CGRP blockade by galcanezumab was not associated with reductions in signs and symptoms of knee osteoarthritis in a randomized clinical trial

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

doi:10.1016/j.joca.2018.08.019

Cited by 40 publications

(24 citation statements)

References 26 publications

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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%

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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Section: Discussionmentioning

confidence: 99%

Development of chimeric and bifunctional antagonists for CLR/RAMP receptors

Chang

Hsu²

2019

PLoS ONE

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“…Galcanezumab, a humanized monoclonal antibody, blocks calcitonin gene-related peptide (CGRP), that plays a role in pain in OA, and has been shown to be efficacious in migraine. In a doubleblind, placebo-and celecoxib-controlled randomized trial galcanezumab (doses 5 up to 300 mg subcutaneously every 4 weeks, twice), was investigated in 266 patients with painful knee OA 29 . Primary outcome was change in WOMAC pain after 8 weeks.…”

Section: Novel Treatmentsmentioning

confidence: 99%

Osteoarthritis year in review 2019: epidemiology and therapy

Kloppenburg

Bérenbaum

2020

Osteoarthritis and Cartilage

408

298

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s u m m a r yOver the past year many studies and clinical trials have been published in the osteoarthritis (OA) field. This review is based on systematic literature review covering the period May 1 st , 2018 to April 19 th , 2019; the final selection of articles was subjective. Specifically those articles considered to be presenting novel insights and of potential importance for clinical practice, are discussed.Further evidence has emerged that OA is a serious disease with increasing impact worldwide. Our understanding of development of pain in OA has increased. Detailed studies investigating widely used pharmacological treatments have shown the benefits to be limited, whereas the risks seem higher than expected, suggesting further studies and reconsideration of currently used guidelines. Promising new pharmacological treatments have been developed and published, however subsequent studies are warranted. While waiting for new treatment modalities to appear joint replacement is an effective alternative; new data have become available on how long they might last.

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“…Although repurposed Osteoporosis drugs show compelling results in pre-clinical testing in OA, clinical trials in late-stage OA, such as multiple phase III trials investigating calcitonin, have not yet demonstrated obvious benefits [ 45 ]. Galcanezumab, a monoclonal antibody targeting calcitonin gene-related peptide, was also unsuccessful in a phase II trial as it did not reduce signs or symptoms of knee OA [ 46 ].…”

Section: Current and Recent Targets In Chondroprotectionmentioning

confidence: 99%

“…Phase II trial is currently looking at denosumab in hand OA (NCT02771860).Calcium-reducing hormoneCalcitonin (osteoporosis drug)Two phase III trials did not show any clinical benefits to patients with symptomatic knee OA [45]. Anti-calcitonin gene-related peptide (migraine drug)Phase II study was terminated as interim assessment showed lack of efficacy [46]. BMPsBMP-7Phase I trial showed a symptom response and no dose limiting toxicity [47].…”

Section: Current and Recent Targets In Chondroprotectionmentioning

confidence: 99%

Chondroprotective Factors in Osteoarthritis: a Joint Affair

Mimpen

Snelling

2019

Curr Rheumatol Rep

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Purpose of the Review Osteoarthritis is widely regarded as a spectrum of conditions that affect all joint tissues, typified by a common entity: cartilage loss. Here, we review recent progress and challenges in chondroprotection and discuss new strategies to prevent cartilage loss in osteoarthritis. Recent Findings Advances in clinical, molecular, and cellular characterization are enabling improved stratification of osteoarthritis subtypes. Integration of next-generation sequencing and "omics" approaches with clinically relevant readouts shows promise in delineating both subtypes of disease and meaningful trial end points. Novel delivery strategies are enabling jointspecific delivery. Summary Chondroprotection requires a whole joint approach, stratification of patient groups, and use of patient-relevant end points. Drug development should continue to explore new targets, while using modern technologies and recent knowledge to revisit unsuccessful therapeutics from the past. The overarching goal for chondroprotection is to provide the right treatment(s) for the right patient at the right time.

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CGRP blockade by galcanezumab was not associated with reductions in signs and symptoms of knee osteoarthritis in a randomized clinical trial

Abstract: NCT02192190.

Cited by 40 publications

References 26 publications

Development of chimeric and bifunctional antagonists for CLR/RAMP receptors

Development of chimeric and bifunctional antagonists for CLR/RAMP receptors

Osteoarthritis year in review 2019: epidemiology and therapy

Chondroprotective Factors in Osteoarthritis: a Joint Affair

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