Zacks Small Cap Research – GRCE: aSAH KOL Summary – Technologist

By John Vandermosten, CFA

NASDAQ:GRCE

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Grace Therapeutics, Inc (NASDAQ:GRCE) held a key opinion leader (KOL) event on November 20^th, 2024 featuring Abhishek Ray, MD of University Hospitals and Andrew Webb, PharmD, BCCCP of Massachusetts General Hospital. The event was hosted by Grace’s CEO Prashant Kohli. As Grace enters the final stretch of its STRIVE-ON trial and guides towards a 1H:25 new drug application (NDA) for GTx-104, the event provides context regarding the targeted indication in aneurysmal subarachnoid hemorrhage (aSAH) and the related unmet needs in the clinic. Nimodipine is the only approved product for treatment post-aSAH to reduce the severity of neurological deficits resulting from vasospasm. While the drug works, the oral form has numerous weaknesses that can potentially be improved by using an intravenous (IV) formulation of the drug.

Some of the main hurdles that an IV version can overcome include ease of administration for patients who cannot swallow, more precise dosing and improved titration and more rapid onset of action. These topics and more were discussed in the hour-long event. We summarize the key takeaways below.

Introduction to aSAH

aSAH is classified as a type of stroke can have signs and symptoms such as severe headache, and depressed consciousness including dizziness and coma if severe. The condition is characterized by a ruptured blood vessel at the branch points in vessels where blood flow is turbulent. From 2% to 8% of the population have aneurysms and the rupture risk is 0.5% to 1% per year. Of the ruptured aneurysms that occur, they are usually aSAH, but 30% can be intracerebral hemorrhage. While the likelihood of rupture is small, when it does happen it is severely morbid and often fatal. The incidence of death is from 30% to 50% with about a quarter of people who suffer the event not even making it to the hospital. Inpatient mortality is 20% and the probability of suffering an aSAH increases with age and with female sex.

The treatment goal in Dr. Ray’s practice is to address the rupture with coiling or clipping within 24 hours of presentation. Complications are a concern for treating physicians and include hydrocephalus, vasospasm and stroke, cardiac ischemia and neurogenic pulmonary edema. In aSAH specifically, patient status can change rapidly from stable and alert to suffering cerebral vasospasm, delayed cerebral ischemia (DCI) and infarction. DCI can occur in almost a third of patients and is associated with worse outcomes in patients.

Nimodipine

Nimodipine is the only FDA-approved drug that provides a degree of neuroprotection for aSAH patients. The calcium channel blocker helps prevent DCI and improves functional outcomes after aSAH. Nimodipine is supported by all treatment guidelines and is the standard of care to reduce the risk of DCI. Initiation of nimodipine within 96 hours of admission is a required quality metric to maintain comprehensive stroke center accreditation. Oral administration is recommended every 4 hours, but in some cases, it is appropriate to fractionate the administration to every two hours in about 25% of all patients. This is appropriate if nimodipine is not well tolerated at the 60 mg dose. Dr. Webb has observed that over 25% of patients experience significant hypotension with oral dosing.

Titration

Titration is frequently needed to maintain blood pressure in an optimal range. Too high and the aneurysm may burst and the patient is at higher risk for DCI. If pressure is too low, there is insufficient perfusion. Dose reduction can change outcomes for the worse. The higher the grade of disease[1] and the thicker the clot of blood, the more likely the patient is to suffer from vasospasm, DCI and infarction. Oral administration of nimodipine produces a substantial variability in blood plasma levels. The oral option can be even more variable when a patient is unconscious and cannot swallow, which requires local preparation of a liquid solution of nimodipine and delivery via a nasogastric tube. Furthermore, oral administration is associated with a delay between administration and effect. According to the KOLs, it can take from 20 to 30 minutes for the oral drug to have an impact and if the dose is too high, the patient is stuck with that decision for hours. IV nimodipine allows for more rapid titration and adjustment.

Other Concerns

Beyond the difficulties of titration and rapidly producing blood plasma levels, there are gastrointestinal side effects associated with nimodipine including diarrhea. Rash and headache are other adverse events associated with the drug. The low bioavailability of the oral form requires over 10x of the drug to be effective compared to the infusion. The KOLs on the call attributed a less than 10% bioavailability for the oral version.

Benefits of IV Formulation

The availability of an IV formulation of nimodipine could address many of the limitations of the oral form. Titration, reduced dose associated with fewer side effects and the ability to use in patients that cannot swallow are primary benefits of using an IV formulation over an oral one. In the context of obtaining formulary coverage and acceptance by providers, there are additional positives. Nimodipine is already accepted as standard of care, the ability to use in the sickest patients, flexibility in dosing and titration are further features. Consistency in blood plasma levels where 100% of the drug makes it to the bloodstream and there are no gastric motility problems.

Next Steps After Approval

Assuming that GTX-104 is approved by the FDA, there are additional steps required before it can be broadly used in patients. One of the first steps is for the candidate to have a champion physician at a hospital that would benefit from the product. The champion will make a case to the pharmacy and therapeutics (P&T) committee and request that the drug be added to the formulary. An interdisciplinary team will consider the request and then vote on whether or not the drug will be added. A cost benefit analysis is run and is another part of the consideration.

Many times, new products are added with restrictions and are only used in specific circumstances. In the case of GTX-104, it might initially be considered most appropriate for those with intolerance to the oral form or who cannot swallow or absorb the oral formulation. Since the use of nimodipine is a quality metric for stroke centers, its safe and effective use is critical and may tip the scales in favor of its use. Dr. Ray felt that at least 50% of patients indicated for nimodipine would be appropriate for the IV version.

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