Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the CGRP Binding Monoclonal Antibody LY2951742 (Galcanezumab) in Healthy Volunteers

Objective – To briefly describe the history of and available data on anti‐calcitonin gene‐related peptide (CGRP) therapies for headache. Background – CGRP was proposed as a target for primary headache therapies. Translational research involved moving from delineating the relationships between CGRP and primary headaches and the clinical development of anti‐CGRP treatments. The first anti‐CGRP treatment, an intravenous CGRP‐receptor antagonist or gepant, olcegepant, was described as effective in terminating migraines in humans in 2004. Methods – The author briefly reviews some of the pathophysiology and translational research that led to the development of the gepants initially and then subsequently to the anti‐CGRP and anti‐CGRP receptor monoclonal antibodies. All accessible randomized controlled trials, abstracts, platform presentations, and press releases on the monoclonal antibody trials are summarized. The trajectory from bench research to the approval of the first anti‐CGRP receptor monoclonal antibody for clinical use in migraine prevention, erenumab, is discussed, as well as potential clinical uses of the anti‐CGRP treatments. Results – The US Food and Drug Administration (FDA) approved erenumab, an anti‐CGRP receptor monoclonal antibody, for prevention of migraine May 17, 2018. At the time of this writing (May 2018), 2 other anti‐CGRP monoclonal antibodies have been submitted to the FDA for the indication of prevention of migraine, galcanezumab and fremanezumab. Galcanezumab has reportedly shown effectiveness in preventing episodic cluster headache as well, although has not yet been submitted to the FDA for this indication. Eptinezumab will likely be submitted to the FDA for prevention of migraine later in 2018. Two gepants, ubrogepant and rimegepant, have completed positive pivotal trials for acute treatment of migraine, but have not yet been submitted to the FDA for this indication. Conclusions – The development of anti‐CGRP therapies opens a new era in the acute and preventive treatment of primary headache disorders.

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“…Fremanezumab is also an IgG2. As a subcutaneous injection, as noted, bioavailability runs from 40 to 74% …”

Section: Overview Of the Four Monoclonal Antibodiesmentioning

confidence: 99%

History and Review of anti‐Calcitonin Gene‐Related Peptide (CGRP) Therapies: From Translational Research to Treatment

2018

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“…There are pitfalls, especially in obtaining accurate quantitative data, but these can be easily avoided. 119,120 The degree of inhibition by galcanezumab on capsaicin-induced DBF is related to drug serum concentration. 121 Eptinezumab differs from the other two, with twice as rapid association but comparable extremely slow dissociation as fremanezumab.…”

Section: Anti-cgrp Mab Drug Specifics For Pk/pdmentioning

confidence: 99%

“…[Silberstein 2017] Combining both study conclusions, there are no significant treatment-emergent antibodies, and their incidence appear to be much lower than that for other anti-CGRP mAbs. 120 No data are provided on 12-placebo only subjects. Nine of 11 were in the second and third lowest doses; 3/11 had baseline pretreatment ADA that increased in titers, all with low titers of 1:10 to 1:80.…”

Section: Fremanezumabmentioning

confidence: 99%

“…138,139 GALCANEZUMAB In a galcanezumab Phase I safety, tolerability PK/PD single ascending dose (SAD) phase of 6 cohorts followed by 1 multiple dose cohort (MDC) study (NCT 01337596), 11/42 (26%) male SAD subjects had treatment-emergent ADAs (TE-ADAs). 120 In a Phase II EM prevention trial (NCT01625988), of 217 total subjects at screening 8 (3.7%) were positive and at completion 20 (9.2%). 120 No data are provided on 12-placebo only subjects.…”

Section: Fremanezumabmentioning

confidence: 99%

“…Fremanezumab and galcanezumab are often described in the literature as fully humanized, 16,120 but without definition, fully humanized may be without meaning. Fremanezumab and galcanezumab are often described in the literature as fully humanized, 16,120 but without definition, fully humanized may be without meaning.…”

Section: Anti-cgrp Mab Drugs: Current and Future Nomenclaturementioning

confidence: 99%

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CGRP, Amylin, Immunology, and Headache Medicine

Taylor

2018

Headache

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Background Calcitonin gene‐related peptide (CGRP) therapeutics introduce new excitement and possibly yet to be determined distressing discords in the field of Headache Medicine. Growth in knowledge of CGRP in the pathophysiology of migraine introduced CGRP antagonism to headache treatment. Potential adverse effects on the other circulatory and neurovascular diseases have been foremost concerns. Failures in development of gepants and growth in knowledge of monoclonal antibody therapeutics combined to deliver the anti‐CGRP monoclonal antibodies (mAbs). Current Situation as of July 2018 Erenumab, eptinezumab, fremanezumab, and galcanezumab are approved, submitted to, or preparing for submission at both the European Medicines Agency and the US Food and Drug Administration (FDA). Methods This Headache Currents update emanates from a symposium on CGRP and immunology in Headache Medicine, and reviews both. Results and Conclusion Understanding CGRP in Headache Medicine requires information on aspects of the CGRP ligand, cell surface G protein receptor, CGRP receptor specifics, and antagonism by CGRP small and large molecules. Recent reports of CGRP’s high affinity for amylin receptors dictate some attention to this family‐related peptide. To better understand potential immunogenic risks and off‐target toxicities of the anti‐CGRP monoclonal antibodies, this review discusses immunology and CGRP and reviews IgG structure and function, monoclonal antibody production, ligand–antigen–antibody relationships, and clinical CGRP mAb specifics. Upon completion, the reader should better summarize CGRP antagonist fundamentals, recall antibody structure and function, restate therapeutic mAbs attributes, and appraise immunogenic risks.

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Effect of Different Doses of Galcanezumab vs Placebo for Episodic Migraine Prevention

et al. 2018

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IMPORTANCE Galcanezumab (LY2951742), a monoclonal antibody against calcitonin gene-related peptide (CGRP), is one of a novel class of new medicines for migraine prevention. OBJECTIVE To assess whether at least 1 dose of galcanezumab was superior to placebo for episodic migraine prevention. DESIGN, SETTING, AND PARTICIPANTS A randomized clinical trial was conducted in the United States (July 7, 2014, to August 19, 2015) in clinics of 37 licensed physicians with a specialty including, but not limited to, psychiatry, neurology, internal medicine, and primary care. Subcutaneous injections of galcanezumab, 5, 50, 120, or 300 mg, or placebo were given monthly during the 3-month treatment period. A total of 936 patients were assessed; 526 did not meet study entry or baseline criteria and 410 patients were randomly assigned to receive placebo or galcanezumab. Analyses were conducted on an intent-to-treat population, which included all patients who were randomized and received at least 1 dose of study drug. INTERVENTIONS Short-term migraine treatments were allowed as needed except for opioids or barbiturates. MAIN OUTCOMES AND MEASURES To determine if at least 1 of the 4 doses of galcanezumab tested was superior to placebo for migraine prevention measured by the mean change from baseline in the number of migraine headache days 9 weeks to 12 weeks after randomization. RESULTS Of the 936 patients assessed, 410 met entry criteria (aged 18-65 years with 4-14 migraine headache days per month and migraine onset prior to age 50 years) and were randomized to receive placebo or galcanezumab. For the primary end point, galcanezumab, 120 mg, significantly reduced migraine headache days compared with placebo (99.6% posterior probability −4.8 days; 90% BCI, −5.4 to −4.2 days vs 95% superiority threshold [Bayesian analysis] −3.7 days; 90% BCI, −4.1 to −3.2 days). Adverse events reported by 5% or more of patients in at least 1 galcanezumab dose group and more frequently than placebo included injection-site pain, upper respiratory tract infection, nasopharyngitis, dysmenorrhea, and nausea. CONCLUSIONS AND RELEVANCE Monthly subcutaneous injections of galcanezumab, both 120 mg and 300 mg, demonstrated efficacy (repeated-measures analysis) for the preventive treatment of migraine and support further development in larger phase 3 studies. All dosages were safe and well tolerated for the preventive treatment of episodic migraine. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT02163993

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Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the CGRP Binding Monoclonal Antibody LY2951742 (Galcanezumab) in Healthy Volunteers

Cited by 59 publications

References 43 publications

History and Review of anti‐Calcitonin Gene‐Related Peptide (CGRP) Therapies: From Translational Research to Treatment

History and Review of anti‐Calcitonin Gene‐Related Peptide (CGRP) Therapies: From Translational Research to Treatment

CGRP, Amylin, Immunology, and Headache Medicine

Effect of Different Doses of Galcanezumab vs Placebo for Episodic Migraine Prevention

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