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
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 mouse (REGN1967) and human (REGN5069) GFRα3-blocking...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-08-01
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| Series: | Neurobiology of Pain |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2452073X23000235 |
| _version_ | 1797405383024705536 |
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| author | Selin Somersan-Karakaya Kenneth C. Turner Luz Cortes-Burgos Jutta Miller Michael LaCroix-Fralish Veronika Logovinsky Yamini Patel Richard Torres Samit Ganguly Aurora Breazna Michelle DeVeaux Rafia Bhore Min Gao Frank J. Delfino Ashique Rafique Jeanette L. Fairhurst Charleen Hunt Robert Babb Ashok Badithe William T. Poueymirou Ronald Surowitz Sylvie Rottey Andrew J. Murphy Olivier Harari Lynn E. Macdonald Susan D. Croll |
| author_facet | Selin Somersan-Karakaya Kenneth C. Turner Luz Cortes-Burgos Jutta Miller Michael LaCroix-Fralish Veronika Logovinsky Yamini Patel Richard Torres Samit Ganguly Aurora Breazna Michelle DeVeaux Rafia Bhore Min Gao Frank J. Delfino Ashique Rafique Jeanette L. Fairhurst Charleen Hunt Robert Babb Ashok Badithe William T. Poueymirou Ronald Surowitz Sylvie Rottey Andrew J. Murphy Olivier Harari Lynn E. Macdonald Susan D. Croll |
| author_sort | Selin Somersan-Karakaya |
| collection | DOAJ |
| description | 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 mouse (REGN1967) and human (REGN5069) GFRα3-blocking monoclonal antibodies and, following in vivo evaluations in mouse models of chronic joint pain (osteoarthritic-like and inflammatory), conducted a first-in-human phase 1 pharmacokinetics (PK) and safety trial of REGN5069 (NCT03645746) in healthy volunteers, and a phase 2 randomized placebo-controlled efficacy and safety trial of REGN5069 (NCT03956550) in patients with knee osteoarthritis (OA) pain. In three commonly used mouse models of chronic joint pain (destabilization of the medial meniscus, intra-articular monoiodoacetate, or Complete Freund’s Adjuvant), REGN1967 and REGN5069 attenuated evoked behaviors including tactile allodynia and thermal hyperalgesia without discernably impacting joint pathology or inflammation, prompting us to further evaluate REGN5069 in humans. In the phase 1 study in healthy subjects, the safety profiles of single doses of REGN5069 up to 3000 mg (intravenous) or 600 mg (subcutaneous) were comparable to placebo; PK were consistent with a monoclonal antibody exhibiting target-mediated disposition. In the phase 2 study in patients with OA knee pain, two doses of REGN5069 (100 mg or 1000 mg intravenous every 4 weeks) for 8 weeks failed to achieve the 12-week primary and secondary efficacy endpoints relative to placebo. In addition to possible differences in GFRα3 biology between mice and humans, we highlight here differences in experimental parameters that could have contributed to a different profile of efficacy in mouse models versus human OA pain. Additional research is required to more fully evaluate any potential role of GFRα3 in human pain. |
| first_indexed | 2024-03-09T03:09:20Z |
| format | Article |
| id | doaj.art-c0682c375e514d369668aca491d09e17 |
| institution | Directory Open Access Journal |
| issn | 2452-073X |
| language | English |
| last_indexed | 2024-03-09T03:09:20Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Pain |
| spelling | doaj.art-c0682c375e514d369668aca491d09e172023-12-04T05:23:43ZengElsevierNeurobiology of Pain2452-073X2023-08-0114100136Monoclonal 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 painSelin Somersan-Karakaya0Kenneth C. Turner1Luz Cortes-Burgos2Jutta Miller3Michael LaCroix-Fralish4Veronika Logovinsky5Yamini Patel6Richard Torres7Samit Ganguly8Aurora Breazna9Michelle DeVeaux10Rafia Bhore11Min Gao12Frank J. Delfino13Ashique Rafique14Jeanette L. Fairhurst15Charleen Hunt16Robert Babb17Ashok Badithe18William T. Poueymirou19Ronald Surowitz20Sylvie Rottey21Andrew J. Murphy22Olivier Harari23Lynn E. Macdonald24Susan D. Croll25Regeneron Pharmaceuticals, Inc., Tarrytown, NY, United States; Corresponding authors at: Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Rd, Tarrytown, NY 10591, United States.Regeneron Pharmaceuticals, Inc., Tarrytown, NY, United StatesRegeneron Pharmaceuticals, Inc., Tarrytown, NY, United StatesRegeneron Pharmaceuticals, Inc., Tarrytown, NY, United StatesRegeneron Pharmaceuticals, Inc., Tarrytown, NY, United StatesRegeneron Pharmaceuticals, Inc., Tarrytown, NY, United StatesRegeneron Pharmaceuticals, Inc., Tarrytown, NY, United StatesRegeneron Pharmaceuticals, Inc., Tarrytown, NY, United StatesRegeneron Pharmaceuticals, Inc., Tarrytown, NY, United StatesRegeneron Pharmaceuticals, Inc., Tarrytown, NY, United StatesRegeneron Pharmaceuticals, Inc., Tarrytown, NY, United StatesRegeneron Pharmaceuticals, Inc., Tarrytown, NY, United StatesRegeneron Pharmaceuticals, Inc., Tarrytown, NY, United StatesRegeneron Pharmaceuticals, Inc., Tarrytown, NY, United StatesRegeneron Pharmaceuticals, Inc., Tarrytown, NY, United StatesRegeneron Pharmaceuticals, Inc., Tarrytown, NY, United StatesRegeneron Pharmaceuticals, Inc., Tarrytown, NY, United StatesRegeneron Pharmaceuticals, Inc., Tarrytown, NY, United StatesRegeneron Pharmaceuticals, Inc., Tarrytown, NY, United StatesRegeneron Pharmaceuticals, Inc., Tarrytown, NY, United StatesHealth Awareness, Jupiter, FL, United StatesGhent University Hospital, Ghent, BelgiumRegeneron Pharmaceuticals, Inc., Tarrytown, NY, United StatesRegeneron Pharmaceuticals, Inc., Tarrytown, NY, United StatesRegeneron Pharmaceuticals, Inc., Tarrytown, NY, United StatesRegeneron Pharmaceuticals, Inc., Tarrytown, NY, United States; Corresponding authors at: Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Rd, Tarrytown, NY 10591, United States.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 mouse (REGN1967) and human (REGN5069) GFRα3-blocking monoclonal antibodies and, following in vivo evaluations in mouse models of chronic joint pain (osteoarthritic-like and inflammatory), conducted a first-in-human phase 1 pharmacokinetics (PK) and safety trial of REGN5069 (NCT03645746) in healthy volunteers, and a phase 2 randomized placebo-controlled efficacy and safety trial of REGN5069 (NCT03956550) in patients with knee osteoarthritis (OA) pain. In three commonly used mouse models of chronic joint pain (destabilization of the medial meniscus, intra-articular monoiodoacetate, or Complete Freund’s Adjuvant), REGN1967 and REGN5069 attenuated evoked behaviors including tactile allodynia and thermal hyperalgesia without discernably impacting joint pathology or inflammation, prompting us to further evaluate REGN5069 in humans. In the phase 1 study in healthy subjects, the safety profiles of single doses of REGN5069 up to 3000 mg (intravenous) or 600 mg (subcutaneous) were comparable to placebo; PK were consistent with a monoclonal antibody exhibiting target-mediated disposition. In the phase 2 study in patients with OA knee pain, two doses of REGN5069 (100 mg or 1000 mg intravenous every 4 weeks) for 8 weeks failed to achieve the 12-week primary and secondary efficacy endpoints relative to placebo. In addition to possible differences in GFRα3 biology between mice and humans, we highlight here differences in experimental parameters that could have contributed to a different profile of efficacy in mouse models versus human OA pain. Additional research is required to more fully evaluate any potential role of GFRα3 in human pain.http://www.sciencedirect.com/science/article/pii/S2452073X23000235REGN5069GFRα3GFRα3-artemin signalingOsteoarthritis pain |
| spellingShingle | Selin Somersan-Karakaya Kenneth C. Turner Luz Cortes-Burgos Jutta Miller Michael LaCroix-Fralish Veronika Logovinsky Yamini Patel Richard Torres Samit Ganguly Aurora Breazna Michelle DeVeaux Rafia Bhore Min Gao Frank J. Delfino Ashique Rafique Jeanette L. Fairhurst Charleen Hunt Robert Babb Ashok Badithe William T. Poueymirou Ronald Surowitz Sylvie Rottey Andrew J. Murphy Olivier Harari Lynn E. Macdonald Susan D. Croll 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 Neurobiology of Pain REGN5069 GFRα3 GFRα3-artemin signaling Osteoarthritis pain |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | REGN5069 GFRα3 GFRα3-artemin signaling Osteoarthritis pain |
| url | http://www.sciencedirect.com/science/article/pii/S2452073X23000235 |
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