Five controlled studies have demonstrated the effectiveness of calcitonin gene-related peptide (CGRP) inhibition in the acute treatment of migraine. The concept of a preventive treatment of episodic migraine with monoclonal antibodies against CGRP was confirmed in two studies. CGRP as a target molecule in the treatment of chronic migraine has not yet been confirmed.
The new facts in short form
Bigal et al. (2015) published data on the effectiveness of a monoclonal antibody against CGRP in the prevention of chronic migraine for the first time in the September issue of Lancet Neurology (2015). The active ingredient TEV-48125 was used. The antibody was injected subcutaneously at 28-day intervals. Doses of 675/225 mg and 900 mg were used. The treatment resulted in a significant reduction in primary and secondary efficacy parameters compared to placebo. The onset of effects came quickly. The data confirm a significant reduction in the number of headache hours and days with moderate or severe headaches within the first month. The treatment was also associated with a reduction in the consumption of acute headache medication to treat migraine attacks. The tolerability and safety of the treatment were good.
What is CGRP?
CGRP is a protein that is part of the calcitonin family. It occurs in two subforms in the central and peripheral nervous systems. Along with other peptides, it is often localized to C and A delta nerve fibers. These nerve fibers are important for the transmission of nerve impulses in the body's pain-processing system. In recent years, studies have extensively examined the importance of CGRP in the development of migraines. CGRP is found in trigeminal nerve endings and nerve nuclei. The release of CGRP causes vasodilatation and inflammation. In the central nervous system, CGRP modulates pain processing. CGRP is being intensively investigated in current studies as an important molecule for the treatment of episodic migraine. In initial pilot studies, the use of CGRP receptor antagonists and CGRP antibodies to prevent episodic migraines was analyzed. The significance for the development of migraines was conceptually confirmed.
The World Health Organization (WHO) ranks chronic migraine as one of the most disabling diseases affecting humanity. Chronic migraine leads to severe individual disability, severe suffering, job loss, family stressful situations, divorce and pain-maintaining psychological comorbidities. Onabotulinumtoxin is the only treatment option approved to date.
TEV-48125 is a monoclonal antibody that binds highly effectively and selectively to CGRP. It thereby prevents the effect of CGRP on the receptor. The study by Bigal et al. (2015) examined for the first time the effectiveness, tolerability and safety of TEV-48125 for the preventive treatment of chronic migraine using two different dosages.
The design of the study
The study was carried out in a randomized, double-blind, placebo-controlled, double-dummy design. Two doses of TEV-48125 (675/225 mg and 900 mg) and placebo were used. It was administered subcutaneously every 28 days for a period of 3 months. Men and women between the ages of 18 and 65 years with a diagnosis of “chronic migraine” according to ICHD (3rd edition, beta version) were included. The patients were able to use their usual acute migraine medication during the study. Patients were ineligible to participate in the study if they had been treated with onabotulinumtoxinA for 6 months prior to study entry, had taken opioids or barbiturates for more than 4 days during the run-in period, or had used three or more preventive treatments without effectiveness.
TEV-48125 or placebo was administered with 4 subcutaneous abdominal injections at the start of each treatment cycle. Patients in the 900 mg group received 4 active injections at the start of each treatment cycle. Patients in the 675/225 mg group received 675 mg initially and 225 mg as a maintenance dose in subsequent treatment cycles. Patients in the placebo group received 4 placebo injections at the start of each treatment cycle.
The main outcome measure was the mean change from baseline in the number of headache hours during the third treatment cycle (weeks 9-12).
The secondary outcome measure was the mean change from baseline in the number of headache days with at least moderate or severe intensity during the third treatment cycle. In addition, further exploratory target parameters were examined.
A total of 264 subjects were recruited. During the baseline phase, there were 169.1 headache hours of any intensity per month in the placebo group, 159.1 in the 675/225 mg group and 157.7 headache hours per month in the 900 mg group. There were 13.9 headache days per month in the placebo group, 13.8 in the 675/225 mg group and 13.1 headache days of at least moderate intensity per month in the 900 mg group.
The mean reduction in headache hours during weeks 9-12 compared to baseline was -67.51 hours (43%) in the 900 mg group, -59.84 hours (38%) in the 675/225 mg group and - 37.10 hours (22%) in the placebo group. The reduction in the number of headache hours was significantly greater for both verum groups than for the placebo group.
The change in the mean number of headache days and migraine days was significantly different between placebo and the 900 mg group, but was not significant between placebo and the 675/225 mg group. Both doses significantly reduced the number of medications needed for acute treatment of migraine compared to placebo.
Adverse events were reported by 40% in the placebo group, 53% in the 675/225 mg group and 48% in the 900 mg group. Mild pain at the injection site and tingling were most commonly reported.
The meaning of the results
The study findings confirm for the first time the therapeutic effectiveness of the use of a CGRP antibody in the preventative treatment of chronic migraine. Clinically relevant improvements in migraines were observed just one month after the start of treatment. The treatment also led to a significant reduction in acute migraine medication.
Specific aspects of the headache phenotype of chronic migraine were taken into account as target points for proof of effectiveness. Chronic migraine usually develops from episodic migraine. This increases the time with headaches. However, the intensity of the headache becomes less, and the headache phenotype also becomes less characteristic and can ultimately develop into a permanent headache with superimposed severe attacks.
For this reason, the total headache time was recorded using the “headache hours” parameter and the time with moderate or severe headaches was determined using the “headache days” parameter. A particular strength of this study is that a cross-section of all patients with chronic migraine was examined. Patients who had previously used other preventive medications and without strict limitations on acute medication could be examined. Patients with persistent headaches were also included.
The study has implications for understanding the development and maintenance of chronic migraine. Peripheral CGRP concentrations are increased in patients with chronic migraine compared to patients with episodic migraine. The study confirms that CGRP is an important molecule in the treatment of chronic migraine. Only a very small proportion (0.1-0.5%) of the antibodies can cross the blood-brain barrier. For this reason, it can be assumed that the CGRP antibodies exert their effect in the area of peripheral nerve structures.
Based on this study, further larger phase 3 studies can now be carried out.
Bigal ME, Edvinsson L, Rapoport AM, Lipton RB, Spierings EL, Diener HC, Burstein R, Loupe PS, Ma Y, Yang R, Silberstein SD. Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine: a multicenter, randomized, double-blind, placebo-controlled, phase 2b study. Lancet Neurol. 2015 Nov;14(11):1091-100. doi: 10.1016/S1474-4422(15)00245-8. Epub 2015, Sep 30. PubMed PMID: 26432181.