Monoclonal antibodies against GFRα3 are efficacious against evoked hyperalgesic and allodynic responses in mouse join pain models but, one of these, REGN5069, was not effective against pain in a randomized, placebo-controlled clinical trial in patients with osteoarthritis pain

• DOI: 10.1016/j.ynpai.2023.100136
• Publication Date: 2023-06-27T01:20:34Z
• Authors: Selin Somersan-Ka...; Kenneth C. Turner; Luz Cortes-Burgos; Jutta Miller; Michael LaCroix-F...; Veronika Logovinsky; Yamini Patel; Richard Torres; Samit Ganguly; Aurora Breazna; Michelle DeVeaux; Rafia Bhore; Min Gao; Frank J. Delfino; Ashique Rafique; Jeanette L. Fairh...; Charleen Hunt; Robert Babb; Ashok Badithe; William T. Poueym...; Ronald Surowitz; Sylvie Rottey; Andrew J. Murphy; Olivier Harari; Lynn E. Macdonald; Susan D. Croll
• Keywords: Allodynia

The artemin-GFRα3 signaling pathway has been implicated in various painful conditions including migraine, cold allodynia, hyperalgesia, inflammatory bone pain, and mouse knees contain GFRα3-immunoreactive nerve endings. We developed high affinity (REGN1967) human (REGN5069) GFRα3-blocking monoclonal antibodies and, following vivo evaluations models of chronic joint pain (osteoarthritic-like inflammatory), conducted a first-in-human phase 1 pharmacokinetics (PK) safety trial REGN5069 (NCT03645746) healthy volunteers, 2 randomized placebo-controlled efficacy (NCT03956550) patients with knee osteoarthritis (OA) pain. In three commonly used (destabilization the medial meniscus, intra-articular monoiodoacetate, or Complete Freund's Adjuvant), REGN1967 attenuated evoked behaviors tactile allodynia thermal hyperalgesia without discernably impacting pathology inflammation, prompting us to further evaluate humans. study subjects, profiles single doses up 3000 mg (intravenous) 600 (subcutaneous) were comparable placebo; PK consistent antibody exhibiting target-mediated disposition. OA two (100 1000 intravenous every 4 weeks) for 8 weeks failed achieve 12-week primary secondary endpoints relative placebo. addition possible differences GFRα3 biology between mice humans, we highlight here experimental parameters that could have contributed different profile versus Additional research is required more fully any potential role