Lack of hemodynamic interaction between CGRP-receptor antagonist telcagepant (MK-0974) and sumatriptan: Results from a randomized study in patients with migraine

Depré, Marleen; MacLeod, Catherine; Palcza, John; Behm, Martin O.; Lepeleire, Inge De; Han, Tae Hyung; Panebianco, Deborah; Smith, William B.; Blanchard, Rebecca; Chodakewitz, Jeffrey A.; Murphy, M. Gail; Hoon, Jan N. de

doi:10.1177/0333102413494272

Cited by 14 publications

(15 citation statements)

References 32 publications

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“…These findings are consistent with non-clinical and clinical experience with CGRP antagonists so far and continue to support the cardiovascular safety of these compounds (Iovino et al, 2004 ; Petersen et al, 2005a , b ; Zeller et al, 2008 ). This is in contrast to current therapies used for the treatment of migraine headache, in particular the ergot alkaloids and the triptans, which both increase blood pressure and arterial stiffness and are therefore formally contraindicated in patients with a higher risk for cerebrovascular or cardiovascular events (de Hoon et al, 2000 , 2001 ; Vanmolkot and de Hoon, 2006 ; Depré et al, 2013 ).…”

Section: Discussionmentioning

confidence: 96%

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

et al. 2017

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Background: Calcitonin gene-related peptide (CGRP) is pivotal in the pathophysiology of migraine headaches and represents a promising target for migraine treatment. The humanized monoclonal antibody galcanezumab (LY2951742) binds to CGRP and may be effective in migraine prophylaxis. Objectives: The primary objective was to evaluate the safety and tolerability of single and multiple doses of galcanezumab in humans. Secondary objectives included assessing the pharmacokinetics and evaluating target engagement. Methods: A double-blind, randomized, placebo-controlled study (NCT 01337596) with single escalating and multiple subcutaneous (SC) doses of galcanezumab was performed in healthy male volunteers. Single doses of 1, 5, 25, 75, 200, and 600 mg of galcanezumab ( n = 7/dose) or placebo ( n = 2/dose) were injected SC in six consecutive cohorts of nine subjects each. One cohort of nine subjects received multiple (4) 150 mg doses of galcanezumab or placebo every other week. Target engagement was evaluated by measuring inhibition of capsaicin-induced increase in dermal blood flow (DBF). Findings: Sixty-three subjects were randomized and included in the safety analyses. Galcanezumab was well tolerated in single doses (1–600 mg SC) and consecutive doses (150 mg SC). There was no dose-dependent difference in type or frequency of treatment-emergent adverse events, and no clinically meaningful difference when compared with placebo. Pharmacokinetics were linear. Galcanezumab induced a robust, dose-dependent, and durable inhibition of capsaicin-induced increase in DBF, supporting the continued clinical development of galcanezumab for prophylaxis in migraine patients.

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Section: Discussionmentioning

confidence: 96%

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

et al. 2017

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“…126 Clinically, studies with telcagepant (MK-0974) showed that it had no effect on spontaneous ischemia in cardiovascular patients, 127 that it did not affect exercise time at supratherapeutic doses in patients with stable angina, 128 that it did not affect nitroglycerin-induced vasodilation in healthy men, 129 nor was there any hemodynamic interaction with sumatriptan. 130 A partially completed study of supratherapeutic doses of telcagepant (600 and 900 mg) in patients with migraine and stable coronary artery disease also supported the cardiovascular safety of the CGRP receptor antagonist mechanism. 131 Cardiovascular safety has also been shown with the CGRP receptor mAb erenumab in patients with stable angina.…”

Section: Safety and Tolerability Of The Cgrp Antibodiesmentioning

confidence: 89%

“…Early human experiments were conducted by Petersen and colleagues, who showed clinically that low doses of the CGRP‐RA olcegepant completely inhibited headache induced by CGRP, yet at supratherapeutic doses there was no effect on blood pressure, the diameter of systemic or cerebral arteries, or cerebral blood flow . Clinically, studies with telcagepant (MK‐0974) showed that it had no effect on spontaneous ischemia in cardiovascular patients, that it did not affect exercise time at supratherapeutic doses in patients with stable angina, that it did not affect nitroglycerin‐induced vasodilation in healthy men, nor was there any hemodynamic interaction with sumatriptan . A partially completed study of supratherapeutic doses of telcagepant (600 and 900 mg) in patients with migraine and stable coronary artery disease also supported the cardiovascular safety of the CGRP receptor antagonist mechanism …”

Section: Safety and Tolerability Of The Cgrp Antibodiesmentioning

confidence: 99%

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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“…The rationale for this decision was based on the previous publication by Depré et al. (30). Time-weighted SBP and DBP were analyzed in a similar fashion as time-weighted MAP.…”

Section: Methodsmentioning

confidence: 99%

Phase 1, randomized, parallel-group, double-blind, placebo-controlled trial to evaluate the effects of erenumab (AMG 334) and concomitant sumatriptan on blood pressure in healthy volunteers

et al. 2018

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Lack of hemodynamic interaction between CGRP-receptor antagonist telcagepant (MK-0974) and sumatriptan: Results from a randomized study in patients with migraine

Cited by 14 publications

References 32 publications

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

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

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

Phase 1, randomized, parallel-group, double-blind, placebo-controlled trial to evaluate the effects of erenumab (AMG 334) and concomitant sumatriptan on blood pressure in healthy volunteers

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