Experimental Agent Boosts Hope for Monoclonal Antibody Treatment of Migraine

SAN FRANCISCO—Preliminary findings of LBR-101, an anti–calcitonin gene-related peptide (CGRP) monoclonal antibody, are promising for the treatment of chronic and high-frequency episodic migraine, according to Marcelo E. Bigal, MD, PhD, who addressed the Seventh Annual Winter Conference of the Headache Cooperative of the Pacific (HCOP).

Dr. Bigal presented pooled results of the phase I program of LBR-101, which assessed the safety and tolerability of the agent when it was administered intravenously to healthy volunteers. Doses were given as a one-time infusion (on day 1), ranging from 0.2 mg to 2,000 mg, or twice (on days 1 and 14), in amounts of 30 mg or 300 mg.

Marcelo E. Bigal, MD, PhD

Patients who received any dose of LBR-101 (n = 94) reported an average of 1.4 treatment-emerging adverse effects, versus 1.3 in those who received placebo (n = 45). The rate was slightly higher—1.6—in the subset of patients receiving 1,000 mg or higher of LBR-101. The overall rate of treatment-related adverse events was 21.2% in patients receiving any dose of LBR-101, 22.4% for those receiving a dose of 100 mg or higher, and 21.7% for those receiving a dose of 1,000 mg or higher; the rate for patients receiving placebo was 17.7%.

In addition, the authors of the report, which was published in the December 2013 issue of Cephalalgia, found no association between LBR-101 and any clinically relevant patterns of change in vital signs, ECG parameters, or laboratory findings. The sole serious adverse event to occur—described by the investigators as “thoracic aortic aneurysm”—was attributed to the participant’s unreported history of Ehlers-Danlos syndrome.

Finding all doses of LBR-101 to be well tolerated, the investigators concluded that overt safety concerns have not emerged, while a maximally tolerated dose has yet to be identified. “If you go with the higher dose, you don’t increase the treatment-related adverse events,” said Dr. Bigal, Chief Medical Officer of the San Mateo, California-based Labrys Biologics, which is developing the agent. “We didn’t find anything relevant at all … such as a patient having an increase in blood pressure or relevant abnormalities in laboratory exams.”

In a follow-up study submitted to Cephalalgia a week before the HCOP conference, he and his coinvestigators reported what happens with cardiovascular parameters after CGRP inhibition using high doses, based on the telemetry and ECG data they obtained. “We hired one of the best regulatory cardiologists in the country, and we did sophisticated analysis,” said Dr. Bigal. “We did not find any relevant cardiovascular abnormalities. We also have not seen signals of liver toxicity or other metabolic changes.”

Monoclonal Antibodies Under Investigation
To date, several small-molecule formulations of CGRP receptor antagonists have advanced as far as phase II or III clinical trials, and all of them have succeeded in terms of efficacy. However, because these compounds were associated with liver toxicity or other safety concerns or have been difficult to formulate as oral medications, researchers have turned to an alternative approach for targeting CGRP: monoclonal antibodies.

Of the four anti-CGRP monoclonal antibodies under investigation, three, including LBR-101, are being developed directly against the peptide (ie, as anti-ligands) and the fourth against the CGRP receptor. Monoclonal antibodies have several key properties relevant to therapy that offer advantages over small-molecule formulations, including longer half-life, larger size, and specific aspects of their binding and effector functions, according to Dr. Bigal.

“CGRP is considered to be the proper intersection between the peripheral and central events of migraine,” he said in an interview with Neurology Reviews. “CGRP inside the brain seems to modulate nociception. Outside the brain, it causes vasodilation and inflammation around the blood vessels…. Since the target is so important to migraines, since [it] is so validated … we started approaching the target via the monoclonal antibodies.

“Monoclonal antibodies have exquisite specificity,” he continued. “They go to the target directly and are not degraded in the liver, so they could actually bypass the issue of liver toxicity.”

An Inside/Outside Therapeutic Approach
Dr. Bigal traced the history of research linking CGRP to migraine. A 37–amino acid peptide, CGRP was first discovered as a potent vasodilator and initially considered important in migraine—specifically as a potential mediator of trigeminal inflammation. “Scientists found that it was a vasodilator and a vascular modulator,” he said. “They thought this was important for a migraine because migraine was considered to be a vascular disorder, which it is not. Indeed, our thoughts about CGRP have evolved dramatically.

“If I had to summarize it to you, I would quote one of the leading investigators in the field, Dr. Andrew Russo, saying that CGRP is crucially positioned in the intersection between peripheral and central events in migraine…. You can block CGRP if you get inside the brain; you can block CGRP if you do not get inside the brain. And if you do not get inside the brain, you will still control CGRP inside the brain just by the neuromodulator effect.”