NoNO, a small Canadian company, will not abandon stroke research – Quartz

There are about 100 billion neurons in the human brain. These microscopic cells transmit and process the information we receive from the outside world and turn our thoughts into action. They are responsible for the way we talk, how we move and how we think. Neurons are, in many ways, what makes us.

Strokes kill neurons. By depriving them of the blood that carries glucose and oxygen, strokes trigger a biochemical cascade that destroys neurons in large numbers. Ischemic strokes, the most common form caused by a blocked blood vessel, kill an average of 1.9 million neurons every minute without treatment. These dead neurons add up, and in 10 hours stroke patients can lose as many neurons as they would in 36 years of normal aging.

About 15 million men, women and children suffer from strokes each year, and about half of them are fatal. Stroke is the second leading cause of death in the world, after its close cousin, heart disease, and far more lethal than cancer and the deadliest communicable diseases such as AIDS and malaria.

Source: World Health Organization (2016)

Yet despite the enormous impact of the brain attack, the pharmaceutical industry has been virtually powerless to treat it. After decades of spending billions of dollars searching for drugs to protect neurons after a stroke without success, most drug companies abandoned this field in the mid-2000s.

Today, less than 5% of stroke victims worldwide receive treatment beyond basic palliative care, and the lack of effective medications for stroke treatment remains the ## 148 ## # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # 39, one of the most glaring needs in medicine.

Stroke is an extremely complex problem. The complexity of the brain, the need for immediate action, and the variability of stroke and stroke victims make designing and testing drugs a big challenge. But the medical facility failed in stroke patients, not only because of the difficulty of the research, but also because of the misaligned incentives, the financial pressures of an industrial development model of the drug and the botched science.

Nihilism of stroke

"Time is the brain" is a long-time cliche among stroke professionals, but it's largely true.

Death then follows when a stroke causes swelling of the brain resulting in oxygen deprivation, or because the stroke destroys the body's ability to regulate breathing or breathing. blood flow. Others die from complications such as pneumonia, which can affect up to one-third of all stroke patients. Strokes weaken the immune system, preventing the body from fighting more effectively against lung infections that can occur when stroke victims who can no longer swallow properly are left with food, water or water. saliva in the lungs.

For most of the story, health workers had no way to help stroke victims. Once a stroke was identified, the patient was put at ease and the family members received the bad news. Stroke was considered a stalemate – for patients, researchers and neurologists looking for solutions – and nihilism strokes still permeates the medical establishment.

Most of the progress in reducing the number of deaths from stroke is due to prevention, particularly the introduction of drugs to lower hypertension, a leading cause of stroke.

The first and, to date, only scientific breakthrough in the treatment of stroke occurred when a drug called tissue plasminogen activator (tPA, sold worldwide under the brands Activase and Actilyse) was approved by the Food and Drug Administration (FDA) in 1996.

The aim of tPA is "reperfusion", which is to restore blood flow to the injured part of the brain. If the neurons in the immediate vicinity of the stroke can not be saved, there is a larger area, called ischemic penumbra, that can be saved if blood flow can be restored. The darker the blood, the less brain there is to save.

With tPA, emergency room doctors finally had a way to treat patients. But, as in most things in the world of stroke, there have been complications.

In this case, the problem was that there were two types of stroke. Although the majority (about 85% in the US) is ischemic and caused by a blockade potentially treated with tPA, the others are haemorrhagic, caused by a broken blood vessel, and tPA can be fatal in these attacks because it prevents the blood coagulation. (For this reason, the drug is also not administered to patients receiving anticoagulants or other complications.) Up to 65% of patients with ischemic stroke are not eligible for tPA).

Doctors can not administer tPA without determining the nature of the stroke. For this, one must examine the brain with a scanner or other advanced brain imaging device. Doctors must administer the medication less than 4.5 hours after the start of stroke – in many cases, the time given to the patient to be scanned is often insufficient. For patients over 80 years of age or those who have had a stroke, the time limit is three hours.

---

Read more: Faced with the repeated failures of the pharmaceutical industry in the development of stroke treatments, doctors specializing in the treatment of stroke have turned to mechanical devices capable of cleaning the blood vessels obstructed in the brain.

---

In addition, tPA is expensive. The drug, developed by Genentech, has no generic competition and a 100 milligram bottle used in a typical treatment can cost more than $ 8,300. It must also be refrigerated, a challenge for clinics in some parts of the world. As a result, the use of tPA is limited to rich countries with sophisticated health systems and, even then, it is rarely applied. Since its introduction, tPA has also been skeptical of its safety due to long-standing criticism of its first clinical trials. As a result, some doctors do not prescribe it, even in eligible patients. According to a 2014 study, less than 5% of patients diagnosed with ischemic stroke had received the drug. In the poorest regions of the world, the number is closer to zero.

Despite the limited reach of tPA, it is extremely profitable and is expected to generate $ 1.5 billion in sales (pdf) this year for Roche, the Swiss pharmaceutical giant, owner of Genentech.

"The lesson they've learned is that they should pursue something else."

Given the limitations of tPA and its huge potential market, researchers focused on finding a drug that preserves neurons until the brain is reperfused. These drugs, called "neuroprotective agents," could save brain cells from darkness until the brain heals or prolongs neuron storage time in stroke patients until a clot dissolves. by the tPA or removed using a mechanical device. In theory, a neuroprotective drug that can be safely administered to the 15 million victims of ischemic disease and Each year, a hemorrhagic stroke – which could be administered without scanning it beforehand – could generate several times the income from tPA.

Jeffrey Saver, a neurologist at the University of California-LA at the forefront of stroke research for decades, calls neuroprotection the "holy grail" of stroke treatment and, at the Like this sacred relic, his quest was an epic tale of frustration and failure.

According to a landmark study, 1,026 potential neuroprotective drugs were tested between 1957 and 2003, in 8,516 separate experiments. The researchers experimented with extracts of old garlic, uric acid and compounds made from pig brain. Their essays have seductive names, constructed from complex acronyms, which suggest that important scientific activities are in progress: VENUS, ACTION, HOLY.

None worked.

These failures cost billions of dollars and wasted the productive years of thousands of scientists. Even worse, they paved the way for future research by introducing what a researcher called "nuclear winter" for neuroprotective research. The pharmaceutical industry has seen more lucrative opportunities elsewhere and moved on to something else.

"Unfortunately, the lesson they learned is that they should pursue something else," says Myron Ginsberg, a neurologist at the University of Miami, who has studied the failures of the industry.

But not all scientists have accepted this conclusion. In the margins of occupational medicine, a neurosurgeon has relentlessly developed a neuroprotective agent over the past two decades.

The great north of neuroscience

The best hope for stroke patients could come not from the pharmaceutical industry's large research labs, the biotech centers in Boston or San Francisco, but the relative backwaters of Toronto, Ontario.

Michael Tymianski, now 55, has been working on his drug, the NA-1, since the late '90s, while researchers were still optimistic about the development of a drug treatment. stroke. A tall, bald man with a furious work ethic, Tymianski is dedicated to developing NA-1 while holding his neurosurgeon position in a Toronto hospital. His plan was still to develop the drug to the point of being able to test it on the man, and then sell it to a pharmaceutical company. But no buyer materialized and Tymianski finally stopped watching.

Reuters / Mike Cbadese

Instead, in 2003, Tymianski founded his small biotech company, fueled by his trust in this drug based on his critical knowledge of brain chemistry.

As a result of a stroke, the neurons are inundated with calcium, which generates free radicals – unstable molecules with an unpaired electron, such as nitric oxide or NO -, which causes havoc in neurons. But Tymianski and his team have identified a drug that prevents a protein called PSD-95 from binding to neurons, allowing them to resist this deadly accumulation of NO. He called the drug "NA-1" and, in the blink of an eye to chemical action, named the biotechnology "NoNO Inc.".

Tymianski speaks with caution and precision, with self-deprecation that does not completely mask his underlying self-confidence; it is clear in our interviews that he loves to play David's Goliath of Big Pharma and consciously attempts to create a medical history. More than once, he began a sentence: "When the NOOK book is written …"

"What should I do? Put that in a desk drawer and forget about it?

He never sought to become a leader in the pharmaceutical sector, but as the pharmaceuticals industry was stranded from the stroke market, Tymianski was forced to go it alone, thus starting to finance his friends. and neighbors. "I was absolutely not qualified to do it," he says. "But what was I supposed to do? Put that in a desk drawer and forget about it? I saw this as a natural extension of my obligations as a physician. "

In the 15 years since the founding of NoNO, Tymianski has raised more than 120 million Canadian dollars (about $ 90.4 million) from over a hundred investors. NoNO is currently testing its neuroprotective drug in two ambitious Phase III trials in humans.

NA-1 is not the first neuroprotective drug to enter the Phase III trials, and there are many reasons to be skeptical about its chances of success. As noted by the German researcher on stroke Ulrich Dirnagl, it has never been proven that neuroprotection works in humans.

Supporter of a more rigorous statistical badysis of stroke research, Dirnagl informally handicaps the chances of participating in various stroke treatment trials. In an email, he gave his prediction for NA-1: "I guess it's between 10 and[%] and 20%. What is the highest rating I have for any current neuroprotection trial ?.

Tymianski understands the doubts. But NoNo has learned from the failures of the pharmaceutical industry and has built its clinical trials to improve its chances of obtaining regulatory approval and launching the NA-1 on the market. "The road to success is unknown because everyone before us has failed," says Tymianski. "We do not necessarily know what to do to succeed, but we know what not to do."

Chinese food to fail

The history of neuroprotection research begins, strangely, with Chinese food.

Monosodium glutamate, an aromatic additive known as MSG, was first identified in Japan in 1908 by chemist Kikunae Ikeda, intrigued by the origins of umami taste in seaweed. With products like Ajinomoto, a flavor enhancer, MSG has become a staple of Asian cuisine.

Chinese restaurants in the US largely use MSG, which was eventually adopted by Western manufacturers like Campbell's Soup and sold in US supermarkets, most commonly under the brand name Accent Flavor Enhancer.

Used for decades without incident, MSG began to grab the attention of the medical community in 1968, when the New England Journal of Medicine issued a letter to the editor describing the symptoms of numbness and palpitations that the writer Robert Ho Man Kwok attributed to Chinese Restaurants. Kwok, himself a recent Chinese immigrant, has identified MSG as a possible culprit. The NEJM described the symptoms as "Chinese Restaurant Syndrome" and triggered a long racist debate about the effects of MSG on health.

The following year, John Olney, a neurologist at Washington University in St. Louis, published an article in Science demonstrating that in mice treated with MSG, neurons would die, resulting in brain damage. Olney became a crusader against MSG and hired Ralph Nader in a campaign to ban the additive by the FDA. In recent years, however, Olney's findings have been questioned. The mice in her experience received an injection of MSG, not a diet, with much higher amounts (relative to the size of their body) than humans have ever ingested. The fears sparked by the MSG that he helped mobilize were widely discredited, but Olney (who died in 2015) had broadened his understanding of brain chemistry and how glutamate can kill neurons.

Reuters / REUTERS / Stefan Wermuth

Glutamate is an amino acid widely distributed in the brain and central nervous system. He lives in axons – the tendrils at the end of neurons – and plays a vital role in sending messages between these neurons. Once its host neuron sends the right signal, glutamate is released and crosses the synapse, the division between two neurons. On the other side of the synapse, glutamate binds to the receptor of another neuron.

Too little glutamate generates a weak signal between neurons and too much, as Olney discovered in the 1970s, can excite neurons to death by flooding them with calcium in a process he called "excitotoxicity." Excitotoxicity is believed to be a culprit range of neurological diseases such as epilepsy, Parkinson's disease, ALS and stroke.

"Some people thought they were getting a Nobel Prize."

During a stroke, the loss of blood causes the neurons to release glutamate into the spaces between the cells. Pooled glutamate excites cell receptors, forcing them to open bridges allowing calcium to flow into neurons. An overload of calcium in cells generates free radicals that can damage parts of the cell, such as DNA and lipids, and eventually kill the neuron. In the 1980s, Steven Rothman, then a neurologist at the University of Washington, had shown during laboratory experiments that this process could be blocked, thus saving neurons. During this period, research in Germany on the effects of blood deprivation in the brain suggested that neurons could survive and be revived after reperfusion.

Stroke doctors were convinced that a major new treatment for stroke was imminent, said Dirnagl. "There was a huge enthusiasm. Many scientists have been on the ground and the industry has been very excited. Some people thought they were getting a Nobel Prize. "

Mike Tymianski was one of the young researchers trained in enthusiasm. "It was really a golden time," he says now. A medical graduate from the University of Toronto in 1987, Tymianski began his training as a surgeon, but he interrupted his studies to obtain a PhD so that he could continue his research while practicing surgery. Neurology offered a special attraction. "What motivated me was the curiosity and the biggest unknowns in the biological sciences were in neuroscience," he says.

His curiosity has led to unusual decisions in his life, both professional and personal, such as choosing to install his own wine cellar in his Toronto home. He spent months installing drywall and installing lighting cables, often working between midnight and 3 am, while he juggled with his other work. "If I hire someone to do something, I will not learn to do it next time," he says. "I would never have learned how to hang drywall and use electricity."

In his free time (extremely limited), he is currently building a St. Lawrence skiff, a 20-foot wooden boat, which he will use in his summer residence with his wife Dawn on the Thousand Islands. Lake Ontario. This is the second marriage of the two. They have each introduced children into what Dawn, Executive Director of the Nurse Practitioners Association of Ontario, calls a "Brady Bunch Wedding". Their four children combined are all grown up now.

Through his work as a surgeon, researcher and now at the helm of one of the few biotechnology startups in Canada – and one of the most promising – Tymianski has gained a prominent place in the establishment of the country. . He was named to the Order of Canada in 2017 – among the highest civilian honors – and wears his pin proudly. But he was born in Israel and has dual nationality.

Poland-> Israel-> Canada

Israel left a powerful impression even though Tymianski went away while he was still a boy. "Israel is a high-intensity country," he says. "I had two wars at the age of 10. It's hard to forget. "Growing up in wartime could have given him more urgency, he thinks now.

Tymianski's father, Marek, was a Polish refugee who fled the Nazis, first to Belarus and then to Uzbekistan, before arriving in Israel in 1950, where he met Tymianski's mother, Rosemary, also from Poland. . Most of their extended family was murdered in the concentration camps.

Marek studied to become an engineer and worked in an Israeli military factory. Rosemary then worked as a lab technician in Canada.

In 1974, the family left Israel to emigrate to France. She lived for a year in Nice, then in Paris, before moving to Ontario, where she had parents. Tymianski did not speak English on arrival, but spoke French enough to survive in a bilingual Canada.

He turned to science at school and studied mathematics and physics at the University of Toronto, with an eye on the medical school. "I did not go to medicine with a mission related to my life," he says. "It's not that I had a brother or a sick brother. I just thought it would be a very interesting area to use as a springboard for things to come. "

After graduating from medical school, as a PhD student in the 1990s, Tymianski took inspiration from the new wave of literature exploring the mechanisms of excitotoxicity and cell death. He began to study the role of calcium in the death of neurons.

Calcium is the "accelerator pedal" in cells, resulting in many cellular actions, he says. Cells regulate calcium, but sometimes they fail and calcium overload can be fatal. Through his research, Tymianski discovered that the story was more complicated, at least with respect to brain cells.

He discovered that when calcium entered through a particular gateway linked to glutamate, called the NMDA receptor, it was toxic. But if it went through another route, the calcium was harmless. Tymianski thought that a protein called PSD-95 (discovered only a few years ago) was responsible for the toxicity of calcium. But to prove that it took years of laborious lab experiments.

Quartz / Oliver Staley

It was a frustrating process, and Tymianski had almost resigned before her graduate student, Rita Sattler, now a professor of neurobiology at the Barrow Neurological Institute in Phoenix, urged her to persevere. Finally, they proved that PSD-95 in NMDA receptors was key to explaining why glutamate floods cells with toxic calcium. When PSD-95 was eliminated, calcium did not create nitric oxide, the lethal free radical for neurons. The results of the experiment were published in Science in 1999.

In 2002, Tymianski's lab developed NA-1, a drug linked to PSD-95, preventing the protein from binding to the NMDA receptor and eliminating its toxic effects. At least that's what he found in laboratory animals.

Tymianski and his team published these findings in Science in 2002 and, in theory, the pharmaceutical industry should have stood in their way, ready to buy the rights to NA-1 and prove that what worked in laboratory animals also worked in humans. .

However, many things had changed over the last decade, and neuroprotection research, once promising, was now being shunned by the pharmaceutical industry. As Tymianski describes it, stroke research has become an outcast.

A most difficult disease

Traditionally, strokes have been considered a disease of the developed world, where fatty diets and tobacco – two main causes of the disease – are prevalent and populations are more likely to live up to an age. advanced. However, because of progress in preventing and improving basic hospital care, fatal accidents due to stroke have stabilized or decreased in affluent countries in recent decades. At the same time, as tobacco and meat consumption has increased in the poorest regions of the world, the incidence of stroke has more than doubled since 1970.

"LCA is now turning into a tropical disease," says Derek Lowe, a former scientific scientist who published a drug discovery blog for Science magazine. Malaria and dengue fever have been without treatment for decades because their victims are often poor people in poor countries and the pharmaceutical industry sees little profit opportunity. A stroke could now suffer the same fate.

Although thousands of compounds can potentially act as neuroprotectants, no patent encourages them to do so by a pharmaceutical company. The United States National Institutes of Health, the federal scientific research agency, can not afford to sponsor thousands of trials. "It really needs to be run by the industry, and the industry really needs to see a profit motive," says Ginsberg.

There are a myriad of other reasons that make the development of drugs for the treatment of stroke so difficult.

On the one hand, the brain is a particularly difficult organ to work. Unlike the heart, which consists essentially of uniform heart muscles, "the brain is a collection of hundreds of small villages, most of which have limited connections to each other," says Steven Cramer, a stroke researcher at the University of Toronto. California-Irvine. "It's really a lot of different bodies that have grown together over the last 100 million years."

This means that strokes can have different impacts depending on where they occur; on the size of the blocked or broken blood vessel; and on the strength of the flow of the collateral circulation system, the network of small vessels that can redirect the flow of blood when a main artery is blocked.

Time is the brain, but the weather is not the same for everyone and, depending on the cabling of the vessels, a severe stroke in one patient may not have the same impact in another.

The diversity of human brains and the extremely varied types of strokes that can affect them mean that identical treatments can produce very different results in clinical trials. Depending on the composition of the group of patients, a clinical trial may indicate that a drug is more effective than what it actually is or could be wrongly qualified for failure.

Reuters / Laszlo Balogh

Meanwhile, patient recruitment is a thorny issue for stroke researchers. A stroke is less like cancer or diabetes, where treatment can be planned over several months and patients can evaluate their options, rather than a car accident, where treatment can not wait. There is little or no time to explain the potential risks of participating in a clinical trial or obtaining consent. In all cases, patients with brain damage often do not have the ability to understand what they are asked to sign. It may be too late to administer the treatment when it is possible to find parents to sign the registration.

Une autre raison pour laquelle le secteur pharmaceutique a lutté contre les accidents vasculaires cérébraux est que les résultats sont imprécis. Des maladies comme le cancer se prêtent à des réponses définitives, telles que la durée d'un médicament pouvant prolonger la vie d'un patient. Mais les traitements de l'AVC sont souvent destinés à améliorer l'état des patients gravement handicapés jusqu'à gravement handicapés, norme floue difficile à reproduire pour tous les patients participant à un essai clinique.

"Le problème, ce sont des idées."

Il existe également d’énormes différences dans la qualité de la réadaptation disponible pour les patients victimes d’un AVC dans différentes régions du monde et dans différentes situations socio-économiques. Particulièrement aux États-Unis, où l’accès aux soins de santé découle du revenu, les patients pauvres peuvent bénéficier d’une rééducation insuffisante et ne présenteront donc pas la même amélioration qu’un patient riche. Cela signifie que les résultats des essais cliniques peuvent être faussés par des facteurs aussi imprévisibles que l’badurance maladie du patient et l’accès aux installations de rééducation.

Il existe également des obstacles financiers à la R & D. De plus en plus, les grandes sociétés pharmaceutiques externalisent l’innovation au profit de petites entreprises de biotechnologie agiles fondées sur la force d’une ou deux idées brillantes. Les sociétés de capital-risque qui financent ces startups n'investissent que là où elles pensent qu'il y aura une sortie lucrative, généralement sous la forme d'une acquisition, et ne placeront donc que des paris sur des médicaments ciblant une zone de traitement en demande, déclare Bernard Munos, un membre de l'Institut Milken qui a déjà travaillé pour Eli Lilly & Co. et est maintenant consultant pour l'industrie pharmaceutique.

Alors que les recherches sur les AVC se multipliaient et que l'industrie pharmaceutique se retirait, les sociétés de capital-risque ont remarqué. "Les VC sont très sensibles aux maladies qui brûlent, car ils pensent aux issues", explique Munos. "Personne ne dit" investissez dans la recherche sur les AVC ".

Mais finalement, c’est le manque d’une bonne idée, et non de mesures incitatives du marché, qui a été le principal obstacle, dit Lowe.

"Plus d'argent aiderait probablement un peu, mais le problème est des idées", dit-il. «Il ya une tonne d’argent, une somme incroyable, réservée à quiconque peut faire quelque chose pour la maladie d’Alzheimer. Avons-nous fait quelque chose à propos de la maladie d'Alzheimer? Nous n'avons pas."

Rongeurs et primates

Après les premières vagues de découverte du rôle du glutamate dans la mort des neurones, les chercheurs ont commencé à expérimenter des composés qui ciblaient les récepteurs NMDA qui contrôlaient le flux de glutamate dans la cellule. De nombreux médicaments ont été prometteurs chez les animaux de laboratoire, mais ont échoué lors d'études chez l'homme, provoquant parfois des effets indésirables graves. Souvent, les médicaments perturberaient efficacement les récepteurs du glutamate de NMDA, mais causeraient des ravages dans le reste du système nerveux.

Rétrospectivement, les essais sur les animaux présentaient de graves défauts, explique Ashfaq Shuaib, professeur de neurologie à l'Université de l'Alberta. Pour économiser de l’argent, les laboratoires utilisent des mammifères plus petits, tels que les rongeurs, les chats ou les chiens, au lieu de primates dont le cerveau ressemble plus à celui de l’homme mais qui est nettement plus cher. Les rongeurs étaient souvent consanguins, ils étaient donc génétiquement similaires, jeunes et en bonne santé. Les chercheurs ont induit des accidents vasculaires cérébraux chez les animaux en injectant un caillot dans l'artère cérébrale moyenne de leur cerveau. Chaque animal a donc subi la même taille et le même type d'attaque.

Cette approche systématique rendait les résultats plus uniformes et les données plus propres, mais elle ne ressemblait pas vraiment à la variété des accidents vasculaires cérébraux chez l’être humain. Les modèles animaux ont présenté aux chercheurs des signaux irréalistes, a déclaré Shuaib. En outre, les animaux ont reçu de fortes doses de médicaments, beaucoup plus importantes que celles qui seraient données aux patients humains. «C'était badez naïf», dit-il maintenant.

Alors que les essais sur les médicaments pour la neuroprotection échouaient de plus en plus, des chercheurs universitaires et de l'industrie se sont réunis en mars 1999 pour examiner leurs erreurs et adopter les meilleures pratiques pour les essais à venir. La table ronde du secteur universitaire sur le traitement des accidents vasculaires cérébraux (ou STAIR) a produit un certain nombre de directives pour les chercheurs (pdf), notamment pour éviter l'utilisation de souris et de gerbilles lors d'essais sur des animaux et garantir que les expériences sont répliquées avec succès dans deux laboratoires ou plus avant de pbader à l'homme. les patients.

Mais, alors que les directives STAIR ajoutaient de la rigueur, elles ne pouvaient toujours pas contrôler les erreurs humaines.

La triste histoire de SAINT

Au milieu des années 90, AstraZeneca, le géant pharmaceutique britannique, a conclu un accord avec Centaur Pharmaceutical, une start-up du secteur de la biotechnologie, visant à développer Cerovive, un candidat médicament neuroprotecteur. Le médicament, également connu sous le nom de NXY-059, s'est révélé prometteur lors d'essais sur des animaux et des stades précoces, et au début des années 2000, l'enthousiasme était élevé, alors même que le reste du secteur repoussait la neuroprotection.

Dans le cadre d’une opération complexe réalisée entre mai 2003 et novembre 2004, AstraZeneca a recruté 1 722 patients, répartis dans 158 hôpitaux de 24 pays, dans le cadre d’un essai sur SAINT destiné à Cerovive. L’essai respectait les critères de STAIR: le médicament pouvait être administré aux patients jusqu’à six heures après leur accident vasculaire cérébral, mais chaque hôpital devait maintenir en moyenne quatre heures. La limite de six heures «a été choisie par commodité plutôt que par évidence pour obtenir autant de patients que possible, le plus rapidement possible», a déclaré Shuaib, l'un des auteurs de l'étude. "C'était une erreur."

«L’impulsion de la part de l’industrie pharmaceutique a été de« terminer l’étude rapidement », ce qui a malheureusement voulu dire que vous l’aurez fait subir à toutes sortes de patients», dit-il.

Les résultats de SAINT, publiés en février 2006, ont montré un bénéfice modeste pour les patients traités par Cerovive. Néanmoins, dans le monde de la neuroprotection, même un petit signe de succès était considéré comme significatif. les investisseurs et la presse financière en ont pris bonne note et les chercheurs en AVC ont célébré les résultats.

Rétrospectivement, les chercheurs auraient dû être plus sceptiques quant aux résultats de SAINT, selon Shuaib. «Il y avait un signe positif, mais c'était juste en marge», dit Shuaib. "Cela répondait aux critères définis par les statisticiens, donc c'était badez bien pour nous tous."

Afin de satisfaire aux exigences de la FDA en matière de deux essais de phase III achevés, AstraZeneca avait simultanément lancé un essai encore plus volumineux, SAINT II, ​​qui devait inclure 1 700 patients. Cependant, en raison des résultats non concluants de SANT I, AstraZeneca a doublé la taille de SAINT II, ​​recrutant 3 306 patients provenant de 362 hôpitaux dans 31 pays.

Le 26 octobre 2006, AstraZeneca a publié un communiqué de presse qui a sidéré le monde médical et financier: selon les résultats de SAINT II, ​​Cerovive a été un échec.

Les actions d’AstraZeneca ont chuté de 7,7%. Les actions de Renovis – une biotech qui a acheté Centaur en 2002 – ont chuté de 76% et mis à pied près de la moitié de ses effectifs l’année suivante. En 2009, Renovis n'était plus.

Le coup à la recherche de la recherche a été plus durable.

John Patterson, AstraZeneca’s head of drug development, declared defeat not just for Cerovive but for the entire clbad of drugs to which it belonged. “We don’t think there is any mileage in a neuroprotectant approach,” he told reporters in a conference call the day the failure was announced, Reuters reported. “We’ll not look to acquire any projects in the stroke area in this particular field… we think we’ve done the definitive study here.”

AstraZeneca declined to discuss its experience with Cerovive.

“It was an embarrbadment.”

While the SAINT trials may have been the most spectacular failure, throughout the history of neuroprotection investigation, researchers let their optimism get in the way of sound science, says UCLA’s Jeff Saver. Scientists didn’t rigorously blind and randomize animal subjects, and they didn’t declare their metrics for success before the trial, instead cherry-picking the results that made the best case for the drug’s effectiveness.

Saver calls the history of neuroprotection “chastening.” There were no villains, he says, and plenty of blame to go around. “It was an embarrbadment but not a scandal,” he says. “Everyone was trying to do right, but we weren’t smart enough to recognize it.”

NoNO for an answer

Tymianski, now the CEO of his own drug company, is philosophical about the failings of the pharmaceutical industry. It’s easy to find mistakes in hindsight, he says. “It’s harder for me to judge what happened now that I’m walking in their shoes.” Still, “there’s no question, in retrospect, you can spot the errors,” he says. He remains astonished that Cerovive could proceed as far as it did with no real evidence it worked. One reason Tymianski chose to form NoNO and develop the drug himself, he says, is “I didn’t trust [pharmaceutical companies] to do the right thing scientifically.”

But even if he was a fan of the drug industry, it’s not like pharma had any interest in NA-1.

After the publication of the 2002 Science paper introducing the drug, there was no stampede to buy NA-1. As Tymianski considered future directions, he reached out to potential mentors, including John Evans, a cardiologist who had chaired Allelix Biopharmaceuticals, one of Canada’s first biotechs. “He said, ‘There’s no such thing as a nice drug company,’ and, ‘stay away from VCs for as long as you can,’” Tymianski recalls.

Reuters/J.P. Moczulski

Tymianski began approaching investors, starting with friends and family. He was his usual blunt self. “The pitch was ‘Kiss your money goodbye. There’s no exit strategy and you’ll probably never see it again. But if we win, our patients will win and you will do fine,’” he says.

To his surprise, most of the potential investors he asked have signed on.

“Kiss your money goodbye.”

One early supporter was Josh Josephson, the owner of a chain of Canadian optician offices, and Tymianski’s neighbor. Others followed, including Ron Kimel, a Toronto real estate mogul, and Kevin O’Leary, a Canadian entrepreneur better known to Americans as “Mr. Wonderful” from his appearances on the TV show Shark Aquarium. Not all of NoNO’s investors are wealthy, Tymianski says, and they all have his mobile number. Tymianski interrupted one of our conversations to take a call from an investor.

Most of his initial investors have stood by him, Tymianski says, and he’s just completed a seventh round of angel investing. NoNO has also secured C$20 million in grants, including more than C$6 million from the Brain Canada Foundation to fund phase III testing. (Tymianski calls himself a “silver-backed gorilla” when it comes to winning grants.)

Because NoNO has made it this far without venture capital or corporate investment, Tymianski has the freedom to develop NA-1 as he sees fit, without pursuing the shortcuts that proved the downfall of other neuroprotection candidates.

For example, NA-1 was tested by independent researchers in multiple centers, to ward against biased findings from Tymianski’s lab. In addition, after it was found to work in rats, NA-1 was given to long-tailed macaques, a monkey species chosen because of its anatomical similarities to humans.

Tymianski also developed an innovative approach to the core challenge that pharma had encountered in human trials: patient recruitment. He did it bypbading stroke patients altogether in his phase II trial.

In his day job as a neurosurgeon, Tymianski often treats brain aneurysms, which are caused by a weak area in blood vessels bulging or ballooning. In the course of repairing these aneurysms with mechanical devices, small ischemic strokes can be caused by dislodged cholesterol and blood clots blocking minute arteries. These small strokes aren’t life-threatening and are predictable and visible through MRI scanning. So Tymianski reasoned that he would have a better chance of proving NA-1 penetrated brain cells in a population of aneurysm-repair patients than trying it in a much more diverse group of ischemic stroke patients who arrived in emergency rooms.

Over two and a half years, NA-1 or a placebo was administered to 185 patients undergoing brain-aneurysm repair surgery at 14 hospitals in the US and Canada, in a phase II trial called ENACT. The results, published in The Lancet Neurology in 2012, showed patients treated with NA-1 had fewer strokes, and a subset of the aneurysm patients that suffered hemorrhagic strokes showed improved neurological functions compared to the placebo group after 30 days.

ENACT, FRONTIER and ESCAPE NA-1

In the small world of stroke research, Tymianski’s work has drawn attention because of the creativity of his approach and the promise of his results. “It was developed in a thoughtful way,” says Ginsberg. Based on the success of ENACT, NA-1 is now being tested in two phase III trials, with the first results expected in early 2020. If they are successful—pending regulatory approval—stroke doctors may at last have a drug that can save brain cells.

One trial, called FRONTIER, is administering NA-1 to stroke victims in ambulances, so it gets into patients as quickly as possible. So far, more than 300 patients have received NA-1 or the placebo, in a median time of 59 minutes after their stroke.

Another trial, called ESCAPE NA-1, is an effort to see if NA-1 can help ischemic stroke patients who have been reperfused with mechanical devices. The trial is being conducted at nearly 50 stroke centers around the world.

“Why not be a good guy?”

Together, Tymianski says, the trials are an attempt to replicate the conditions where he knows NA-1 works: in lab monkeys given the drug soon after strokes are induced, and where blood is restored to the penumbra. Unlike in the trials for Cerovive and other experimental neuroprotectants, where the drug went from the carefully controlled environment of the lab to the chaotic emergency rooms of stroke care, NA-1 is being tested in humans in situations designed to give it the best chance of showing results and winning regulatory approval.

Quartz/Oliver Staley

If successful, Tymianski will need to decide what to do with NA-1. Options include an outright sale of NoNO to a pharma company, licensing the drug, or forming a partnership. Or NoNO could try to commercialize the drug itself, perhaps by filing an IPO. “We will do what’s best for the company, and for the people that it serves,” Tymianski says.

Maintaining control of NA-1 would give NoNO some say in its pricing, and availability in the developing world, where it could potentially be the first stroke treatment of any kind.

Because NA-1 doesn’t operate in blood vessels like tPA, the hope is that it can be safely administered to victims of both hemorrhagic and ischemic strokes, obviating the need to CT scan patients first. The drug could therefore be given to stroke patients in rural settings or poor countries where the medical infrastructure required to administer tPA is unavailable.

Tymianski says he’d like to be able to offer NA-1 at cost in countries where most people couldn’t afford even a modest price. “There is no profit to be made from people who have no money,” he says. “Why not be a good guy?”

The high cost of failure

Prescription drug prices in the US have risen dramatically in recent decades: 57% from 2006 to 2014. The pharma industry blames the growing list prices on the costs of developing a successful drug. And drug discovery is certainly expensive: A recent study places the cost at $2.6 billion for a single approved medicine. That’s a lot for a pharma company to make up in the 20 years of a drug’s patent-protected life.

But that price tag doesn’t just include the cost of originating a successful drug; it also folds in the R&D costs of the many more unsuccessful attempts. Drug companies can’t endlessly absorb those losses, so they are pbaded along to consumers in higher overall drug prices.

Failure is part of science. It’s build into the most basic concept of trial and error that underpins the scientific method. We need to tolerate failure—and pay for it—in order to benefit from the successes. But the expectation is that failure is the result of honest attempts, based on the best information available, using the most rigorous and sophisticated methodology.

When the drug industry wastes billions of dollars because of sloppy science, we are quite literally paying for its mistakes.

The fact that the prognosis of millions of future stroke patients may rest on the part-time job of a Canadian surgeon speaks to how badly broken stroke research has become.

At the institutional level, stroke is an unwanted step-child. A disease of both the blood system and the brain, it falls between the cracks of cardiology and neurology, embraced by neither discipline. The neglect is apparent in the funding: While research into lung disease and Alzheimer’s each received almost $2 billion in federal funding from the National Institutes of Health in the 2018 fiscal year, stroke research was given just $349 million.

Stroke has few advocates. Its victims are often already old and infirm, and its survivors are ill-equipped to hold rallies and lobby their legislators. There is no ice-bucket challenge for stroke.

Many of the approximately 25 million survivors of stroke living around the world today have serious impairments, some permanent, that tax resources for families and healthcare systems. Stroke costs the planet 113 million disability-adjusted life years annually (a metric that includes the impact of early deaths and total years lived with disability). In the US alone, stroke cost $34 billion in medical expenses and lost economic activity in 2013, the most recent year for which data are available.

Despite the pharma industry’s abdication, neuroprotection is a big enough problem—and represents a big enough jackpot for the researcher that solves it—that Tymianski isn’t alone in trying. Treatments in clinical trials include a drug that increases the supply of oxygen to the ischemic penumbra and a stem-cell therapy that promotes healing in damaged cells. Other studies are experimenting with nitroglycerin patches to control blood pressure in stroke patients, and drugs to reduce brain swelling.

In a world where very little is known to work, very little can be ruled out. There is a long tradition of medical research advancing through blunders and happenstance —Alexander Fleming famously discovered penicillin by accident. It may be that stroke’s best hope is a result of the industry ignoring Tymianski when he first discovered NA-1, allowing him to develop it free of their meddling

As a global society, we tackle diseases not in the order of greatest need, but according to the priorities of the pharmaceutical industry. Their decisions are shaped by the potential return on investment, and a distorted regulatory structure that can make a treatment for a rare disease more profitable than one for a mbadive killer.

On occasion, the needs of the drug industry and society line up, and we have a bounty of new cancer drugs as a result. But when the research is hard and the patients are poor, the market fails. We can hope for people like Mike Tymianski to provide cures, but we shouldn’t have to count on it.