Effect of Telcagepant on Spontaneous Ischemia in Cardiovascular Patients in a Randomized Study

Behm, Martin O.; Blanchard, Rebecca; Murphy, M. Gail; Palcza, John; Harris, Dawn; Butterfield, Kristin; Smith, William B.; Preston, Richard A.; Chodakewitz, Jeffrey A.; Krucoff, Mitchell W.

doi:10.1111/j.1526-4610.2011.01901.x

Cited by 19 publications

(15 citation statements)

References 27 publications

(55 reference statements)

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“…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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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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“…In addition, telgagepant was studied for effects in cardiovascular disease and exercise tolerance time . Concerns have been raised that eliminating or blocking CGRP could cripple compensatory vasodilation in the setting of ischemia .…”

Section: Small Molecule Cgrp Receptor Antagonists (Gepants)mentioning

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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“…In a randomized, double-blinded, placebo-controlled, cross-over study, it was proved that telcagepant (two 300 mg doses administered 2 h apart) was generally safe and well tolerated in a small cohort of migraine patients with stable coronary artery disease, as there were no consistent treatment-related changes in cardiovascular parameters [21]. In a randomized, double-blinded, placebo-controlled, cross-over study, it was proved that telcagepant (two 300 mg doses administered 2 h apart) was generally safe and well tolerated in a small cohort of migraine patients with stable coronary artery disease, as there were no consistent treatment-related changes in cardiovascular parameters [21].…”

Section: Calcitonin Gene-related Peptide Antagonistsmentioning

confidence: 99%

Management of acute and chronic migraine

Schoenen

2012

Current Opinion in Supportive &Amp; Palliative Care

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Effect of Telcagepant on Spontaneous Ischemia in Cardiovascular Patients in a Randomized Study

Cited by 19 publications

References 27 publications

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

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

Management of acute and chronic migraine

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