LY2951742, a monoclonal antibody against CGRP, failed to reduce signs and symptoms of knee osteoarthritis

Jin, Yan; Smith, Claire; Monteith, David K.; Brown, Robert D.; Camporeale, A.; McNearney, T. A.; Deeg, Mark A.; Raddad, Eyas; Peña, Angélica; Kivitz, Alan; Schnitzer, Thomas J.

doi:10.1016/j.joca.2016.01.114

Cited by 12 publications

(9 citation statements)

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“…A total of 266 patients were randomized to 1 of 6 treatment arms: LY2951742 5 mg, 50 mg, 120 mg, or 300 mg, celecoxib 200 mg, or placebo. Using a Bayesian dose–response longitudinal model, response rates to all four LY2951742 treatment arms were not different from placebo while celecoxib met criteria for a positive study [ 68 ].…”

Section: Resultsmentioning

confidence: 99%

“…Dermal electrical current stimulation in humans caused increased CGRP in blood [ 48 ]. However, a recent study randomized, double-blind, placebo and active-controlled study in patients with osteoarthritis knee pain did not demonstrate efficacy of LY2951742, monoclonal antibody to CGRP against placebo and the trial was terminated [ 68 ]. However, the study was only done in patients with mild and moderate symptoms.…”

Section: Discussionmentioning

confidence: 99%

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Calcitonin gene-related peptide and pain: a systematic review

et al. 2017

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BackgroundCalcitonin gene-related peptide (CGRP) is widely distributed in nociceptive pathways in human peripheral and central nervous system and its receptors are also expressed in pain pathways. CGRP is involved in migraine pathophysiology but its role in non-headache pain has not been clarified.MethodsWe performed a systematic literature search on PubMed, Embase and ClinicalTrials.gov for articles on CGRP and non-headache pain covering human studies including experimental studies and randomized clinical trials.ResultsThe literature search identified 375 citations of which 50 contained relevant original data. An association between measured CGRP levels and somatic, visceral, neuropathic and inflammatory pain was found. In 13 out of 20 studies in somatic pain conditions, CGRP levels had a positive correlation with pain. Increased CGRP levels were reported in plasma, synovial and cerebrospinal fluid in subjects with musculoskeletal pain. A randomized clinical trial on monoclonal antibody, which selectively binds to and inhibits the activity of CGRP (galcanezumab) in patients with osteoarthritis knee pain, failed to demonstrate improvement of pain compared with placebo. No studies to date have investigated the efficacy of monoclonal antibodies against CGRP receptor in non-headache pain conditions.ConclusionThe present review revealed the association between measured CGRP levels and somatic, visceral, neuropathic and inflammatory pain. These data suggest that CGRP may act as a neuromodulator in non-headache pain conditions. However, more studies are needed to fully understand the role of CGRP in nociceptive processing and therapy of chronic pain.Electronic supplementary materialThe online version of this article (doi:10.1186/s10194-017-0741-2) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Calcitonin gene-related peptide and pain: a systematic review

et al. 2017

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“…In animal models, CGRP increases acute neurogenic inflammation and joint pain [107, 108]; whereas CGRP antagonists reduces osteoarthritis pain [61, 107, 109]. However, an anti-CGRP antibody (i.e., galcanezumab) failed to reduce osteoarthritis pain in patients [59, 60]. The lack of efficacy could be due to the inability of antibodies to reduce CGRP in the synovial joint to a therapeutic level.…”

Section: Discussionmentioning

confidence: 99%

“…Although anti-CGRP antibody therapies showed efficacy in patients, they are inadequate for the control of severe migraine in many patients and are ineffective for reducing osteoarthritis pain [59–61]. Therefore, there is still a substantial unmet medical need of therapeutics that can better control CLR/RAMP-mediated pain response and tumor growth/angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

Development of chimeric and bifunctional antagonists for CLR/RAMP receptors

Chang

Hsu²

2019

PLoS ONE

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CGRP, adrenomedullin (ADM), and adrenomedullin 2 (ADM2) family peptides are important neuropeptides and hormones for the regulation of neurotransmission, vasotone, cardiovascular morphogenesis, vascular integrity, and feto‒placental development. These peptides signal through CLR/RAMP1, 2 and 3 receptor complexes. CLR/RAMP1, or CGRP receptor, antagonists have been developed for the treatment of migraine headache and osteoarthritis pain; whereas CLR/RAMP2, or ADM receptor, antagonists are being developed for the treatment of tumor growth/metastasis. Based on the finding that an acylated chimeric ADM/ADM2 analog potently stimulates CLR/RAMP1 and 2 signaling, we hypothesized that the binding domain of this analog could have potent inhibitory activity on CLR/RAMP receptors. Consistent with this hypothesis, we showed that acylated truncated ADM/ADM2 analogs of 27–31 residues exhibit potent antagonistic activity toward CLR/RAMP1 and 2. On the other hand, nonacylated analogs have minimal activity. Further truncation at the junctional region of these chimeric analogs led to the generation of CLR/RAMP1-selective antagonists. A 17-amino-acid analog (Antagonist 2–4) showed 100-fold selectivity for CLR/RAMP1 and was >100-fold more potent than the classic CGRP receptor antagonist CGRP8-37. In addition, we showed (1) a lysine residue in the Antagonist 2–4 is important for enhancing the antagonistic activity, (2) an analog consisted of an ADM sequence motif and a 12-amino-acid binding domain of CGRP exhibits potent CLR/RAMP1-inhibitory activity, and (3) a chimeric analog consisted of a somatostatin analog and an ADM antagonist exhibits dual activities on somatostatin and CLR/RAMP receptors. Because the blockage of CLR/RAMP signaling prevents migraine pain and suppresses tumor growth/metastasis, further studies of these analogs, which presumably have better access to the tumor microenvironment and nerve endings at the trigeminal ganglion and synovial joints as compared to antibody-based therapies, may lead to the development of better anti-CGRP therapy and alternative antiangiogenesis therapy. Likewise, the use of bifunctional somatostatin-ADM antagonist analogs could be a promising strategy for the treatment of high-grade neuroendocrine tumors by targeting an antiangiogenesis agent to the neuroendocrine tumor microenvironment.

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“…Although CGRP inhibition showed promising analgesic effects in animal models of OA [112] [113], a neutralizing monoclonal antibody failed to reduce signs and symptoms of knee OA in a phase 2 clinical trial. [114]…”

Section: Peripheral Mechanisms Of Oa Painmentioning

confidence: 99%

Peripheral Mechanisms Contributing to Osteoarthritis Pain

et al. 2018

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Both peripheral and central mechanisms contribute to OA pain. Clinical evidence suggests that a strong peripheral nociceptive drive from the affected joint maintains pain and central sensitization associated with OA. Mediators present in the OA joint, including nerve growth factor, chemokines, cytokines, and inflammatory cells can contribute to sensitization. Furthermore, structural alterations in joint innervation and nerve damage occur in the course of OA. Several interrelated pathological processes, including joint damage, structural reorganization of joint afferents, low-grade inflammation, neuroplasticity, and nerve damage all contribute to the pain observed in OA. It can be anticipated that elucidating exactly how these mechanisms are operational in the course of progressive OA may lead to the identification of novel targets for intervention.

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LY2951742, a monoclonal antibody against CGRP, failed to reduce signs and symptoms of knee osteoarthritis

Cited by 12 publications

References 0 publications

Calcitonin gene-related peptide and pain: a systematic review

Calcitonin gene-related peptide and pain: a systematic review

Development of chimeric and bifunctional antagonists for CLR/RAMP receptors

Peripheral Mechanisms Contributing to Osteoarthritis Pain

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