What does the humanized monoclonal anti-CGRP antibody (TEV-48125) teach us about the perception of migraine headache? (P2.159)

Objective: To understand better how a humanized monoclonal anti-CGRP antibody (CGRP-mAb) modulates meningeal sensory pathways. Background: A large body of evidence supports an important role for CGRP in the pathophysiology of migraine. This evidence gave rise to a global effort to develop a new generation of therapeutics that reduces the availability of CGRP in migraineurs. Recently, the second generation of such drugs, all humanized monoclonal anti-CGRP antibody was found to be effective in reducing the frequency of chronic or episodic migraine. Design/Methods: Single-unit extracellular recording techniques were used to determine the effects of TEV-48125 (30 mg/kg IV) and its isotype (control) on spontaneous and evoked activity in naive and CSD-sensitized central trigeminovascular neurons in the medullary and upper cervical dorsal horn in anesthetized male and female rats. Results: The study demonstrates that the CGRP-mAb TEV-48125 inhibits naive high-threshold (HT) but not wide dynamic range (WDR) trigeminovascular neurons, that the inhibitory effects are limited to their activation from the intracranial dura but not facial skin or cornea, and that when given sufficient time, this drug prevents activation and sensitization of HT but not WDR neurons by cortical spreading depression. This inhibition was similar in the male and female rats. Conclusions: For patients whose chronic and episodic migraines are relieved by the CGRP-mAb, the findings raise the possibility that HT neurons play a critical role (not recognized before) in the initiation and chronification of the perception of headache whereas WDR neurons contribute to the associated allodynia and central sensitization. Clinically, the findings may help explain why the therapeutic effects of CGRP-mAb are selective to headaches of intracranial origin such as migraine and why this therapeutic approach may not be effective for every migraine patient. Study Supported by: Teva Pharmaceuticals NIH Grants: R37 NS079678 and NS085510 Disclosure: Dr. Melo-Carrillo has nothing to disclose. Dr. Strassman has nothing to disclose. Dr. Schain has nothing to disclose. Dr. Reuven-Nir has nothing to disclose. Dr. Burstein has received personal compensation for activities with Allergan, GSK, and Merck as a consultant or member of the scientific advisory board.