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One Toronto neurosurgeon's crusade to develop an effective stroke drug Add to ...

Big Pharma struck out on developing an effective stroke drug – 1,026 times. But one Toronto neurosurgeon wouldn’t give up. As Craig Offman reports, he’s spent 17 years on a new medication. And his eccentric approach just might work

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The only stroke medication on the market has a laundry list of restrictions. NA-1 should help tens of thousands of patients.
KEVIN VAN PAASSEN/FOR THE GLOBE AND MAIL

Around the time of the dot-com craze and the real-estate bubble, Big Pharma was banking its own big money on neurology’s holy grail: stroke medication. In the late 1990s and 2000s, Pfizer, Merck and other behemoths spent billions on the development of neuroprotectants, a class of drugs that defend brain cells from the brushfire-like damage wrought by stroke. In total, there were 1,026 trials.

Every one of them failed. The most notorious of the bunch was NXY-059, a bland name with a devastating legacy. U.K.-based AstraZeneca spent at least $300-million to develop it, and when the company broke the news of its failure in 2006, the share price dropped 7.5 per cent, translating into $7.7-billion in lost shareholder value. The shares of Renovis, the small biotech company that developed and licensed the drug, bottomed out, dropping more than 75 per cent.

NXY-059 wasn’t just another neuro-debacle. It arguably triggered what many call the “nuclear winter of stroke research,” a deep chill of pessimism that continues to this day.

Researchers complain that, ever since, pharmaceutical companies have thrown up their hands. “If you came to Big Pharma with an idea, you wouldn’t even get a smile. They’d kick your ass out of there,” says Ulrich Dirnagl, a leading German neurologist. “They don’t even want to hear the word ‘stroke.’”

While Big Pharma has recently been throwing money at brain research that does not involve stroke, the disease remains the second biggest killer in the world. In Canada, someone has a stroke every seven minutes, around 50,000 people – and a cost of $3.6-billion – a year. In the United States, that number rises to 800,000 people and the social costs are around 10 times as great. As an overwhelming segment of the population ages, strokes will be an even greater burden for patients, their families and the social safety net. The disease will particularly punish middle- and working-class people who can’t afford the after-care needed for victims: physiotherapy, nursing, transportation.

It’s a doomsday scenario, but also a breathtaking business opportunity for anyone who can stomach the risk. Today, with almost all major players having retreated from the field, there is one Quixotic man left standing.

About two years ago, Dr. Dirnagl heard a speech at a medical conference in Cincinnati given by a Toronto neurosurgeon named Mike Tymianski. Dr. Tymianski explained that a stroke drug he had helped develop, NA-1, had undergone successful trials with mice, primates and a small human population. Better still, NA-1 didn’t show any serious side effects.

Most of the neurologists at the conference were buzzing about the talk. But Dr. Dirnagl was skeptical at first, his enthusiasm cryogenically frozen. His hopes had already been raised enough times, and this was bound to be neuroprotectant number one-thousand-and-toast. “It was too good to be true,” says the wry clinician, who works at Berlin’s Charité Hospital. “Seriously, with all the previous setback and nihilism around, I wasn’t prepared for it.”

But after returning to Berlin, he couldn’t shake the idea. He read some of Dr. Tymianski’s papers on NA-1 in the journals Science and Nature, and started to reconsider. There was something to this.

Two months ago, he bumped into Dr. Tymianski again at a Vancouver conference. The two struck up a conversation, and the Canadian said he was moving forward with another, bigger human trial. Dr. Dirnagl was so enthused that he wanted to run his own NA-1 trial.

Even more striking was that Dr. Tymianski was doing all this without the help of a major pharmaceutical company or venture capital: raising his own money, designing his own trials, going it alone. A flashback to the pre-Big Pharma era of inventor-entrepreneurs, he plays the dual (and duelling) roles of CEO and leading researcher, the drug’s greatest cheerleader and most careful skeptic.

So far, he has raised $30-million in private funding, and is ready to test NA-1 on hundreds of Canadian stroke patients in January. If the therapy succeeds, it will be a victory against one of the world’s great medical scourges, perhaps even a Nobel Prize contender. If the drug fails, it will join the gilded scrapheap of neuroprotectant failures.

CHAPTER II

Toronto neurosurgeon Mike Tymianski has been working on a new stroke drug, called NA-1, for 17 years. He starts a major round of tests on humans in January. PETER POWER/FOR THE GLOBE AND MAIL

When I first meet Mike Tymianski in his office at Western Hospital’s Krembil Neuroscience Centre, I ask him how lab-rat Mike, the one who helped to discover NA-1, and Mike the CEO, the one pushing it to market, get along. Usually different people would be in those positions at a big company, and they’d occasionally be at each others’ throats. Researchers want time, CEOs revenue.

Lanky and disconcertingly alert, the soft-spoken 50-year-old tilts his head. “Sometimes I get along with myself,” he says with a bemused smile, as if he just might enjoy being underestimated.

As much as Dr. Tymianski downplays his internal tensions, different personalities can emerge. On the one hand, he will lightly mention that NA-1 could win him the Nobel Prize, a sentiment shared by his backers. That’s the CEO talking. On the other hand, Dr. Mike can cast a clinician’s cold eye on his so-so chance of success. “I tell shareholders that they may as well give their money to the casino in Monte Carlo.”

Dr. Tymianski grew up in a family of Israeli immigrants. They lived for a few years in France before moving to Toronto when Mike was 13. As a student, he did well enough in school but he wasn’t exactly MIT material. What he really excelled at was gymnastics. His coach was like a second father, his fellow gymnasts his family. He started to compete at a national level – providing him a critical lesson in discipline.

“It taught me how persistence and dedication can work in helping you achieve your goal,” he says.

I tell shareholders that they may as well give their money to the casino in Monte Carlo.
Dr. Mike Tymianski on the risk factor ahead for private investors in his new stroke drug, NA-1

His homework, however, suffered. He had to make a choice, and in the end he quit sports for school. “It felt like a total betrayal,” he recalls. “It was a world unto itself that I had to abandon. But it shaped me for what was to come. Sacrifice and determination.”

After getting his bachelor’s degree at the University of Toronto, he was accepted at its venerable medical school. Again, focus became an issue. As early as high school, he knew he wanted to be a researcher. But of what? George H.W. Bush, who was U.S. president at the time, answered the question for the fledgling doctor: The nineties, he declared, would be “the decade of the brain.”

The idea resonated with Mike – he was an inveterate problem-solving nut. There had been advances in heart and even cancer research – transplants, treatments for leukemia – yet no one was cracking the codes of neurology. The field 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.”

But he also wanted some immediate gratification from his job. “I thought, well, I’m a patient man, but it would also be good to get results, so I picked neurosurgery.”

Now he’s the head of the neurosurgery division at Toronto’s University Health Network. He’s one of the world’s few doctors who performs a delicate laser surgery that modifies blood flow in the brain to prevent stroke. He also created the world’s first same-day surgery process for aneurysms, the potentially lethal ballooning that forms when an artery wall swells with blood.

And he’s a researcher. As director of the Neuroprotection Laboratory at Toronto Western Research Institute, he helped to discover the critical role of a protein called PSD-95 in the cerebrovascular drama of a stroke – knowledge that could result in Canada’s biggest pharmaceutical breakthrough since insulin.

CHAPTER III

There are two kinds of strokes. Around 85 per cent are ischemic: blood clots near the brain act like road blocks, preventing oxygen and glucose from reaching the cells. Without these vital nutrients passing through, the cells, or neurons, die. The other 15 per cent of strokes are hemorrhagic, when there is so much bleeding in the brain that it overwhelms normal blood flow and kills brain cells.

After a stroke, brain cells immediately start dying off – two million a minute. The likelihood of a positive outcome decreases 10 to 20 per cent every half an hour. In the worst-case scenario, the results are life-altering for patient and family, anything from loss of memory or vision to paralysis on one side of the body that leaves a patient wheelchair-bound. The key is to find a drug that can protect living cells from the onslaught of stroke – and quickly.

The only stroke medication on the market, tPA, is a clot-buster intended for build-up either in the heart or the brain. Nicknamed Brain-O, the tissue plasminogen activator is used on ischemic patients – but it has a laundry list of restrictions that narrows eligibility in Canada to eight in every 100 ischemic patients.

Most strokes, around 85 per cent, are ischemic. The other 15 per cent of strokes are hemorrhagic.
Source:Heart and Stroke Foundation of Canada

Before tPA is administered, the patient must first go to a hospital to have a brain scan. If the stroke is hemorrhagic, the patient is ineligible for the drug; it could intensify the bleeding. The hospital also needs to screen patients’ medical histories. If they have had recent surgery, for example, or are on blood thinners, tPA is not for them.

The ultimate disqualifier, however, is time. If more than 4 1/2 hours have passed since the onset of a stroke, the treatment is useless. “The biggest problem is getting people to go to the emergency room quickly,” says Jill Bolte Taylor, a noted Harvard-trained neuroanatomist who herself had a stroke almost 20 years ago.

To begin with, she explains, many people have strokes that a physician will never attend to. Stroke isn’t like heart attacks, in which most people know the symptoms. If the stroke occurs in the right brain and language is not interrupted, many people don’t go for help because they are afraid for one reason or another – afraid of the cost of care (at least in the U.S.), afraid of having the event on their medical record, afraid of the treatment.

That’s where NA-1 could be essential. It buys patients’ time before they arrive at the hospital. It can keep their brain cells alive.

In the early 1990s, as Genentech was developing tPA to bust up blood clots, Dr. Tymianski and a team of researchers were looking at stroke from a different angle: Why do brain cells die when they are deprived of oxygen and glucose?

It took almost a decade to answer the question, but in 1999 he and his collaborators floated their theory in the periodical Science. They identified a protein found in neurons called PSD-95 as the central villain in the stroke narrative, a facilitator and harbinger of cellular doom.

A neuron releases a chemical messenger called a neurotransmitter that activates a receptor in the neighbouring neuron. A stroke causes neurons to release a lethal excess of neurotransmitters, including the chemical glutamic acid. tPA is a clot-buster used on ischemic patients.
Sources: Dr. Michael Tymanski; Heart and Stroke Foundation of Canada; CNX.org

When one neuron sends a signal to the next, it releases a chemical messenger called a neurotransmitter that activates a receptor in the neighbouring neuron and binds to it. The most common analogy of how they function is a lock-and-key mechanism. Think of the neurotransmitter as the key and the receptor as the lock. If the key, the neurotransmitter, fits in the lock, the receptor, this binding will translate the signal from chemical to electrical.

A stroke causes neurons to release a lethal excess of neurotransmitters, including the chemical glutamic acid – the same potentially damaging substance that makes up the notorious flavour enhancer monosodium glutamate (MSG). The clots formed by the stroke also cut off oxygen and glucose, depriving the cells of the vital nutrients they could have used to fight off all that nasty glutamic acid. Instead, glutamate binds to the neurons’ receptors, which in turn causes them to activate a flurry of destructive chemical reactions and electrical signals. That flurry includes a free radical toxin called nitric oxide, or NO, which kills the neuron.

Dr. Tymianski’s team started to focus on the relationship between glutamate and the formation of NO: How does all that signal chaos result in the collapse of a brain cell? The group singled out PSD-95 as the essential intermediary between glutamate receptors and the maker of nitric oxide, an enzyme called neuronal nitric oxide synthase, or nNOS.

If you inhibit PSD-95, they found, the glutamate receptors can’t stimulate nNOS. If nNOS isn’t stimulated, it can’t produce the free radical toxin and neuron killer called NO.

The PSD-95 protein is the essential intermediary between the glutamate receptors and the enzyme responsible for generating neuronal nitric oxide synthase, or nNOS. The drug NA-1 removes PSD-95. But first it must get past the blood-brain barrier.Once NA-1 has broken past the BBB, it can block PSD-95. Sources: Dr. Michael Tymanski;
Heart and Stroke Foundation of Canada; CNX.org

In 2003, Dr. Tymianski founded NoNO Inc. to bring a drug to market to do just that, one of hundreds hoping to make the near-impossible leap from theory to practice.

One common obstacle for neuroprotectants is the blood-brain barrier, or BBB, where many others have met their demise. BBB could just as easily stand for the Berlin Wall of Biology. “Think of it like Checkpoint Charlie,” says Lee Schwamm, director of stroke services at Massachusetts General Hospital and neurology professor at Harvard. The BBB protects the body’s central nervous system from potentially harmful chemicals by permitting water and some gases through – but only after the gatekeeper has checked their ID. Typically a neuroprotectant won’t get by the checkpoint, so like a Cold War spy, it requires a stolen passport.

More than a decade ago, scientists came up with an elaborate biological ruse that Dr. Tymianski’s team uses with NA-1. The HIV-1 virus can infiltrate the BBB with devastating results, but a sequence of its harmless amino acids can also potentially do a world of good, acting like a fake ID for PSD-95 inhibitors. In animal and human trials thus far, the trick has worked. It has also been successful in a small human trial with patients who had small blood clots as a result of aneurysms.

Now his team will try it on a large population of ischemic stroke patients.

“I’ve seen a lot of other drugs fail in human clinical trials that succeeded in animal trials,” says Dr. Schwamm, “but I’m cautiously optimistic about this one.”

CHAPTER IV

Neorosurgeon Dr. Michael Tymianski, photographed at Toronto Western Hospital's Krembil Discovery Tower in Toronto, Ontario on May 1, 2014, is trying to find new ways of treating stroke victims.
PETER POWER/THE GLOBE AND AMIL

Dr. Tymianski is going it alone because he didn’t have a choice.

In his office, he explains how Big Pharma has given up on stroke. He’s getting a little worked up, his gentle didactic streak taking on an edge, his sentences punctuated with the nasally drone of “riiight?”

As he sees it, companies allowed business to get in the way of science, creating a decade of self-fulfilling failures. To justify their massive investments, pharmaceutical giants had to ensure that their neuroprotectants reached as wide a population as possible, so they created drugs that left too generous a window for timing.

Dr. Tymianski shows me some graphs. “Not a single trial enrolled a patient in less than four hours. There’s 12 hours. And 72 hours! What would happen to a steak if you leave it on the counter for 12 hours? Would you eat that? That thing is really dead. No drug is going to resurrect dead.”

Timing isn’t the only obstacle to making the investment in a stroke drug pay off. There’s frequency as well. A neuroprotectant is a one-off medication, not a daily prescription or a blockbuster for occasional use. “Big Pharma looks at a potential investment differently than a physician might,” says Dr. Tymianski. “From a physician’s perspective, if I had a drug that I know is safe and that could even help a fraction of the patients I can’t help now, I’d use it.”

Even though Dr. Tymianski took on the role of CEO, he wanted the research, not the money, to call the shots. He didn’t want venture capital companies to fund him; they’d have their own deadlines and probably force their own management team on him.

Instead, he wanted absolute freedom to pursue the science until it was ready for prime time, no corners cut. So he decided to chase private money. Even with the puzzling name and wildly nebbish company slogan – “An unusual company in most respects” – NoNO’s scientific bona fides, the Tymianski résumé and the remote prospect of a Canadian blockbuster have drawn a wide range of financial support. He has raised his $30-million from Toronto’s real-estate magnates, tech tycoons and business leaders.

Greg Wolfond, a notable serial investor, calls his NoNO funding a philanthropic investment. “I know the odds are long but it’s worthwhile. If we don’t do this, who will?”

Mr. Wolfond, along with his other supporters, says that Dr. Tymianski is a quick study, hoovering business, legal and medical issues at a ruthless clip. At the beginning, though, the researcher needed a lot of help on the CEO side. That’s where the overheated swimming pool of Dr. Josh Josephson, a high-end optical retailer in Toronto, came in. It was NoNO’s incubator.

A decade ago, Dr. Tymianski moved to the patrician environs of Toronto’s Lawrence Park along with his wife, Dawn, and the family from his first marriage. The city was swamp-hot in a summer heatwave, and the pool, owned by Dr. Josephson, looked enticing from a distance. “You could see the steam coming off,” says Dr. Tymianski. “It was like watching money evaporate.”

The two would bump into each other, and Dr. Josephson invited him over for a swim. At first, Dr. Josephson found his visitor aloof, very private. But after a few poolside chats, the doctors warmed to each other and talked shop. Dr. Tymianski mentioned his work on neuroprotectants, and Dr. Josephson, who enjoys reading the odd research paper, was immediately riveted by his neighbour’s article in Science.

It’s a boneyard for investors. Billions and billions have been lost.
Kevin O’Leary on his initial response to Dr. Tymianski’s stroke drug. He’s now one of his investors.

Dr. Tymianski complained that NoNO was going nowhere – he needed to find a way to raise money. Increasingly impressed with the neurosurgeon, Dr. Josephson asked him if he wanted to go for dim sum in Scarborough, and subsequently offered to help him. “I need to help you move this forward,” he told his neighbour.

As the businessman started connecting Dr. Tymianski to other businessmen and lawyers who could advise him, Dr. Josephson got to know his neighbour and his problem-solving obsessions a little more. “The guy assembled his own road bike. He wanted to build a wine cellar, a contractor gave him too high an estimate, so he built his goddamn wine cellar, and computerized it to boot!”

The two started fanning out in search of high-level advice and financial support. Dr. Josephson eventually enlisted Toronto real-estate heavy Ron Kimel as one of the first major investors, and Dr. Tymianski made a serious investment of his own, hiking down to Canali in Yorkville and buying a $1,200 suit. “All these Bay Street guys were wearing Armani. I had to pony up.” (He still has the suit, even though it has a hole in the back.)

Dr. Tymianski met John Evans, a major civic leader in Toronto and Oxford-trained cardiologist who became an important mentor and navigator through the city’s health system. Charles Tator, the Western Hospital neurosurgeon renowned for his research and advocacy on sports concussions, also got behind the project. So did Dr. Gerald Halbert, a University Health Systems board member who raises significant money for the system’s neurological research centres.

Wine also was an important financial lubricant. Dr. Josephson belongs to the Toronto chapter of La Confrérie des Chevaliers du Tastevin, a Burgundian wine society that has its own initiation rites, songs and celebratory dance. It’s the Bacchanalian order of Toronto’s establishment.

At one Confrérie event, Dr. Josephson introduced the NA-1 inventor to CBC television host Kevin O’Leary, who didn’t invest on the first round, and even had the temerity to waffle on the second. “In so many words, I told him to get off the [expletive] pot already!” recalled Dr. Josephson.

The combative TV personality remembers meeting Dr. Tymianski over a glass of Burgundy. “He said he was a brain surgeon. I thought he was joking.”

Mr. O’Leary’s mother died from a stroke, which made him want to help. But there were too many negatives to NA-1. “It’s a boneyard for investors,” he says. “Billions and billions have been lost.”

After several meetings with Dr. Tymianski, however, he came away impressed. Mr. O’Leary was used to pitches from creative guys with no fiscal sense, or vice versa. Here was a guy who had both talents. “Tymianksi is such a cheap bastard – he doesn’t waste a cent!”

Mr. O’Leary anted up. NA-1 is the medical version of Pascal’s Wager, he says: better to invest in it than to doubt its power. “Either it works or it doesn’t, and I have to be prepared to write this to zero,” says the CBC host, who allots about five per cent of his portfolio to these kinds of risky endeavours. “As Canadians we have to hope this works. This is Mount Everest.”

CHAPTER V

Paramedic Claude Muir draws the NA-1 drug into a syringe while working in the back of an ambulance in Toronto on Thursday, May 8, 2014.
DARREN CALABRESE/FOR THE GLOBE AND MAIL

Three ambulance services across the country have made a different kind of investment, one that is arguably as critical.

In January, paramedics from Toronto, Peel Region and Vancouver EMS will participate in NoNO’s pivotal trial with 518 stroke patients. Ambulances will be equipped with IV bags of NA-1 and refrigerators to keep the bags cool. Paramedics will be trained to vet patients with the help of an on-call physician and to administer the IV. It’s a double-blinded experiment, meaning that there will be a placebo used as well. This is where the rubber meets the road.

Neurologists have a critical time frame called the Golden Hour: Ideally, no more than 60 minutes should pass between the onset of a patient’s stroke symptoms and the administration of tPA. Beyond that, the brain damage accelerates. This trial, called FRONTIER – which roughly stands for the Field Randomization of NA-1 in Early Responders – has enlisted paramedics to inject the drug on-site or in the ambulance, a pre-emptive step that previous neuroprotectants trials did not take. (Since the drug has no negative side effects, it still can be injected into a patient with a hemorrhagic stroke. It just won’t work.) The treatment can then be followed up with tPA.

Joining Toronto’s EMS on a mock run, I learn that paramedics do little more than observe, report and console stroke patients. They can assess them for a possible stroke by asking questions: Can she lift her arm and turn up her palm? Can she close her hand? Can she repeat a sentence such as, “The fox ran through the woods?” Paramedics can take the patient’s blood sugar count and monitor her oxygen.

Beyond that, though, there must be an ache of futility to the job, a yearning to do more than just monitor the 1,000 stroke victims the Toronto EMS transports each year. “Stroke is pretty unique. There are no interventions you can do on the way,” says Kim McKinnon, the EMS spokeswoman who played the role of patient for me.

The head of Toronto’s EMS, Paul Raftis, has brutally intimate familiarity with the fact that “time is brain” in stroke patients. His mother, Helen, had her first stroke at 60. She was taken first to a community hospital in Guelph, Ont., – where she didn’t receive tPA – and by the time EMS transferred her to a stroke centre, she was outside the drug’s time window, no more than 4 1/2.

“She was paralyzed on the left side,” Mr. Raftis says before showing me a slide show of his mother, wheelchair-bound and joking with her family. “And she lives with the result of that today.”

Six years later, Mr. Raftis’s mother suffered another stroke. But by then neurologists and EMS had implemented streamlined stroke protocols, and she was rushed directly to a stroke centre in nearby Kitchener, where she received tPA, significantly containing the brain damage.

The experience left Mr. Raftis acutely aware that stroke patients need some kind of early intervention – a way to keep brain cells alive as ambulances scramble to reach a stroke centre. NA-1 could be that very thing. “It’s buying time,” he says. “It’s like a ventilator to the brain – allowing the cells that are starving for oxygen to stay alive.”

For Mr. Raftis, FRONTIER represents the next paradigm in emergency-services. Over the last 10 years, there has been a cultural shift that began with CPR and defibrillators: hand over the equipment to trained first-responders who can offer immediate assistance in the field. “Why don’t we treat the patient outside of the hospital to fix some of their issues and then once we get to the hospital fix some of those more definitive issues?”

Some cities are already ahead of the curve. Houston announced last February that it would try out a mobile stroke unit with a CT scanner that can assess whether patients are having an ischemic or hemorrhagic stroke. A German joint-venture has created a customized stroke ambulance called Vimed Stemo.

The idea of treating stroke patients in ambulances was pioneered by UCLA neurologist Jeffrey Saver, something of a legend in his field for his research on identifying stroke before patients arrive at the hospital.

Over the past eight years, Dr. Saver has led a Phase III clinical trial called FASTMAG. FAST stands for the Field Administration of Stroke Therapy, MAG for magnesium sulfate, which dilates blood vessels in the brains of animals, expanding the area so that more blood can flow through.

FASTMAG’s ambition was a juggernaut of a trial that involved 1,700 patients, 315 ambulances, 40 EMS agencies, 60 hospitals and almost 3,000 paramedics across the Los Angeles area. When the results were announced three months ago, the FAST part of the name delivered on its promise. Paramedics were quick off the mark, applying the drug within minutes after stroke onset. But the trial results for magnesium sulfate were neutral. It joined the boneyard.

CHAPTER VI

Right now, patients are screened at a stroke centre before getting treatment. But two million brain cells die every minute after a stroke. By the time many patients get help irreversible damage has been done. The drug NA-1 buys patients more time by blocking brain cells from shutting down. It can be administered in an ambulance en route to a stroke centre. PETER POWER/THE GLOBE AND MAIL

Dr. Tymianski and his Portuguese water dog, Churchill, greet me at his home on a Saturday morning. The Victorian house is in a much-coveted neighbourhood, but the big-time doctor doesn’t live in a sprawl of self-congratulation. A 10-year-old Audi A4 and a newish Ford sit in the driveway.

Inside the house, however, there are other distractions. Poor Churchill, dying from all kinds of cancer, throws up as I enter, so as the neurosurgeon dutifully cleans up the damage I gawk at his impressive collection of native Canadian art, including a Morrisseau.

Can you imagine that it took him seven months to get his drug to patients? Seven months? It has taken me more than 17 years.
Dr. Tymianski on Sir Frederick Banting, one of the inventors of insulin. A painting by Dr. Banting hangs in Dr. Tymianski’s foyer.

Once he’s done, he tells me about the history of the Portuguese water dog and shows me his aquarium, an astoundingly intricate built-in oceanscape that features LED lighting that can mimic the noon-day sun in an equatorial environment.

Eventually we sit down for Montreal bagels and lox, the no-nonsense Dawn joining us. I ask him if the name of his company is goofy. Think about it: NA-1 may be Canada’s biggest drug since insulin and the company that makes it is called NoNO?

Sitting behind him, Dawn nods her head up and down, but he defends the name. “Love it or hate it, it sticks,” says her husband. “It’s memorable.” He also likes the defiant irony to it: A lot of people tell him that what he’s doing is doomed.

The more he is gently teased, the more animated he becomes. Joking, the bald doctor explains that NoNO shares a name with a hair-removal product, No!No! “If I could use it I could have said that I’m both CEO and a customer.”

Dr. Tymianski has a tightly coiled kind of confidence, always ready to spring. Even when he is saying that the whole NA-1 enterprise could sink this fall – two decades of gruelling work and opportunity costs he has missed out on – he sounds oddly confident. Does he ever doubt? “I don’t self-doubt. I’m a realist.”

As a realist, he must have envisioned how he would feel if the FRONTIER trial is a bust. He tells me that he already knows.

Three years ago, NoNO was conducting its Phase II trial, using NA-1 on 197 patients who had ruptured brain aneurysms. The aneurysms produce little clots that travel toward the brain and cause small strokes. The trial set out to discover if NA-1 could protect the brain cells against a stroke.

As CEO, he had to stay at arm’s length from the proceedings. He could help design it. He could ensure that it complied with medical protocol and was legal. But he couldn’t go near the trial while it was in progress, to avoiding skewing the results. The relationship is what New York University medical ethicist Dr. Arthur Caplan calls “the Ulysses Contract,” meaning that the doctor, like the epic traveller, has to ignore the Sirens for the purpose of self-preservation. Using another analogy, Dr. Caplan says that the trial should be looked at as a child, for whom a parent may not be the most objective evaluator. “If you’re a parent, you can’t sign up to be the drama critic of her high-school musical.”

So Dr. Tymianski had to put his trust in Michael Hill, a well-respected, blunt-spoken neurologist from the University of Calgary’s Hotchkiss Brain Institute, to carry out the trial.

One morning in May 2011 at around 8:30, Dr. Hill got the results and called Dr. Tymianski, who was travelling the world, checking out MRI facilities and giving speeches.

NA-1 had no positive impact on strokes, Dr. Hill told his colleague, who was in a hotel room in Singapore. In other words, the trial was a failure.

Dr. Tymianski remembers weeping at the news. Dr. Hill, on the other hand, recalls his colleague pushing back: The results couldn’t be right, he said. There must be a software error. Something.

The stubbornness didn’t surprise his colleague. “Doing clinical trials is like starting a new business,” says Dr. Hill. “You have to show it can work and convince people to lend you money, agencies to support you. The better case you can develop, the better your story is.”

Bursting with disbelief, Dr. Tymianski asked Dr. Hill to have the results independently retested. He also commissioned his own independent retesting, thus beginning a three-month odyssey of revision, rethinking and eventually redemption. It turned out that a software glitch had produced nonsensical data that skewed the initial results. The trial was actually successful.

Sitting at his breakfast-room counter in Toronto’s Lawrence Park three years later, his fingers rolling around his bagel’s poppy seeds, Dr. Tymianski says that the failure was actually liberating. “Would I be disappointed if this failed? Yes. But I would be free. And I would have known I had done everything possible to make it happen.”

On the way out in the foyer, he shows me a painting of a village by Sir Frederick Banting, amateur artist and co-developer of insulin. “Can you imagine that it took him seven months to get his drug to patients? Seven months? It has taken me more than 17 years.”

More than just a painting, Banting’s work is the urgent voice of a successful ancestor, a spectre that pushes Dr. Tymianski out the door in the morning and stares him down when he returns at night. As if he needs the pressure.

Craig Offman is a features writer with The Globe and Mail.

Graphics by Matthew Bambach/The Globe and Mail.

Follow us on Twitter: @globeandmail

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