Migraine headaches affect millions of individuals worldwide with an estimated 30 million migraine sufferers in the U.S. alone. Despite that high prevalence only a limited number of effective treatment options for migraine currently exist, which include nonsteroidal anti-inflammatory drugs (NSAIDs) and triptans (5-HTIB/1D agonists). Those medicines are not effective in all migraine patients and they do have side-effect issues. That is why there has been a search for more effective treatments. Unfortunately, up until recently, finding new therapies to prevent and treat migraines has proved to be a "headache" for both biotech and big pharma companies alike. However, the future is starting to look a little brighter for migraine research as companies have begun to focus on drugs that target the calcitonin gene-related peptide (CGRP), a 37-amino acid neuropeptide released in the brain during migraine attacks.

Well-Defined Target

"The development of CGRP antagonists as a specific treatment for migraine is an exciting area thanks to late-stage clinical research conducted by such companies as Merck," Randall Schatzman, president and CEO of Alder BioPharmaceuticals, told BioWorld Insight. "CGRP is now a well-defined target with research showing that CGRP has a role as a trigger for migraine attacks, and inhibiting the peptide is a promising therapeutic strategy in preventing the onset of migraines."

While Merck & Co. Inc. discontinued development of telcagepant, its investigational CGRP receptor antagonist, in 2011, Alder hopes that its own antibody therapeutic candidate, ALD403, targeting CGRP for treatment of migraine will be successful in meeting the need of patients who experience migraines on a routine basis.

Although Alder has several ongoing projects in its pipeline, its focus on migraine is attractive because it is an area in which antibodies haven't played a significant role in the past.

The company's antibody is completing a Phase I placebo-controlled, single ascending-dose study to evaluate the safety and tolerability of ALD403 administered via both intravenous infusion and subcutaneous injection. "Patients who are afflicted with migraines three or four times a week would find it difficult to pay the high price tag that antibodies claim in other diseases such as cancer and rheumatoid arthritis," John Latham, chief scientific officer, told BioWorld Insight. That is why the company's scalable, low-cost approach to making full-length antibodies could provide an advantage, he added.

Alder has developed a yeast expression system that has the ability to make fully functional whole antibodies at a fraction of the time and cost of other technologies.

Ultimately, if ALD403 proves its worth in clinical trials, Latham said he thinks it would be self-administered by patients on a periodic dosing schedule, much like Abbott's TNF-alpha inhibitor Humira (adalimumab) is administered by rheumatoid arthritis patients.

ALD403 is unpartnered at the present and to help support that research, as well as other projects in their clinical pipeline, Alder raised $38 million in a Series D financing in April. (See BioWorld Today, April 20, 2012.)

Other Developers

Alder doesn't have the CGRP therapeutic antibody space entirely to itself. Cambridge, Mass.-based biotech start-up Arteaus Therapeutics LLC licensed the global rights to a migraine antibody technology from Eli Lilly and Co., of Indianapolis, last year. (See BioWorld Today, Oct. 20, 2011.)

Arteaus raised $18 million in a Series A financing from Atlas Venture, of Cambridge, Mass., and OrbiMed Advisors, of New York, to advance the technology in collaboration with Lilly.

According to David Grayzel, CEO of Arteaus and managing director of Atlas Venture Development Corp., it was the encouraging data from a Phase I single ascending-dose study that supported the decision to move forward with the antibody's development.

The antibody's mode of action appears to block CGRP from binding to its ligand, preventing the vasodilation and pain transmission in the brain that characterizes migraine and, thus, prevents the debilitating headaches themselves.

Using a virtual team and collaborating with Lilly's Chorus unit – an autonomous unit that focuses on early drug development through proof of concept – the company will develop the antibody through Phase II randomized trials to demonstrate proof of concept in migraine prevention. Upon completion of the study, Lilly will have the option to continue to develop the antibody at pre-negotiated terms, including milestones and royalties. If Lilly declines to reclaim the migraine compound, Arteaus has the option to pursue another buyer or fund the company for additional trials.

The significant market opportunity for drugs to prevent and treat acute migraine is attracting other biotech companies who are employing other therapeutic strategies. For example, Ariel Pharmaceuticals Inc., of Broomfield, Colo., is developing lead product AP-1531 , which it in-licensed from health care company BTG International Ltd. The company said there is evidence to demonstrate that prostaglandin E2 (PGE2) binding to the EP4 receptor causes dilation of small blood vessels in the brain, while leaving coronary and pulmonary arteries unaffected, and can stimulate a variety of inflammatory mechanisms. AP-1531 is a selective EP4 receptor antagonist that specifically targets PGE2-EP4 binding, which may treat migraines.

AP-1531 has shown promising results in several disease models of migraine and acute pain and inflammation. Ariel is gearing up to start a Phase II trial of AP-1531 in migraine this year, and according to company President and CEO Steve Orndorff, a Phase IIb study comparing the drug to triptans likely would follow. Six Phase I studies turned up a "clean safety profile," according to Orndorff, as well as efficacy data for both pain and migraine. (See BioWorld Today, Oct. 3, 2011.)

MAP Pharmaceuticals Inc., of Mountain View, Calif., also is pressing on with its plans to resubmit a new drug application for Levadex (dihydroergotamine) inhalation aerosol for the acute treatment of migraine in adults later this year. In March, the company received a complete response letter for Levadex. Although the FDA did not request that any new clinical trials be conducted, it did raise questions relating to chemistry, manufacturing and controls, as well as issues related to a facility inspection at a third-party manufacturer. (See BioWorld Today, June 22, 2012.)