Development of a novel antibody to calcitonin gene-related peptide for the treatment of osteoarthritis-related pain

Abstract

LY2951742 is a high affinity, neutralizing antibody to CGRP. Neutralization of CGRP is efficacious in several OA pain models and works independently of NSAID mechanisms of action. LY2951742 holds promise for the treatment of pain in OA patients.

Translational Pharmacodynamics of Calcitonin Gene-Related Peptide Monoclonal Antibody LY2951742 in a Capsaicin-Induced Dermal Blood Flow Model

“…This is in agreement with the observation that several parts of the brain involved in pain transmission by the trigeminal nerve appear not to be protected by the BBB and are therefore potential targets of CGRP-R antagonists (Eftekhari et al, 2013). Additionally, should CGRP antibodies prove efficacious for the treatment of other chronic impairments, such as osteoarthritis (Mapp et al, 2012;Hirsch et al, 2013;Benschop et al, 2014) and menopausal flushing (Gupta et al, 2007;Hay and Poyner, 2009), the favorable dosing scheme of antibodies over small molecules could increase their therapeutic value. The first positive results from clinical proof-of-concept studies in migraine prevention with LY2951742 and ALD-403 were presented at the 2014 American Academy of Neurology conference, and additional clinical trials with LY2951742 (Bigal and Walter, 2014) and other antibodies to CGRP (LBR-101) or CGRP-R (AMG334) are underway.…”

“…The results obtained with two different antibodies to CGRP (LSN2915644 and LY2951742) clearly demonstrated that both antibodies can effectively neutralize CGRP in vivo in animals for a prolonged period of time. We have previously reported the inhibition of capsaicininduced DBF in the rat using LY2951742 (Benschop et al, 2014). A similar method has been used by others to assess the target engagement of small molecule inhibitors of the CGRP receptor in the periphery in both preclinical (Hershey et al, 2005;Salvatore et al, 2008) and clinical (Salvatore et al, 2010;Sinclair et al, 2010) settings.…”

“…Human IgG4 antibodies were generated as previously described (Benschop et al, 2014). In these studies, two related and equally potent [based on inhibition of CGRP-induced cAMP production in SK-N-MC cells in vitro (Benschop et al, 2014)] CGRP neutralizing antibodies (LSN2915644 and LY2951742) were used.…”

“…In addition, antibodies generally display a long pharmacokinetic (PK) profile, making an antibody potentially more suitable for the treatment of chronic conditions. LY2951742 (Benschop et al, 2007) is a humanized monoclonal antibody that selectively binds and neutralizes CGRP and has been identified for clinical development in migraine prophylaxis (Dodick et al, 2014) and osteoarthritis pain (Benschop et al, 2014). LY2951742 binds both a-and b-CGRP with approximately equal affinity.…”

“…The capsaicin-induced DBF change can be quantified using laser Doppler imaging (LDI), and CGRP was identified as the key mediator involved in this model (Van der Schueren et al, 2008). This neurogenic inflammation model, therefore, can be used to evaluate the target engagement of compounds that inhibit the CGRP pathway both preclinically (Salvatore et al, 2008;Benschop et al, 2014) and in clinical development (Salvatore et al, 2010;Sinclair et al, 2010).…”