Three Men and the Pursuit of a Stroke Treatment is about nudging a new drug that can save many lives to the regulatory finish line. The drug, AYT-0003, treats victims of strokes triggered by aneurysms. And the team now seeks partnerships with trialists and foundations interested in cures.
By David Stone
Assorted Ideas, Large & Small
At Quarterback: Justin Mulvey
Few of us are called on to save our own lives. And fewer still lead the charge into saving others.
But Roosevelt Island resident Justin Mulvey’s a rare bird.
“Understanding drug development, healthcare, and mechanisms is the only way I have kept myself alive, being my own quarterback and developing my own therapies.”
Mulvey was born with a unique partner, an auto-immune disease. It remains undiagnosed.
Symptoms — rheumatoid arthritis, abnormal blood clotting, and inflammatory bowel disease — keep him a lifelong member in the Undiagnosed Diseases Program of the National Institutes of Health.
Those conditions can shatter anyone’s morale, but instead, they inspired Mulvey to a career in medicine. Mulvey’s resume includes a B.A. in chemistry from Columbia and an M.D./Ph.D. from the Tri-Institutional Program under Cornell, Rockefeller University, and Sloan-Kettering.
Mulvey sought opportunities for working on new drugs for patients like himself. He explored drug synthesis at Columbia, in Japan, at the Tri-Institutional Drug Discovery Institute, and for the international pharmaceutical company AstraZeneca.
His pursuit of a stroke treatment emerged from the neighborhood.
Three men in pursuit of a stroke treatment…
Enter Mitchell Wong
Mutual friends put Mulvey in contact with a patent lawyer, Mitchell Wong. Wong is, coincidentally, also a resident of Roosevelt Island in Manhattan.
Also like Mulvey, Wong studied at Columbia and Cornell, focused on economics and law. After nearly 20 years of practice, Wong became an expert in pharmaceutical regulations and patents.
“One drawback with my field of practice is that cases can take years to finish, allowing me to help very few clients at a time,” Wong told us.
“This project presented an opportunity to pair my legal skills with my science background to improve the chances for thousands of stroke patients each year.”
The nearly ideal partnership lacked some expertise. They needed a collaborator with deep understanding of SAH treatments and patients.
The power to heal
Wong and Mulvey thus sought out Ziev Moses, currently Assistant Professor of Neurosurgery at the University of Massachusetts. And also serves as the university’s Director of Neurological Surgery at Milford Regional Hospital.
“As a practicing neurosurgeon, I see firsthand the profound impact stroke can have on patients,” says Moses. “While there have been significant strides made in the treatment of stroke and its sequelae, many patients continue to suffer from persistent neurological deficits.”
But first, what is a subarachnoid hemorrhage (“SAH”)?
“In strokes involving SAH (subarachnoid hemorrhage), the disease process commonly begins with an aneurysm, which is a bulging of an artery in the brain,” Wong explains. “The bulging is caused by a weakening of the artery wall.”
Aneurysm is like bubblegum expanding as a kid blows into it. Eventually, the force is too great, and the aneurysm bursts.
Released from the confines of a blood vessel, blood rushes into the subarachnoid area surrounding the brain.
Individuals who have suffered a subarachnoid hemorrhage describe it as a “thunderclap headache” or “the worst headache of their life.”
10 to 15% will not survive long enough for medical help to save them. The rest are in danger of complications and long term damage.
Subarachnoid hemorrhages are particularly devastating because they disproportionately strike younger people. This was the same type of stroke that killed 49-year old Mythbusters star Grant Imahara in July 2020, 29-year old NFL tight-end Konrad Reuland in 2016, and 49-year old WABCTV reporter Lisa Colagrossi in 2015.
Survivors of subarachnoid hemorrhage include rapper-entrepreneur Dr. Dre, Game of Thrones actress Emilia Clarke (“Daenerys Targaryen”), and then-Senator Joe Biden (in 1988).
In the aftermath, cerebral vasospasm
Once an SAH patient reaches the hospital, the stroke is confirmed by imaging. The aneurysm must be secured to avoid re-bleeding. The most common techniques for securing an aneurysm involve either surgically clipping the aneurysm or an endoscopic technique called “coiling.”
But while that stops the initial storm, danger lies ahead.
One of the most dreaded events 3-14 days after an SAH is called “cerebral vasospasm.”
Cerebral vasospasm is a narrowing of the large arteries in the brain. Vasospasm is believed to occur when bleeding into the subarachnoid space irritates surrounding blood vessels.
When these arteries narrow during vasospasm, blood and oxygen cannot reach brain tissue as readily. The lack of circulation can cause tissue death and brain injury.
Currently, the only drug approved by the FDA for treatment of SAH is nimodipine, approved in 1988.
However, a 2017 study of 118 consecutive SAH patients at the University of Maryland Medical Center found that 83% of patients did not receive the full dose of nimodipine because the drug reduced blood pressure.
Reduced blood pressure is dangerous in SAH patients because they need blood pressure to continue forcing circulation through the brain.
Pursuit of a stroke treatment: Trials so far bring hope…
While researching an article, Wong came across AYT-0003, a drug candidate that demonstrated statistically significant improvements in patient outcomes and few effects on blood pressure.
Randomized prospective trials had been performed on AYT-0003, using placebo controls and comparator (nimodipine) controls.
In the placebo-controlled trial, fewer patients randomized to receive AYT-0003 exhibited vasospasm, cerebral infarctions, and poor outcomes, than patients who received placebo. Notably, 12% of patients who received AYT-0003 exhibited poor outcomes, in contrast to 26% of patients given placebo, which is statistically significant.
In the head-to-head trial comparing AYT-0003 to nimodipine, 74% of the AYT-0003 group demonstrated good outcomes compared with 62% of the nimodipine group, another statistically significant difference. No significant differences were seen between the two groups in all other outcome measures, suggesting that AYT-0003 is just as good on all those other measures.
In sum, AYT-0003 produces significantly better outcomes, lower instances of hypotension, and is non-inferior on all other measures in comparison with current standard of care.
“If we’re successful, this will be the first drug in 30 years to be approved for the treatment of subarachnoid hemorrhage,” says Wong.
These three men, two from Roosevelt Island, have brought their passion in pursuit of a stroke treatment to a real time solution.
But now, “We have begun to look for institutional partners. We are currently in the process of finding a trial center,” says Wong.
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