develop hypotension, in addition to all the other challenges that the patient is dealing with, what starts off as a localized stroke quickly devolves into a pathophysiological multifactorial problem with these patients. Trying to manage that patient with nimodipine therapy, the oral solution that is available causes diarrhea. Managing that as well creates a lot of complications. It increases the cognitive workload in the ICU.
Over the past year, since we published our data from STRIVE-ON, we have spent a lot of time talking to physicians, to the quote-unquote "buying center," including pharmacists and nurses and P&T administrators. That's where the IV value proposition really tends to resonate.
Okay. That's a perfect segue obviously to the phase III STRIVE-ON study, a safety study. But just help us understand, what were the main goals of the trial, primary endpoint? Of course, sounds like you've been doing a lot of the really important work with the clinicians to understand their level of enthusiasm and potential use practices. Maybe, help us understand the data and then the KOL responses.
We'll start with the trial. When we met with the FDA pre-pandemic, the regulatory pathway was locked in at that point in time, and the agency has been very consistent ever since. Step one was a pharmacokinetic bridge study that we successfully accomplished in 2022, in late 2022. Step two that the FDA guided us to was a safety trial in patients, 100 patients, a comparative safety where we had to be numerically about the same as oral, 50 IV and 50 oral. Patients were randomized across 30 high volume academic medical centers in the country and the treatment period was up to 21 days. That's what the nimodipine label indicates for therapy.
There's a follow-up period, day 30 and day 90, for the STRIVE-ON trial. Those two follow-on periods is where efficacy measures were evaluated. Modified Rankin Scale is a gold standard efficacy measure in subarachnoid hemorrhage. It's a physician-administered efficacy scale. We also measured quality of life. That's patient-reported measure as well. Then, healthcare resource utilization was also collected. That was the overarching regulatory strategy and the last clinical trial that we conducted with STRIVE-ON.
Now, what are the KOL perspectives? Give our opinion first, and we'd love to hear obviously the most important feedback from the clinicians. We view the relative dose intensity outcome as most compelling, as from a very simple perspective, it means you're getting more drug into the patient, which presumably should translate to better outcomes as we talk about all these limitations around oral nimodipine and Nymalize. Clearly clinicians understand that nimodipine is the standard of care. Just help us understand exactly where the KOLs are glomming onto.
We'll talk about the data now for STRIVE-ON and I'll shed more perspective on your question. Our primary endpoint for the STRIVE-ON was hypotension, clinically significant hypotension events between the IV and the oral arm. We were numerically better on the IV arm. We had almost 20% patients with fewer clinically relevant hypotensive events versus the oral arm. The other measure you talk about, RDI or relative dose intensity, is a measure of how much dose compliance that a particular patient was in terms of the amount of drug that they could receive versus how much did they actually receive.
The RDI on the IV arm, we had almost 55% of patients that had 95% or higher RDI measure as opposed to on the oral was only 8%. Difference between majority of the patients on IV receiving nimodipine therapy as opposed to single digit on the oral arm. The next question which you ask, which is very, very, very logical, do we see any signal from an efficacy standpoint? We know that IV is predictable concentration, addresses all the pharmacokinetic issues that I talked about earlier, better hypotension, hemodynamic control, and much higher relative dose intensity. We do see an excellent signal from a recovery perspective from an mRS standpoint, Modified Rankin Scale.
Almost 30% patients on the IV arm had good functional recovery relative to the oral arm. Not only on the mRS scale, which is physician-reported, but also QOL from a quality of life patient-reported as well. For example, we had zero patients that were bedridden day 90 as opposed to almost 15%, 16% on the oral arm. That's a significant indicator of morbidity long term as well. We're very excited to see, you know, data hold up across multiple domains. In addition, we saw very strong pharmacoeconomic data as well. Fewer ICU length of stay days, fewer mechanical ventilation days. We collected eight pharmacoeconomic parameters. Every single of those eight were favorable to the IV arm.
To answer your question about the receptivity from a KOL physician standpoint, physicians are most excited about better hypotension control leading to much higher dose compliance, and we are seeing strong efficacy signals there. The administrator is really excited about the potential of reduced hospital resources.
Okay. makes a lot of sense from the clinician perspective. we do get some questions from investors on the baseline characteristics of the Hess severity as well as some questions on the AEs such as mortality. it's interesting the clinicians seem to have very little issue, but just help us understand what are the nuances in this specific patient population?
The baseline characteristics, we ended up with more severe patients at baseline on the IV arm versus the oral arm. Hunt and Hess Grade V, we had four patients on the IV arm versus one on the oral arm. The Hunt and Hess Vs have much higher, significantly higher, mortality and morbidity. In spite of that, when you look at the body of safety evidence from STRIVE-ON, we are very comparable head-to-head between IV and oral. The events, the safety events, including from an SAE perspective, very, very comparable. Because of some of the imbalance issues, we did end up with more patients that did not survive on the IV arm versus the oral arm.
The mortality rate, even on the IV arm, is far less than what is already on the label of nimodipine and what was part of the pivotal trials as reported in the summary basis of approval for nimodipine. To your point, clinicians, unfortunately, mortality is an expected outcome in this patient population. When you factor in some of the imbalance in severity levels, the overall safety profile is very comparable between the two treatment arms.
Okay. We're fast approaching the PDUFA date with a successful submission of the NDA. To the extent that you can comment, how are the interactions, regulatory interactions with the FDA, these days, in recent times, increased sensitivity to regulatory risks, to the extent that you can comment would be very helpful.
We had a pre-NDA meeting, about one year ago where we aligned with the FDA on our path for the NDA submission. Our NDA was accepted for review in the fall of last year with a target PDUFA date coming up in a few weeks, April 23rd. The interactions have been, the FDA has been very engaged in our file. A lot of questions back and forth ever since our NDA was accepted for review. Questions cutting across CMC, non-clinical, as well as clinical. Nothing that we have seen causes us any alarm or raises issues. We remain confident in our NDA application. And so far the FDA has been very active, actively engaged with our file.
Okay. You talk about all the different secondary outcomes that really should lead to reduced spend in the hospital at the end of the day. What are you and the company able to do now ahead of approval and launch to work with the key opinion leaders in the aneurysm space and stroke, and champions of stroke to really raise awareness of GTx-104?
Over the past several months, we have been spending a lot of resources and time and effort in terms of educating the market, shining light on the problem with oral nimodipine, the challenges associated with hypotension-related frequent dose interruption. The American Heart Stroke Association care guidelines clearly spells out nimodipine as Level I Class A evidence. They also correlate dose compliance with improved outcomes. We see strong signal playing out with the STRIVE-ON trial for GTx-104. We kicked off two major continuing medical education events in December. We have had 10,000 learners so far already between those two events. These are neurointensivists, critical care physicians, nurses, as well as pharmacists that have gone through the training.
In addition, last month, we launched a non-branded disease awareness site as well, asahinfocus.com. We presented our data at the seminal event medical congress for us, Neurocritical Care Society, in the fall of last year. We have two additional medical congresses coming up, very relevant for us, where we are presenting data and/or posters, the Society of Critical Care Medicine and the American Association of Neuroscience Nurses. Both of those events are coming up end of March that we are really excited about. That's where a lot of our work has been, is educating the market, physicians, nurses, pharmacists on the challenges associated with oral, the guideline recommendation, and the data from our work.
Okay. You guys have certainly been staying busy. Clearly, as you kind of outline all the different stakeholders when it comes to the decision-making of adding GTx-104 to the formulary, just maybe help us walk us through the idiosyncrasies for each hospital and what you're learning there.
Yeah, that's a great question because there are idiosyncrasies, and there is variability. Most people in general, investors, hospital sales driven by P&T committee, formulary, cost challenges, cost pressures, and so forth. You know, we're not necessarily immune to all of those, but we think that there are some exceptions here that deserve, warrant particular attention. First of all, the buying center, quote-unquote, we're treating a rare disease. The DRG reimbursement rate is one of the highest for a critical care illness across therapeutic category, tipping in at over half a million dollars. So it's a rich, you know, DRG from that perspective, and that goes on to show how challenging treating these patients are.
In terms of, you know, two different approaches here, one is a P&T-driven formulary process to onboard a drug into a hospital driven by a physician champion, where a hospital pharmacist then typically does a lot of the evaluation and presents to the pharmacy, to the committee, the P&T committee. What we're also finding out are a lot of exceptions. Major health systems have given a lot of autonomy, especially to this particular disease in the neurocritical care unit where they bypass the formulary process entirely and have the flexibility of onboarding a drug if they believe that's in the best interest of the patient.
The other variation to that, and based on the data that was presented at NCS, we had our SAB meet last week to synthesize the work that we have done over the past year, and they were commenting on getting texts from their physician colleagues about when IV will launch because they have a non-formulary requisition process where they bypass the formulary entirely to start trial of a certain drug. It was really encouraging to hear that perspective that physicians are looking at this and looking at different ways of getting their hands on the IV to experience that and look at the benefit and not necessarily be driven by the rigid P&T formulary process that we are all probably too familiar with.
It sounds like that would be an upside scenario for what investors typically view as a hospital setting. Understood. Of course, you all are at the same time also looking at the size of the market, doing a lot of work there when it comes to claim analysis versus the prevalence, who actually comes into the hospital, who gets treated. Just help us understand the latest thoughts there.
We've done a fair bit of work, you know, there in terms of looking at claims data, looking at, doing our own primary research in terms of the prevalence, the cases of aSAH, and it's a wide range. goes anywhere from 40,000- 70,000. Based on our work with STRIVE-ON where we had 30 sites, high volume sites, including a lot of interactions with other hospitals, we think a realistic number is closer to 45,000 in terms of the actual number of cases of aSAH in the country. We're looking just for the U.S. market as there's an upside potential ex-U.S. as well.
Even within this patient population, our value proposition is very clinically strong and relevant. Number one is hemodynamic stability, number two is exposure reliability, and number three is ICU workload management and healthcare resource reduction. You know, from that perspective, our conversations with clinicians and particularly our SAB have been around while the patient is in the ICU, they should be on the IV to address those challenges and the value proposition that we are really focusing and honing in on.
Of course, we will ask about pricing for GTx-104, and it's ongoing work I'm sure for the team. Just help us understand maybe how you're thinking about the cost relative to oral nimodipine and maybe even Nymalize.
It is ongoing work for us. We have done pricing studies. We have explored various scenarios in terms of how best do we maximize value for the company, also more importantly, how do we have this major innovation that a disease has not seen in over 40 years be available to patients and have a meaningful impact in their lives and their caregivers. We take those considerations very seriously when we evaluate different pricing decisions. The current oral capsule is generic. However, the liquid formulation that's on the market and has similar challenges as oral that I outlined earlier, in addition has a GI side effect, is priced almost 4x-5x over oral.
From our perspective, you know, we can certainly look at varying different pricing scenarios, but our approach in general is to be very pragmatic, keep our philosophy in mind of making an impact on patient care. As we approach launch, we will disclose more information about our pricing strategy.
As we think about the base case scenario, when we've done our diligence, we hear that it can take time for hospitals to add drug to formulary. Clearly, you all are working pretty diligently on trying to figure out ways to accelerate that timeline. Just in general, just help us understand. Sounds like it's can take some time, six-nine months. Is it fair to think about it that you all are taking a stepwise approach? Just help us set expectations. How many hospitals or stroke centers? What are the right targets for you all?
Yeah. We'll start off by talking about the intensity of hospitals and patient volume. 250 hospitals roughly are treating majority of the patients, and that's the target market that we will be focused on for launch. A subset of those are the 25-30 STRIVE-ON sites. Those are the ones that we are hyper-focused on the initial eight-12 months in terms of converting those early adopters. They have a lot of thought leaders, KOL at those sites, including, you know, our SAB, to make sure that we can be out there with early case studies that can be published, that can be communicated by thought leaders at these medical congresses.
The peer-to-peer conversations we believe is gonna be very, very critical to have that play out. Then we'll have more information as well about what is the split between a purely formulary-driven process, and not two hospitals have similar frequency of meeting those committees and so forth, and then others that have more autonomy. Once we have more tangible information, you know, we'll share that with you and the market.
Okay. What are your views on maybe how big this opportunity could be, from a, again, a base case scenario? We can see a lot of upside from that. Those will be different moving pieces that we'll see in real time.
A conservative scenario, I'll just put it in terms of patient size, let's just say it's 45,000 patients a year in the, in the U.S. Our, our serviceable market, by serviceable, you know, day one market, are patients that are higher severe grade patients. These are Hunt and Hess Grades III, IV, and V. These are patients that are intubated, they cannot swallow. We hear that all the time from physicians that nurses, even mild grade patients, they spit up, throw up, the nimodipine capsule. We believe that represents about 60% of the market.
To us, that is the starting base in terms of positioning GTx ultimately as the standard of care for all patients during their stay in the ICU. In STRIVE-ON, on the oral arm, the patients were in the ICU for 18 days. This is a terrible condition. I go back to our value proposition, hemodynamic stability, exposure control and ICU workload management. We don't believe that patients should be cherry-picked in terms of IV versus oral. We think that should be the default, set it and forget it paradigm for this disease.
Okay. Understood. In the last few moments, remind us on the durability as it relates to the GTx-104 potential launch. What kind of IP do you have as a moat?
We have an orphan drug designation that should convert into an exclusivity upon approval. That's our foundation. We have an excellent patent firewall. Our youngest patent goes all the way to 2043. That's a method of use patent. We have various formulation patents that go to 2037. A strong three-layered firewall that provides us with access to 15- 16 years of protection upon launch. Not only that, nimodipine is a foundational therapy for subarachnoid hemorrhage. You can no longer do a placebo-controlled trial anywhere, and any new innovation will be on top of the nimodipine therapy.
We believe the IV, once it's positioned as the standard of care and be written into the care guidelines, will be a very long-term franchise.
Okay. Well, clearly a lot of hard work, ongoing for the team. Really exciting to see the progress that's being done currently and looking forward to seeing all the progress this year and next.
Thank you, Stacy. I appreciate the time.
Thank you.
Take care.