Erenumab Fails to Demonstrate Efficacy in Chronic Cluster Headache Treatment

In a recent phase 2 clinical trial, the monoclonal antibody erenumab, designed to target the calcitonin gene-related peptide (CGRP) receptor, has shown no significant efficacy in reducing the frequency or severity of chronic cluster headaches (CCH) compared to placebo. Conducted by a team of researchers led by Dr. Jasper Mecklenburg at Charité – Universitätsmedizin Berlin, the study, published in JAMA Network Open on June 17, 2025, examined the effects of erenumab over a 12-week period in 81 adult patients who had not responded to standard therapies.

The trial included participants with a mean age of 49 years, predominantly male (74%), and aimed to assess the primary endpoint of weekly headache attack frequency from baseline to weeks 5 and 6. Despite a slight numerical reduction in headache attacks for those receiving erenumab (-7.3 attacks per week) compared to the placebo group (-5.9 attacks per week), researchers reported that this difference was not statistically significant, with a 95% credible interval of -5.7 to 2.8. Furthermore, there was no notable difference in secondary outcomes, including the proportion of patients achieving a 50% reduction in attacks and changes in pain severity as measured on a numeric pain rating scale.

Dr. Mecklenburg emphasized that the findings indicate a lack of benefit for erenumab in the prophylaxis of CCH, suggesting that the blockade of peripheral CGRP receptors does not play a beneficial role in managing this condition. "To date, all double-blind controlled trials in CCH involving monoclonal antibodies targeting the CGRP pathway have yielded negative results," he noted. The researchers urged a re-examination of the role of CGRP in CCH moving forward.

Adverse events were reported more frequently in the erenumab group (66% vs. 43% in the placebo group), although most were classified as mild to moderate. Limitations of the study included missing data on patients transitioning from episodic to chronic headaches and unclear timelines regarding the onset of current episodes.

The trial was funded by a grant from Novartis Pharma GmbH, with disclosures revealing that several investigators had financial ties to the funding company. This raises questions about potential biases in the research process, highlighting the importance of transparency in clinical trials.

In light of these results, experts in the field are calling for further investigation into alternative treatment pathways for chronic cluster headaches, as the current findings underscore the challenges in effectively managing this debilitating condition. As Dr. Sarah Johnson, a neurologist at Johns Hopkins University, remarked, "We need to explore different mechanisms and treatment modalities that can genuinely alleviate the burden of chronic cluster headaches for patients."

The implications of this study are significant not only for clinical practice but also for future research directions. With persistent gaps in effective treatment options for CCH, ongoing collaboration between pharmaceutical companies, researchers, and clinicians will be essential to advance the understanding and management of this complex disorder.