To prevent migraine attacks, neurologists commonly prescribe drugs designed to treat epilepsy, high blood pressure, or depression. Monoclonal antibodies currently in development could one day become the first prophylactic therapies specifically targeted to migraine. The antibodies are administered through an injection and block the activity of calcitonin gene-related peptide (CGRP), which may cause migraine by promoting vasodilation and neuroinflammation. If clinical trials prove the antibodies to be safe and effective, they could prevent migraine attacks for as long as a month.
Alder Biopharmaceuticals, Arteaus Therapeutics, and Labrys Biologics are developing monoclonal antibodies that bind with CGRP and prevent it from reaching CGRP receptors. In addition, Amgen is testing AMG 334, a monoclonal antibody that binds to the CGRP receptor and inhibits the function of CGRP. In theory, both approaches could be equally effective, although only the clinical studies will demonstrate nuanced differences in clinical efficacy and safety between them, said Marcelo E. Bigal, MD, PhD, Chief Medical Officer of Labrys in San Mateo, California.
Small-Molecule Drugs First Targeted the CGRP Receptor
Treating migraine by blocking the function of CGRP is not a new idea. Merck, Boehringer Ingelheim, and Bristol-Myers Squibb developed small-molecule CGRP receptor antagonists that proved their efficacy in phase II and phase III trials. The drugs demonstrated “placebo-like tolerability in several of the tested doses” and were “superior to placebo in all the efficacy end points for migraine,” Dr. Bigal told Neurology Reviews.
The medicines caused minor increases in liver enzymes in a subgroup of patients, however, and companies discontinued development for many of them because of liver toxicity. Yet the hepatotoxicity of the CGRP receptor antagonists was approximately one-fifteenth that of triptans, said Lars Edvinsson, MD, PhD, Professor of Internal Medicine at Lund University in Sweden. New small-molecule CGRP receptor antagonists are in development, and these therapies eventually could be effective for the acute treatment of migraine, said Dr. Edvinsson.
The Advantages of Antibodies
The antibodies in development are large-molecule biologics, which are not degraded in the liver and do not have the same potential for drug–drug interactions as small molecules. “The hope is that we will be able to maintain or improve efficacy,” compared with the original CGRP receptor antagonists, said Dr. Bigal.
Large-molecule therapies generally have fewer off-target side effects, compared with small molecules, said Cen Xu, PhD, Scientific Director of Amgen in Thousand Oaks, California. Antibodies also have a longer plasma half-life than small molecules, which makes them more suitable for prevention than for acute treatment. LBR-101, the antibody that Labrys is developing, has a half-life of more than 45 days. A long plasma half-life also reduces dosing frequency, which can improve compliance with an injectable drug.
Topiramate, valproate, and propanol are current preventive medications for migraine with moderate efficacy. Migraine days are reduced by 50% in approximately half of patients who take any of these drugs.
Companies Seek to Enable Self-Injections
Because biologics cannot be delivered orally, the four companies must decide whether to formulate their antibodies for IV, intramuscular, or subcutaneous delivery. IV injections would enable the delivery of large doses, but they would have to be administered by a health care professional. Non-IV formulations are more convenient because they enable self-administration at a place and time of the patient’s choosing, noted Dr. Bigal.
The antibodies are too large to pass through the blood–brain barrier, so they all work outside the brain. “There is solid evidence to support that inhibiting CGRP outside the blood–brain barrier is what you want because you would have efficacy but, from a theoretical perspective, not cause CNS adverse events,” said Dr. Bigal. LBR-101 binds to CGRP that is released from the trigeminal nerve endings. AMG 334, on the other hand, targets the CGRP receptors on the dural vasculature neuromuscular junction and the trigeminal afferent signaling pathway. This mechanism of action “is similar to [that of] the small-molecule CGRP receptor antagonists.” noted Dr. Xu.
Because of their long half-lives, the antibodies would be most appropriate for patients who require preventive therapy. This population includes all patients with chronic migraine, according to the guidelines of the American Academy of Neurology. Patients who have frequent episodic migraine (eg, six or more disabling days of headache per month) also could be candidates for the antibodies, said Dr. Bigal.
Antibodies Are Entering Phase II Trials
Results from preclinical and phase I studies indicate that LBR-101 is tolerable and does not cause cardiovascular or metabolic dysfunction. “At this point, we have proof of mechanism of action,” said Dr. Bigal. “We have evidence of safety in humans at a phase I level. Pharmacokinetics [and] pharmacodynamics [are] totally demonstrated.”