The Promise of a Canadian Stroke Drug to Help the Brain

The Promise of a Canadian Stroke Drug to Help the Brain

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By: Beatrice Ballarin

Stroke is the second leading cause of death worldwide. It is the area of focus of Dr. Michael Tymianski, the principal investigator of the Neuroprotection Laboratory at the Krembil Research Institute and the discoverer of NA-1, a promising drug for treating stroke. Over the past 15 years, Dr. Tymianski and his team have worked diligently to bring NA-1 to the point where it is now being evaluated in humans in Phase 3 clinical trials. Venturing into a realm where every other pharmaceutical company has failed, Dr. Tymianski’s team hopes that NA-1 will be proven to combat damage induced by stroke to the brain—an achievement that would place NA-1 among the most meaningful contributions to modern medicine.

The young Mike Tymianski started university when he was only 16. His interest in medicine led him to become the first medical doctor (MD) in his family. During his third year of medical school, he became fascinated by neurosurgery. He recalls that at the time when there were many advances in heart and cancer research, the brain was a “tabula rasa.”

“All the discoveries were yet to be made,” Dr. Tymianski says. “There were so many diseases of the brain we could do so little about.” He wanted to do something good with his time that could help people, and neurosurgery met his ambitions. During his residency in neurosurgery, Dr. Tymianski took a break to pursue a PhD under the supervision of Dr. Charles Tator, another neurosurgeon and world-leader in spinal cord research. Dr. Tymianski didn’t know it at the time, but this would be the first step to discovering NA-1.

Dr. Tymianski’s PhD work focused on calcium homeostasis and cell death as secondary damage after spinal cord injury. This work lead to a high-impact article published in Journal of Neuroscience in 1994.1 Dr. Tymianski’s work showed that not all calcium is equally toxic to neurons, but if calcium entered neurons specifically through the NMDA receptor, the neurons would die quickly. At the same time, another laboratory characterized the interaction between the NMDAR ion channel with a protein called PSD-95.2 It turned out that this molecular arrangement was indeed responsible for inducing calcium toxicity through NMDA; when PSD-95 was suppressed in culture, cell death was attenuated. The activity of NMDAR was unaffected and nitric oxide (NO) production (known to be very toxic to the cell) was reduced, conferring the rescue of neurons and therefore neuroprotection. This discovery was the first Science paper published by the Tymianski lab only three years after opening and marked the beginning of the NA-1 concept.3 However, there was still one more issue to be resolved: how to bypass the blood brain barrier (BBB) and deliver NA-1 to the brain. Luckily, in 2001, another group showed that it was possible to shuttle a molecule of interest across the BBB by fusing it to the HIV Tat transduction domain.4 In 2002, the Tymianski group published their second Science paper, creating the peptide Tat-NR2B9c, the initial sequence of the interfering peptide fused with tat (or NA-1).5 NA-1 was not only able to reduce NO production in cultured neurons, but when given in vivo to rats, ischemic brain damage was reduced. This result was achieved without interfering with normal NMDAR activity (which is involved in all basic brain functions), a major drawback of previous failed clinical trials in stroke neuroprotection.

One reason why previous clinical trials failed when the NMDA receptor was blocked completely was the dosage. Dr. Tymianski explained, “The dosage required to protect [the brain] from stroke by blocking the NMDA receptor directly was not tolerable in humans, and at a lower dose it did not have any [neuroprotective] effect. We, instead, had a drug that could inhibit NMDA-mediated excitotoxicity without inhibiting NMDAR.

Confident that the pre-clinical work was conducted using rigorous scientific methods, Dr. Tymianski was ready to pursue a clinical trial. To his disappointment, none of the big pharmaceutical companies were interested in what they believed was a risky endeavor.

“In the old days they would have called me, but back then they had just lost billions of dollars in stroke clinical trials and they didn’t want to do it again.” So, there was only one option left: “I had to do it by myself; I had a social responsibility to move this forward.” This was the beginning of a journey that saw Dr. Tymianski and a number of his colleagues founding a company, called NoNO Inc. (after NA-1’s mechanism of action which blunts Nitric Oxide production in neurons). NoNO Inc. is sponsoring the NA-1 clinical trials. Today, while all major pharmaceutical companies have retreated from the field, the Tymianski team is still left standing.

After successful Phase 1 studies to demonstrate that NA-1 is safe, Dr. Tymianski and his team conducted a Phase 2 trial, the first to demonstrate efficacy in patients experiencing stroke. At the same time, more preclinical studies continued in the lab; however, it was necessary at this point to test NA-1 in higher-order brains. To this end, the Tymianski lab conducted experiments in high-order, old world primates (Macaque monkeys). The group was able to show a reduction of infarct size in monkeys when NA-1 was delivered 3.5 hours after the start of the ischemia.6 Seeing these data, NoNO Inc. was able to move forward into the third phase of clinical trials.

Despite the clear efficacy of NA-1, permanent brain damage can occur within minutes after stroke onset and having the right drug is not enough if it can’t be administered quickly. Thus, after approval from both the Food and Drug Administration and Health Canada, Dr. Tymianski and his team designed the trial with this in mind. The drug needed to be delivered as early as possible.

“If you wait for several hours, it’s too late, even for a magic drug.” Thus, in one of the clinical trials, paramedics administer the drug to patients in the ambulance. “Paramedics are good at following protocols, even better than doctors, they are wonderful people, and they do a great job,” says Dr. Tymianski. NA-1 would have to be administered en route to the hospital, thereby being administered as early as possible after the onset of stroke symptoms—a strength, but also a limitation. “There is no CT scan on an ambulance, and even with the use of clinical training and judgment, it’s never possible to confirm that the patient is suffering an acute ischemic stroke, the target of NA-1 therapy.” This is one of the major limitations of the ambulance-based clinical trial: it is not easy to determine if a patient is a good candidate.

For this reason, Dr. Tymianski’s team are also conducting a second Phase 3 trial. This study is enrolling patients who have already arrived to the hospital, and have had their stroke confirmed by a CT scan. In this study, NA-1 is being tested as an adjuvant to endovascular stroke therapy—a treatment that results in restoration of blood flow to the brain by removing the blood clot that is blocking a major brain artery. Dr. Tymianski’s team have shown in primates that giving NA-1 in this scenario produces a significant neurological improvement in the study animals.6 This clinical trial, called “ESCAPE-NA-1” is being conducted globally (in Canada, the USA, Europe, South Korea, and Australia) and will provide an answer in approximately 3 years.

As I listened to Dr. Tymianski recount his story, it struck me that as his entire career has been building up, each piece of the puzzle falling—slowly—into place. At this point, there is only one thing left for him to do: bring NA-1 to the clinic as a first-line defense for stroke. Science has driven his approach to drug development and, in his words, “Science wins in the end.”

 

References

  1. Tymianski M, Charlton MP, Carlen PL, Tator CH. Source specificity of early calcium neurotoxicity in cultured embryonic spinal neurons. J Neurosci Off J Soc Neurosci. 1993 May;13(5):2085–104.
  2. Kornau HC, Schenker LT, Kennedy MB, Seeburg PH. Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. Science. 1995 Sep 22;269(5231):1737–40.
  3. Sattler R, Xiong Z, Lu WY, Hafner M, MacDonald JF, Tymianski M. Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein. Science. 1999 Jun 11;284(5421):1845–8.
  4. Nagahara H, Vocero-Akbani AM, Snyder EL, Ho A, Latham DG, Lissy NA, et al. Transduction of full-length TAT fusion proteins into mammalian cells: TAT-p27Kip1 induces cell migration. Nat Med. 1998 Dec;4(12):1449–52.
  5. Aarts M, Liu Y, Liu L, Besshoh S, Arundine M, Gurd JW, et al. Treatment of ischemic brain damage by perturbing NMDA receptor- PSD-95 protein interactions. Science. 2002 Oct 25;298(5594):846–50.
  6. Cook DJ, Teves L, Tymianski M. Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain. Nature. 2012 Mar 8;483(7388):213–7.