“An antibody having this high an affinity will shut down the biology of CGRP very quickly. The same is true for the very high–affinity anti-TNF and anti-interleukin-6 antibodies used in rheumatology. ALD403 will not only bind to free CGRP, it will actually pull CGRP off the receptor. Everything goes towards the antibody; it acts as a sink,” Dr. Smith replied.
This study was too small to identify predictors of hyperresponsiveness. Investigators hope to hunt down useful biomarkers in the large upcoming phase III studies, he added.
TEV-48125: Dr. Bigal presented the first-ever clinical trial of any CGRP-inhibiting antibody in patients with chronic migraine, defined as 15 or more headache days per month. All other studies to date have been conducted in patients with episodic migraine, who typically have far less cardiovascular disease and other comorbidities. Another unique feature of this trial was that current users of migraine preventive medications weren’t excluded; indeed, roughly half of participants were current users.
In this 263-patient, multicenter, double-blind, placebo-controlled, 3-month, phase II study, once-monthly subcutaneous TEV-48125 at 900 mg resulted in a 6.3-day reduction in the monthly number of moderate to severe headache days, while a regimen consisting of a 675-mg loading dose followed by 225 mg achieved a 6-day reduction, compared with baseline. Both of these outcomes were significantly better than the 4-day reduction seen with placebo.
Moreover, efficacy was evident just 1 week into the study. At that point, patients on either the high or low dose of TEV-48125 already showed a significantly greater reduction in the number of headache hours recorded in an electronic headache diary than did controls.
The monoclonal antibody–treated patients also resorted to acute medications significantly less frequently than did controls by a margin of roughly 2 fewer days per month.
The benefit of both TEV-48125 dosing regimens was equally robust regardless of whether they were on conventional prophylactic medications.
A 75% or greater reduction in monthly headache days was achieved in 32% of patients on the 900-mg dose, in nearly 30% of those on 675/225 mg, and in 16% of controls.
“These patients had suffered with frequent migraine for an average of 18 years, and now they come in and say, ‘I’m basically free of headaches for the first time in my life,’” Dr. Bigal said.
Dr. Robert Lenz
AMG 334: This fully human monoclonal antibody to the CGRP receptor was the focus of a multicenter, phase IIb, double-blind, dose-ranging study in 483 patients with 4-14 migraine days per month at baseline. Patients with comorbid depression and/or anxiety disorders were eligible to participate.
The most effective dose, and the one being carried forward into phase III, was 70 mg given subcutaneously once per month. The mean number of monthly migraine days was reduced by 3.4 days in patients on that regimen from a baseline of 8.7 days, significantly better than the 2.28-day reduction with placebo. In a prespecified secondary analysis, there was no difference in efficacy between patients with more than 8 monthly migraine days at baseline and those with fewer than 8 days, reported Dr. Robert Lenz of Amgen in Thousand Oaks, Calif.
The safety data showed no signal of any adverse event. Fewer than 3% of patients of the AMG 334 group discontinued treatment for any reason.