Pharmacokinetic-Pharmacodynamic Relationship of Erenumab (AMG 334) and Capsaicin-Induced Dermal Blood Flow in Healthy and Migraine Subjects

Vu, Thuy; Ma, Pelosi; Chen, Jiyun Sunny; Hoon, Jan de; Hecken, Anne Van; Yan, Libo; Wu, Lei; Hamilton, Lisa; Vargas, Gabriel

doi:10.1007/s11095-017-2183-6

Cited by 79 publications

(88 citation statements)

References 21 publications

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“…Following completion of the ETT mean erenumab concentration was at least 2‐fold higher than the C max reached following 140 mg SC administration. Thus, the use of 140 mg IV dose of erenumab ensured rapid and robust blockade of the CGRP receptor, providing a substantial margin over concentrations achieved by subcutaneous administration of 140 mg …”

Section: Discussionmentioning

confidence: 99%

A Randomized, Double‐Blind, Placebo‐Controlled Study to Evaluate the Effect of Erenumab on Exercise Time During a Treadmill Test in Patients With Stable Angina

Antalik²,

et al. 2018

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ObjectiveTo determine the potential impact of erenumab, a human anti‐calcitonin gene‐related peptide (CGRP) receptor monoclonal antibody, on total exercise time (TET), time to exercise‐induced angina, and ST depression in a double‐blind, placebo‐controlled study in patients with stable angina due to documented coronary artery disease.BackgroundThe relative importance of the CGRP receptor pathway during myocardial ischemia has not been established.MethodsAn exercise treadmill test was conducted following a single IV infusion of erenumab 140 mg or placebo. The primary endpoint was the change from baseline in exercise duration as measured by TET with a noninferiority margin of −90 seconds. Safety follow‐up visits occurred through week 12. Eighty‐eight participants were included in the analysis.ResultsLS mean (SE) change in TET was −2.9 [14.8] seconds in the erenumab group and 8.1 [14.4] seconds in placebo; adjusted mean (90% CI) treatment difference was −11.0 (–44.9, 22.9) seconds. The CI lower bound (–44.9 sec) did not reach pre‐defined non‐inferiority margin of −90 seconds, demonstrating that TET change from baseline in the erenumab group was non‐inferior to placebo. There was no difference in time to exercise‐induced angina in erenumab and placebo groups (median [90% CI] time of 500 [420, 540] vs 508 [405, 572] seconds; hazard ratio [90% CI]: 1.11 [0.73, 1.69], P = .69) or time to onset of ≥1 mm ST‐segment depression (median [90% CI] time of 407 [380, 443] vs 420 [409,480] seconds; hazard ratio [95% CI]: 1.14 [0.76, 1.69], P = .59). Adverse events were reported by 27% and 32% of patients in erenumab and placebo groups.ConclusionsErenumab did not adversely affect exercise time in a high cardiovascular risk population of patients, supporting that inhibition of the canonical CGRP receptor does not worsen myocardial ischemia.

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Section: Discussionmentioning

confidence: 99%

A Randomized, Double‐Blind, Placebo‐Controlled Study to Evaluate the Effect of Erenumab on Exercise Time During a Treadmill Test in Patients With Stable Angina

Antalik²,

et al. 2018

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“…). This hypothesis is supported by the differential activity of the CGRP neutralizing antibodies (galcanezumab and eptinezumab) vs erenumab, the CGRP receptor antibody, in the CIDV pharmacodynamic assay that is a measure of CGRP activity in the peripheral vasculature . In this assay, the CGRP neutralizing antibodies appear to block the CIDV response less than the CGRP receptor antibody erenumab at exposures that are clinically equi‐effective in migraine prevention.…”

Section: Comparing the Cgrp Antibodies Clinicallymentioning

confidence: 95%

Calcitonin Gene‐Related Peptide Modulators – The History and Renaissance of a New Migraine Drug Class

2019

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Several lines of evidence pointed to an important role for CGRP in migraine. These included the anatomic colocalization of CGRP and its receptor in sensory fibers innervating pain‐producing meningeal blood vessels, its release by trigeminal stimulation, the observation of elevated CGRP in the cranial circulation during migraine with normalization concomitant with headache relief by sumatriptan, and translational studies with intravenous (IV) CGRP that evoked migraine only in migraineurs. The development of small molecule CGRP receptor antagonists (CGRP‐RAs) that showed clinical antimigraine efficacy acutely and prophylactically in randomized placebo‐controlled clinical trials subsequently gave definitive pharmacological proof of the importance of CGRP in migraine. More recently, CGRP target engagement imaging studies using a CGRP receptor PET ligand [11C]MK‐4232 demonstrated that there was no brain CGRP receptor occupancy at clinically effective antimigraine doses of telcagepant, a prototypic CGRP‐RA. Taken together, these data indicated that (1) the therapeutic site of action of the CGRP‐RAs was peripheral not central; (2) that IV CGRP had most likely evoked migraine through an action at sites outside the blood‐brain barrier; and (3) that migraine pain was therefore, at least in part, peripheral in origin. The evolution of CGRP migraine science gave impetus to the development of peripherally acting drugs that could modulate CGRP chronically to prevent frequent episodic and chronic migraine. Large molecule biologic antibody (mAb) approaches that are given subcutaneously to neutralize circulating CGRP peptide (fremanezumab, galcanezumab) or block CGRP receptors (erenumab) have shown consistent efficacy and tolerability in multicenter migraine prevention trials and are now approved for clinical use. Eptinezumab, a CGRP neutralizing antibody given IV, shows promise in late stage clinical development. Recently, orally administered next‐generation small molecule CGRP‐RAs have been shown to have safety and efficacy in acute treatment (ubrogepant and rimegepant) and prevention (atogepant) of migraine, giving additional CGRP‐based therapeutic options for migraine patients.

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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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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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Pharmacokinetic-Pharmacodynamic Relationship of Erenumab (AMG 334) and Capsaicin-Induced Dermal Blood Flow in Healthy and Migraine Subjects

Cited by 79 publications

References 21 publications

A Randomized, Double‐Blind, Placebo‐Controlled Study to Evaluate the Effect of Erenumab on Exercise Time During a Treadmill Test in Patients With Stable Angina

A Randomized, Double‐Blind, Placebo‐Controlled Study to Evaluate the Effect of Erenumab on Exercise Time During a Treadmill Test in Patients With Stable Angina

Calcitonin Gene‐Related Peptide Modulators – The History and Renaissance of a New Migraine Drug Class

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

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