NAOMIOSAKA

problems. “What skilled athletes and musicians do are voluntary movements. Cortical areas such as the medial prefrontal cortex encode higher levels of representation and the importance of certain motor behaviors. When the stakes are higher, you pay more attention; but if the stress level gets too high, it can get counterproductive, interfering with the volitional component of movement and flipping you into a reflex, reactive mode. You lose focus on where you are; anxiety becomes a distraction from what you’re trying to do.”

A Silver Lining?

The dark side of performers’ lives may enlighten the public at large about mental health and illness. “Fifteen years ago, people didn’t talk about this,” says Katrina Gay, chief development officer at National Association for the Mentally Ill. “When athletes and elite influencers share their journey, it encourages people in their own struggles with mood disorders and anxiety. It encourages them to seek help.”

The willingness of an admired figure like Simone Biles to make substantial sacrifices for her mental well-being inspires others to do likewise, says Gay. “I’ve noticed more people willing to take a time-out, a mental health break from their own work.”

The power of example may be particularly important for groups reluctant to seek help for mental health problems, such as men and racial minorities. A 2020 paper in Academic Psychiatry cited the example of wrestler/action movie star Dwayne “The Rock” Johnson, who has talked openly and tweeted about his depression. “You are not alone,” he told his millions of followers.

Kevin Love, a five-time National Basketball Association All-Star, also inspired countless performers and others when he began advocating for mental health awareness after suffering a panic attack during a game in November 2017. His powerful essay for the Players Tribune in 2020 about living with anxiety and depression has helped remove the stigma about seeking treatment that has long plagued high-profile performers.

“Talk to somebody. You would be amazed at how freeing it is just to talk to somebody and tell them the truth about what you’re going through. And listen, I’m not trying to sell you some fairy-tale version of mental health. It took me years and years—hell, it genuinely took 29 years for me to realize what I needed.

I needed medication. I needed therapy. I still need those things now, and I probably always will.” l

Research from four labs in different parts of the world led to a major breakthrough—and the 2021 Brain Prize.

THE ROAD TO NEW TARGETED

TARGETED DRUGS

BY BRENDA PATOINE

Illustration By Zo Van Dijk

LIKES TO PACKAGE ITS SUCCESSES IN NEAT STORIES THAT SHOW that. The “bench-to-bedside” story—when biological insights yield targeted treatments—is a long-time favorite. Reality, however, doesn’t always cooperate, and history is littered with basic-science discoveries that seemed important but failed to yield viable treatments. When they do succeed, it’s cause for celebration—and awards. Migraine research is an example.

Although it is the second most disabling condition in the world, affecting one billion people, migraine had long been relegated to the backwaters of scientific research. Only recently has research bloomed—scientific papers sharply increased from the 1990s onward, with discoveries in basic science driving a new class of drugs that some in the field are calling game changers. This year, the recognition of four migraine researchers with a major neuroscience award has pushed the field into the limelight of science.

of Lund University, of King’s College London and UCLA; Michael Moskowitz of Harvard Medical School/ Massachusetts General Hospital; and Jes Olesen of the University of Copenhagen and the Danish Headache Center—will accept the Brain Prize from the Crown Prince of Denmark at a ceremony in Copenhagen on October 25. The prize, worth 10 million Danish krone (about $1.5 million USD), has been awarded yearly since 2011 by Denmark’s Lundbeck Foundation.

The Holy Grail of Scientific Progress?

The 2021 Brain Prize recognizes science that embodies the so-called bench-to-bedside research described above. That’s a jargony term scientists seem to love that denotes the rare and wonderful occurrence when laboratory research aimed at illuminating fundamental mechanisms (the “bench”) yields insights that lead to drugs that ultimately help millions of sick people (the “bedside”). In the case of migraine research, the leading character is a neuropeptide called calcitonin gene-related peptide (CGRP).

“The winners of The Brain Prize discovered a novel and powerful molecular target and took it from the bench to the bedside,” says Richard B. Lipton, a headache specialist at Montefiore Headache Center, who has been involved in clinical trials of the new drugs. He says therapeutics based on the discoveries are “changing the lives of people with migraine all over the world.” That accomplishment, Lipton says, is worthy of a Nobel.

The drugs are classic receptor blockers. They plug up the molecular keyhole where CGRP binds to the cell surface or alter CGRP itself so it can’t lock onto its receptor. This seemingly simple switch stops migraine in its tracks—at least for some people, some of the time, to some degree. Even with those caveats, it’s arguably the biggest news in the clinical treatment of migraine in a decade or more. It’s also the first migraine-specific therapy, since most drugs used to treat migraine were developed for other conditions, such as epilepsy. All have their limitations. The approval since 2018 of seven new drugs for migraine—six of them targeting CGRP—changes the landscape, even if the drugs have been slow to catch on.

The biggest victory may be for translational science. “CGRP demonstrates that if you understand enough about the problem, you can actually make a difference for some patients,” Peter Goadsby says. “A real difference.”

Still, it wasn’t exactly a straight line from there to here. As so often goes in science, the path included its share of zigs and zags, mixed in with the healthy disagreements that sometimes propel science forward and other times slow it down.

A Penchant for Peptides

At the center of the story is an ambitious young Swede with a penchant for peptides. In the 1970s, Lars Edvinsson was mapping the autonomic nerves in cerebral circulation for his Ph.D. thesis at Lund University. In 1976, one year after receiving his doctorate, he discovered what would later be recognized as the first neuropeptide—a short chain of amino acids that neurons use as messenger chemicals.

Edvinsson called it vasoactive intestinal peptide (VIP). He teased out what VIP does and how it works, showing that when it is released by nerve fibers terminating in the blood vessels around the brain, it causes these vessels to dilate. The finding was “kind of a revolution to the field,” he recalled in a session at the International Headache Congress (IHC) on Sept. 11. It showed that peripheral nerves regulate blood flow around the brain via these peptide messengers. It set off a race to identify other such compounds, and many more were found.

When CGRP was discovered in 1983 by a team at the University of California San Diego led by Michael Rosenfeld, Edvinsson, who already had his lab set up to study neuropeptides, immediately started investigating it. But not because he was interested in migraine, per se—he was focused on unraveling the biology. The CGRP-headache connection was made a couple of years later.

At an INSERM (the French National Institute of Health and Medical Research) meeting in Paris in 1984, Edvinsson laid out what he had discovered about CGRP and some other peptides of scientific interest, including the research darling at the time, Substance P. It was, in retrospect, a watershed moment in the building of the scientific case for CGRP, and a defining moment for the young scientist’s career. But at the time, it didn’t go over well.

Edvinsson recounted the occasion in a recent Zoom interview: “No one believed it.” His suggestion that CGRP was a more important drug target than Substance P went against the conventional wisdom of the time, which was fueling a flurry of drug-development efforts. The chairperson of the scientific session in which he delivered it, an esteemed Harvard neurologist who was himself a Substance P advocate, challenged the data and questioned Edvinsson’s conclusions in front of the 1,000 or so attendees. Ironically, the antagonist was none other than Brain Prize co-winner Michael Moskowitz.

A few years before the Paris encounter, Moskowitz had coined the term trigeminovascular system (the trigeminal nerve sends sensations of pain to the brain) and hypothesized that Substance P and other “as yet unidentified peptides” might be important in headache pain. As such, he had conceptualized a role for migraine and drew attention to the system as a target for therapeutics. The thinking was based on the very kinds of discoveries that Edvinsson was working toward in his laboratory in Lund.

Recalling those years at the recent IHC session, Edvinsson said: “We showed that CGRP was the only neuropeptide released in patients during migraine and chronic headache, but no one was interested. People were interested in Substance P.”

In an interview, he expounded further: "I had a tough time in science because for the first 20 years, no one was interested in CGRP.” There were a few exceptions to the general lack of belief in CGRP, including Brain Prize co-winner Peter Goadsby. As Edvinsson recalls it, “this young fellow from Sydney” approached him at a scientific meeting to talk about the data he had presented. Coffee led to collaboration and a series of experiments over ten years, including audacious human studies that measured CGRP in blood taken directly from patients’ jugular veins during a migraine attack. “When Lars and I started this, people said it was crazy,” Goadsby recalls. “We got a lot of heavy-duty flack.” They kept at it, nonetheless, publishing their work with patients in 1990 and laying the groundwork for CGRP as a therapeutic target.

As history would have it, Substance P turned out to be a 20-year sidetrack that ultimately failed to deliver clinical benefits in migraine. The trial that drove the final nail in the coffin was published in 1999. Only then, Edvinsson says, did science—and industry—start paying attention to CGRP. And things started to blossom.

Game Changers in An Overlooked Field?

Today, two types of drugs are based on the CGRP target: monoclonal antibodies (mAbs) that bind CGRP or its receptor to block its action, and gepants, which are classic small-molecule receptor blockers. Four monoclonal antibodies are approved to prevent migraine; three are given by subcutaneous injection and one by intravenous infusion. Of the two gepants, one is approved for acute treatment and one for both acute and preventive treatment. A third is under review as a preventive.

Lipton, a neurologist at Einstein College of Medicine, says he believes the drugs are game changers for a number of reasons. For starters, he says the joint approval for both acute treatment and prophylaxis represents a “new treatment paradigm.” Gepants may also overcome a problem called medication overuse headache, in which taking pain medicine too frequently paradoxically increases headache frequency. Gepants have the opposite effect when used frequently as acute treatment. In addition, triptans, the last wave of drugs used for migraine, hold a risk of cardiovascular complications due to their vasoconstrictive action.

“The gepants are safe in cardiovascular disease and make clear that vasoconstriction is not necessary for effective acute treatment,” says Lipton. “This represents an important therapeutic advance and mechanistic insight.”

How exactly the drugs work is a current focus of investigation for Edvinsson. CGRP is known to be a potent vasodilator—it opens blood vessels when activated— but Edvinsson doesn’t believe that’s the mechanism of therapeutic action. “The story that CGRP dilates blood vessels is old news,” he says. His lab’s recent work suggests something far more complex, that the drugs interfere with the way different nerve fibers interact in signaling pathways inside cells. “This is how people think about it today,” he says.

Both Edvinsson and Goadsby have described the profundity of prescribing these drugs for their patients after having been so closely involved in their development. “The first time I wrote a prescription for a CGRP medicine,” Goadsby said at the IHC session, “I thought, ‘Wow, really?’ To have gone from a laboratory concept to something that is real and that people are prescribing today in the world—I find that pretty exciting.”

Despite the hope and accolades, the drugs’ pick-up among migraine sufferers has been slow, for many reasons. For one, the mAbs require injections; then there’s the hesitancy of insurance companies to pay for them, since the older triptans are available as generics and therefore less expensive. Many payors require that triptans be tried first and allow the more expensive drugs only if the triptans fail. The choices for migraine treatment are many, even if none work in all—or even most—people. Many people also find relief in nonpharmacological approaches and lifestyle changes to eliminate migraine triggers.

Migraine Research “Coming of Age”

Together, the CGRP findings and the new targets they have uncovered within the trigeminovascular system “take the field out of the 19th century,” Moskowitz says. That bodes well for sustaining the progress in future generations of research. “It can’t be seen as a sort of mystery disease if you want to attract people into the field,” Moskowitz says. “Success begets success.”

Olesen, who spearheaded a decades-long effort to create an internationally accepted classification system for headache—a Herculean endeavor that has been integral to progress in the field—says that migraine “used to be in the back alley of research.” Despite being “ridiculously underfunded” by the NIH, he says migraine is becoming one of the better understood conditions in neurology. “The field has opened up for basic research, for intelligent basic neuroscience. The progress per dollar is bigger than in any other field. That itself is a big achievement.”

Goadsby sees the recognition of their research as a coming of age for the field, reflecting its transition from "being a pastime of either cranks or people at the margins, to being a topic that is respectable enough for mainstream science to ask biological questions that relate to migraine.” As the current president of the American Headache Society, he is working with the U.S. NINDS (National Institute of Neurological Disorders and Stroke) to set benchmarks for progress in migraine research—an indication, he says, of the maturity of the field.

A roadmap for research might address some unanswered questions. We still don’t know what causes migraine, for example. We don’t know why migraines are more frequent and severe in women—a question Edvinsson’s lab is focused on answering. And a healthy debate continues as to whether the pain and associated symptoms of migraine are vascular or neural at their root—recent evidence points to the latter, against longstanding convention—and how the two interplay. Yet, for once, it seems the medical “mystery disease”—long ignored and stereotyped by society and science alike—is getting seen. l