[Corrected, 8:58 am PT. See below.] Nobody has ever come up with a drug that can stop migraine headaches before they start. This will be the year that Bothell, WA-based Alder Biopharmaceuticals finds out if it can achieve that lofty goal, and change the way patients and physicians think about treating migraines.
Alder passed its first 96-patient clinical trial last year, which suggested a single dose of its injectable antibody for migraines was safe, potent, and potentially deliverable as a once-monthly shot. That result has prompted Alder to sprint ahead this year with a placebo-controlled study of 160 patients that’s designed to show investors, and partners, that this drug candidate is the real thing. The answer to that question should arrive by the end of this year, in time to see if Alder can stay near the front of an increasingly crowded field.
“Our data looks very, very good,” says Alder CEO Randy Schatzman. “It’s going to be a horse race of sorts.”
The prize here could be worth billions. An estimated 6 million people in the U.S. complain of chronic migraine headaches that strike at least 15 times a month. Instead of coming up with more pills, like the conventional generic “triptan” drugs, companies are striving to make long-lasting injectable antibodies that attack migraines in a different way, by pursuing a molecular target called calcitonin gene-related peptide (CGRP). Merck helped kick-start this competition when its conventional small molecule against this target had safety issues, but showed it was effective against migraines. The big idea in biotechland is that a genetically engineered antibody could block the same molecular pathway, but without causing the liver toxicity that derailed the Merck compound. There’s so much interest in migraine treatment today that an old reformulated drug from MAP Pharmaceuticals (NASDAQ: MAPP), which hasn’t yet won FDA approval, was acquired this week for almost $1 billion by Allergan.
For a while in 2010, when Alder was gearing up discovery work for became ALD403, it thought it might be the only company actively pursuing the idea of an antibody against CGRP. But the moment didn’t last long. Alder knew that Pfizer’s Rinat Neuroscience unit had a competing program, but various corporate restructurings put it on the shelf. The program recently got new life when Corey Goodman, a prominent neuroscientist-turned-Pfizer-executive-turned-venture-capitalist, scooped it up at Labrys Biologics. Lilly also spun out its CGRP antibody, with an $18 million investment from Atlas Venture and OrbiMed Advisors, into a new company called Arteaus Therapeutics. Amgen also has a competing program moving ahead in clinical trials, and Bristol-Myers Squibb is reported to be active here, too.
Researchers have known for many years that constricting blood flow to the brain can have some effect against migraine. The traditional triptan pills are thought to work this way for about half to three-fourths of patients. But there are limits, because the drugs can only be taken after migraine pain begins, and the drugs only last a couple of hours, allowing opportunity for so-called “rebound” headaches to strike back. The drugs also come with a warning that they can cause high blood pressure and other side effects like stroke.
The biotech drug developers of the world, Alder included, see a big new opportunity to constrict blood flow to the brain through the CGRP pathway. By being more targeted, the new drugs shouldn’t cause some of the cardiovascular side effects that dogged the triptans. And, because antibodies can be designed to last a long time in the bloodstream, it creates the possibility of a once-monthly or once-quarterly injection that can prevent new headaches or rebound headaches. Antibodies have also traditionally come with high prices, and Alder has said it believes it can deliver a valuable new treatment to the healthcare system, at a price of $5,000 to $7,000 a year, partly because patients lose so much productivity and work time when they suffer from headaches. [A previous version said $5,000 to $7,000 per month. We regret the error—Eds.]
None of these drugs will be in position to hit the market anytime soon, but critical questions are being answered in clinical trials. Alder, for example, designed its antibody to hit the ligand that binds with the CGRP receptor, not the receptor itself. Alder went that route because it should be able to achieve the same result with a smaller dose of its drug in the bloodstream, which should translate into a clean side effect profile and low manufacturing costs, Schatzman says. By making a drug that binds with the CGRP ligand, the patient should be unable to start the molecular process that leads to migraine symptoms.
“We think it’s a better place to play,” Schatzman says, referring to ligand targeting.
It’s still too early to say how the drugs will differentiate themselves, if all of them pass clinical trials. The Labrys candidate, known as RN-307, has completed a Phase I clinical trial and is thought to have a 45-day half-life, which raises the possibility of an injection that could be taken quite infrequently, Schatzman says. The Arteaus candidate, given in a subcutaneous injection, just under the skin, was designed to be given once every two weeks in a 190-patient clinical trial that started last year, according to clinicaltrials.gov.
Alder’s antibody for clinical testing is still currently being given in an intravenous form, not a subcutaneous formulation that would make it possible for patients to conveniently inject themselves at home. A self-injectable drug has obvious marketing benefits, because migraine patients wouldn’t need to go to the doctor every month to get their shot. But in a sign of how competitive this market is, Alder has chosen to plow ahead with its big 160-patient trial this year in the IV form, so that it could find out quickly if it’s got a serious contender in the market. Trials with the subcutaneous form can come later, Schatzman says.
“We could have done the subcutaneous form [for this trial], but it would have delayed us,” Schatzman says. “We decided, let’s find out if this hypothesis works as fast as we can.”
Alder’s trial is designed to ask a series of key questions over a 12-week observation period. Researchers want to know what percentage of patients respond to treatment, and what difference the drug makes in the number of migraine episodes per month, and in severity. The trial will also provide crucial evidence on how long the drug lasts in the bloodstream, which could determine how frequently (or infrequently) patients might have to submit to injections.
Since the trial is designed to enroll 160 patients and compare those on the drug to a placebo, Alder is spending some significant money to gather compelling evidence it will need to muster support from its investors, potential partners, physicians, and payers. The company raised $38 million in venture capital last year, and much of that investment is riding on the outcome of this study, along with one another experimental drug for oral mucositis in cancer patients.
If clinical trial enrollment stays on schedule, Alder could have a big decision to make at the end of this year. By then, it should know how good its drug is, more about how it stacks up competitively, and how much interest it stirs from investors and partners. “This is a multi-billion dollar market,” Schatzman says. “If we can effectively address that, it’s going to be an interesting play for us.”
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