The background

Five controlled trials have demonstrated the efficacy of calcitonin gene-related peptide (CGRP) inhibition in the acute treatment of migraine. Two studies confirmed the concept of preventive treatment of episodic migraine with monoclonal antibodies against CGRP. The effectiveness of CGRP as a target molecule in the treatment of chronic migraine has not yet been confirmed.

The new facts in brief

Bigal et al. (2015) published the first data on the efficacy of a monoclonal antibody against CGRP in the prevention of chronic migraine in the September issue of Lancet Neurology (2015). The drug used was TEV-48125. The antibody was administered subcutaneously every 28 days. Dosages 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 action was rapid. The data confirm a significant reduction in the number of headache hours and days with moderate to severe headaches within the first month. The treatment was also associated with a reduction in the use of acute headache medication for the treatment of migraine attacks. The treatment was well tolerated and safe.

What is CGRP?

CGRP is a protein belonging to the calcitonin family. It exists in two subtypes in the central and peripheral nervous systems. Along with other peptides, it is frequently located on C- and A-delta nerve fibers. These nerve fibers are crucial for transmitting nerve impulses in the body's pain processing system. Recent studies have extensively investigated the role of CGRP in the development of migraine. CGRP is found in trigeminal nerve endings and nuclei. Its release causes vasodilation and inflammation. In the central nervous system, CGRP modulates pain processing. Current studies are intensively investigating CGRP as an important molecule for the treatment of episodic migraine. Initial pilot studies have analyzed the use of CGRP receptor antagonists and CGRP antibodies for the prevention of episodic migraine. These studies conceptually confirmed its role in the development of migraine.

Chronic migraines

The World Health Organization (WHO) considers chronic migraine one of the most disabling diseases in the world. Chronic migraine leads to significant individual disability, severe suffering, job loss, family stress, divorce, and pain-related psychological comorbidities. Onabotulinumtoxin is currently the only approved treatment option.

TEV-48125

TEV-48125 is a monoclonal antibody that binds highly effectively and selectively to CGRP. It thereby prevents CGRP from acting on the receptor. The study by Bigal et al. (2015) was the first to investigate the efficacy, 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 randomized, double-blind, placebo-controlled, and conducted in a double-dummy design. Two dosages of TEV-48125 (675/225 mg and 900 mg) as well as placebo were used. Administration was subcutaneous every 28 days for 3 months. Men and women aged 18 to 65 years with a diagnosis of chronic migraine according to the ICHD (3rd edition, beta version) were included. Patients were allowed to continue their usual acute migraine medication during the study. Patients were excluded from the study if they had been treated with onabotulinumtoxin A within 6 months prior to study entry, if they were taking opioids or barbiturates for more than 4 days during the run-in phase, or if they had used three or more prophylactic treatments without efficacy.

TEV-48125 or placebo was administered via four subcutaneous injections in the abdominal region at the start of each treatment cycle. Patients in the 900 mg group received four active injections at the start of each treatment cycle. Patients in the 675/225 mg group initially received 675 mg and then 225 mg as a maintenance dose in subsequent treatment cycles. Patients in the placebo group received four placebo injections at the start of each treatment cycle.

The main target parameter was the mean change compared to baseline regarding the number of headache hours during the third treatment cycle (weeks 9-12).

The secondary endpoint was the mean change from baseline in the number of headache days with at least moderate or severe intensity during the third treatment cycle. Additional exploratory endpoints were also investigated.

The results

A total of 264 participants were recruited. During the baseline phase, the placebo group experienced 169.1 headache hours of any intensity per month, the 675/225 mg group 159.1, and the 900 mg group 157.7. The placebo group experienced 13.9 headache days per month, the 675/225 mg group 13.8, and the 900 mg group 13.1 headache days of at least moderate intensity.

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 headache hours was significantly greater for both treatment groups than for the placebo group.

The change in the mean number of headache days and migraine days differed significantly between placebo and the 900 mg group, but was not significant between placebo and the 675/225 mg group. Both dosages significantly reduced the number of medications required for the 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. The most frequently reported adverse events were mild pain and tingling at the injection site.

The significance of the results

The study findings confirm for the first time the therapeutic efficacy of using a CGRP antibody in the preventive treatment of chronic migraine. Clinically relevant improvements in migraine symptoms were observed as early as one month after the start of treatment. The treatment also led to a significant reduction in the need for acute migraine medication.

Specific aspects of the headache phenotype of chronic migraine were considered as target points for demonstrating efficacy. Chronic migraine typically develops from episodic migraine. The duration of headaches increases, while the headache intensity decreases, the headache phenotype becomes less characteristic, and it can eventually progress to persistent headache with superimposed severe attacks.

For this reason, the total headache duration was recorded using the parameter "headache hours," and the time spent with moderate or severe headaches was determined using the parameter "headache days." A particular strength of this study is that it examined a cross-section of all patients with chronic migraine. Patients who had previously used other preventive medications and without strict limitations on acute medication could be included. Patients with persistent headaches were also included.

This study has implications for understanding the development and maintenance of chronic migraine. Peripheral CGRP concentrations are elevated in patients with chronic migraine compared to those with episodic migraine. The study confirms that CGRP is an important molecule in the treatment of chronic migraine. Only a very small fraction (0.1–0.5%) of the antibodies can cross the blood-brain barrier. Therefore, it can be assumed that CGRP antibodies exert their effects within peripheral nerve structures.

Based on this study, further, larger phase 3 studies can now be conducted.

 

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.