Fresh Target in Hunt for a Migraine Cure

Story first reported from WSJ.com

The hunt is intensifying for new treatments for migraines, the common and debilitating headaches that have confounded scientists for decades.

Of greatest focus for researchers is a brain chemical known as CGRP, which appears to play a role in the transmission of pain, but not in other brain functions, such as cognition or mood. Researchers are trying a variety of experimental drugs to stop CGRP from working by blocking its receptors in the brain. Others are working on artificial antibodies that could soak up the chemical in the bloodstream or brain before it can trigger migraines.

The hunt is intensifying for new treatments for migraines, the common and debilitating headaches that have confounded scientists for decades. WSJ's Shirley Wang reports on the latest approaches. Photo: Getty Images

Experts say the need for new medicines to treat migraine pain once it begins is great because current drugs only provide some benefit for 50% to 60% of sufferers and can't be used in people with heart disease or who have had a stroke. Also, they aren't a cure, and in many cases, the headaches tend to come back within 24 hours.

There also is a separate category of preventive drugs, which tend to be used by a small proportion of people who suffer from more frequent or debilitating migraines.

"People need migraine drugs that have a rapid onset of action, that take the pain away and keep it away," says Richard Lipton, director of the Montefiore Headache Center in New York.

Headache disorders are among the most common medical conditions world-wide. More than 1 in 10 adults globally are affected by migraines, which can be incapacitating, according to the World Health Organization. International studies have found that 50% to 75% of adults have reported a headache in the past year, with up to 4% of the global population reporting having a headache in half or more of the days each month, WHO says.

There isn't such a thing as a "regular" headache, but rather more than 300 types, says David Dodick, a professor of neurology at the Mayo Clinic's branch in Phoenix and chairman of the American Migraine Foundation. People having migraines usually experience intense pain, sensitivity to light, dizziness and sometimes nausea and visual and sensory symptoms called auras. Two other major types of headaches are caused by tension or medication overuse.

Breaking the Headache Cycle

Nonsteroidal anti-inflammatory painkillers such as ibuprofen work for some migraine sufferers. But the class of migraine medicines that hit the market in the 1990s called triptans remain the best or only treatment option for many patients. Nevertheless, about half of sufferers don't respond to them or can't take them because of other health reasons.

CGRP, which stands for calcitonin gene-related peptide neurotransmitter, has long been thought to play a role in migraines, but for much of that time for the wrong reason. Part of the confusion was because of a misunderstanding of migraines themselves.

Why they occur still isn't clear, but specialists say they have recently begun to understand the migraine as a brain disorder and not a vascular disorder. Until about 12 years ago, they were believed to stem from constriction of blood vessels in the brain. The dilation of the vessels to compensate then led to the throbbing pain, so the thinking went.

Now, it appears more likely that migraines "hijack" the brain's normal pain circuitry, says Dr. Dodick. The brain's normal pain-sensory system, in which nerve endings send messages to the brain about a threat, goes awry in migraines.

Experts disagree about how a migraine is triggered, but the trigeminal nerve—an important pathway that carries sensory information about the face—and its connections to numerous other nerves and the brain appear to be responsible for transmitting the pain.

Researchers also have isolated certain genes that might be linked to a predisposition for migraines, Dr. Dodick says.

Triptans, which promote blood-vessel constriction and inflammation, block the release of CGRP in the trigeminal nerve. While CGRP does aid the blood-vessel dilation process, its role activating the nerves in the brain appears to be the key when it comes to migraine pain.

In the mid-1980s, Peter Goadsby, a neurologist and headache specialist at the University of California San Francisco, and his colleagues found that CGRP is released in migraines and that triptans decreased CGRP action.

Several researchers and companies have been trying to develop drugs that bind to the CGRP receptors to prevent the chemical from activating the pain network. But because CGRP has a complex receptor—the slot where the molecule must bind in order to initiate actions in the body—it took chemists 15 years to figure out how to block the effects of CGRP, and even longer to develop a compound that could be taken orally, says Dr. Goadsby.

Bringing to market CGRP blockers, or antagonists—the most advanced of the new drugs in development for migraines—has proved challenging. Several investigational compounds have been shown to be toxic to the liver, a challenge that highlights the difficulty in developing drugs for conditions that affect the brain.

CGRP antagonists don't appear to work as well as triptans, but the blockers have an advantage in they don't appear to cause cardiovascular complications, says Stephen Silberstein, a neurology professor and director of Thomas Jefferson University's Headache Center in Philadelphia.

"You trade one kind of risk for another," says Dr. Silberstein, who has served as an investigator on several companies' clinical trials.

Merck & Co. had a promising CGRP-receptor antagonist under development but discovered in late-stage clinical-trial testing that some patients experienced liver enzyme changes. In July of last year, the company said it was discontinuing development of the compound, telcagepant, after looking at all its trial data. Germany's Boehringer Ingelheim GmbH was also working on a CGRP antagonist but canceled development. A spokesman declined to comment.

Bristol-Myers Squibb Co. is conducting several early stage studies on CGRP antagonists and other companies are testing or may begin development of similar compounds as well.

Researchers and companies also are trying to develop artificial antibodies that, when injected, would glom onto CGRP in the bloodstream or brain, before it reaches the receptors in the brain, or by blocking the receptors.

Research into these biologic antibody-based approaches is at an earlier stage than the testing of antagonist drugs, but antibodies eventually might be able to block CGRP action regularly so that migraines don't ever begin.

"The CGRP story is a story of developing an acute treatment for migraine," says Dr. Goadsby. "But the antibody story is testing the larger idea [that] if you blocked continuously CGRP, would you have a preventive treatment."

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Fraudulent Scientists

First appeared in Time: Heartland

Dipak Das

In January 2012, University of Connecticut officials announced that Das, director of the Cardiovascular Research Center, had fabricated his research 145 times in papers published in 11 scientific journals. Das studied the effects of a compound in red wine, resveratrol, on the heart.

The university launched an investigation of Das’ work in 2008 after an anonymous tip raised questions about  images in his papers, which were turned out to be manipulated.  In its 60,000 page report, the investigators say some of the images were created at a time when there wasn’t anyone in the lab with the proper expertise to generate them, and that Das divided the work on experiments so that even lead authors of papers weren’t fully involved in preparing data and figures. Das testified to the investigators that he had no knowledge of the manipulations, a claim that the panel says “lacks credibility.” The report was filed with the U.S. Office of Research Integrity, which is conducting its own investigation into the fraud. As for Das, a university spokesperson said he “remains employed by the UConn Health Center pending dismissal proceedings per university bylaws.”

Andrew Wakefield

Do vaccines cause autism? Medical experts say no, but we can thank Wakefield for introducing the doubt that won’t die in many parents’ minds. In 1998, the  gastroenterologist at Royal Free Hospital in London published a study describing a connection between the measles-mumps-rubella (MMR) vaccine and autism, after he found evidence of these viruses, presumably from the shot, in the guts of a dozen autistic children, eight of whom developed autism-like symptoms days after receiving their vaccination.

Other scientists could not replicate Wakefield’s findings, nor verify a link between the vaccine and autism. In 2010, the journal that published his paper retracted it, and its editors noted that “it was utterly clear, without any ambiguity at all, that the statements in the paper were utterly false.” Later that year, the General Medical Council in the U.K. revoked Wakefield’s medical license, citing ethical concerns over how he recruited the patients in the study as well as his failure to disclose that he was a paid consultant to attorneys representing parents who believed their children had been harmed by vaccines.

The final shoe dropped a year later, when another prestigious medical journal concluded that his research was also fraudulent, after evidence that some of the timelines of the children’s symptoms were misrepresented.

Wakefield maintains his innocence, and penned a book defending his work and his continued belief in a connection between vaccines and autism. Infectious disease experts and pediatricians, meanwhile, routinely confront conflicted parents who question the safety of vaccines, despite immunization’s long-standing record of successfully controlling childhood diseases with relatively few side effects.

Woo Suk Hwang

It’s not often that scientists achieve rock star status, but that’s what Hwang enjoyed when, seemingly out of nowhere, the Seoul National University professor of veterinary medicine catapulted South Korea to the top of the science hierarchy with his 2004 success in cloning human cells and making human embryonic stem cells.

Or at least that’s what he and everyone else in the world thought he had done. It was the first time anyone had taken a human cell, inserted it into a donor egg, and coaxed it to grow, in theory into a clone of the original cell. He followed that stunning announcement a year later with another first — using the same process to generate embryonic stem cells from patients with spinal cord injury and diabetes, opening the possibility that patients might benefit from stem cell therapies to cure these and other diseases.

That same year, however, anonymous tips raised questions about images depicting the stem cell lines in one of the papers, and a university and government investigation revealed that the stem cells did not come from the cells as Hwang claimed, but from IVF embryos. Hwang said was not aware of the fraud, which he maintained was perpetrated by members of his lab, but was stripped of his position at the university and banned from conducting stem cell research in Korea. He is reportedly seeking investors to fund his research outside of the country.

Dr. Roger Poisson

Sometimes fraud can be driven by good, but misguided intentions. Poisson, a professor of surgery at the University of Montreal, was a member of the prestigious National Surgical Adjuvant Breast and Bowel Project (NSABP), a joint U.S. and Canadian research effort that since 1958 has conducted studies on some of the most effective treatments for breast cancer. In 1994, the U.S. Office of Research Integrity found that for nearly a decade, Poisson had enrolled patients who were not eligible for trials and then falsified or fabricated their medical records to cover up their ineligibility, in an effort to involve as many women as possible in the studies. Investigators found two sets of patient books in Poisson’s lab, one marked ‘true’ and another labelled ‘false.’ The women were part of trials that established that lumpectomy plus radiation was as effective as mastectomy in lowering risk of recurrent breast cancer.

Other studies have since confirmed the benefits of lumpectomy combined with radiation, but the misrepresentation caused many who underwent the procedure to question whether they had made the right decision. “People who are not on the front line of the battle have no idea how frustrating it can be to prepare an eligible patient for a trial, with several pep talks and a great deal of discussion, explanation for the informed consent and to convince the patient to participate and — at the last moment — to realize the patient [is ineligible],” he wrote to the investigators in his defense. Poisson was banned from receiving U.S. government research funding for eight years.

The “Baltimore Case”

The difference between making a mistake and committing fraud is one of intention, and it’s often a fine and obscure line.

That became clear in 1989, when Congress opened hearings into alleged misconduct by Thereza Imanishi-Kari, an assistant in the lab of Nobel laureate David Baltimore at Massachusetts Institute of Technology. In 1985, Baltimore and Imanisi-Kari had published a paper describing their success in injecting a mouse with a gene that altered its immune system so the animal could produce antibodies against a given bacteria or virus. The findings raised the possibility that the human immune system could be modified in the same way, enhancing our ability to ward off infections.

A postdoctoral fellow working in the lab failed to reproduce the results, however, and those concerns eventually led to the Congressional hearings in which Baltimore staunchly defended the work. Imanishi-Kari was found guilty of scientific fraud and Baltimore’s reputation was tarnished by association, leading him to resign from his new position as president of Rockefeller University.

In 1996, however, an appeals board of the National Institutes of Health re-analyzed the case and determined that the paper did not contain fraudulent data, but errors that both co-authors later acknowledged. Imanishi-Kari was exonerated and Baltimore went on to helm California Institute of Technology.

Charles Dawson

The passion of belief, even in scientific discovery, can be enough to perpetuate a hoax across decades, as the case of “Piltdown man” shows. In 1912, Charles Dawson, an amateur archeologist, claimed to have been presented with pieces of a skull dug up by a laborer in the English village of Piltdown. Along with a respected member of the Natural History Museum, Dawson presented his fossil as a remnant of man’s earliest ancestor. Other funny-looking fragments from the same region were unearthed in following years, all eagerly labelled as fossils of an early man.

It wasn’t until 1953, when more sophisticated dating techniques became available, that the fossils were determined to be a hoax, actually made from what appeared to be an orangutan’s jaw. It’s not clear whether Dawson was the original mastermind behind the fraud, or whether he was the front for others who had reason to stick it to the British scientific establishment (Sir Arthur Conan Doyle, of Sherlock Holmes fame, was one possible candidate), but regardless who the culprit was, he was certainly the one who enjoyed the last laugh.