A phase 1 study to assess the pharmacokinetics, safety, and tolerability of fremanezumab doses (225 mg, 675 mg and 900 mg) in Japanese and Caucasian healthy subjects

Cohen‐Barak, Orit; Weiss, Sagit; Rasamoelisolo, Michele; Faulhaber, Nicola; Yeung, Paul; Loupe, Pippa S.; Yoon, Esther Y.; Gandhi, Mohit D.; Spiegelstein, Ofer; Aycardi, Ernesto

doi:10.1177/0333102418771376

Cited by 44 publications

(35 citation statements)

References 22 publications

(26 reference statements)

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“…Sixteen of them were repeated publication or post-hoc analysis of the same study and two of them were not RCTs. In addition, 4 articles were excluded for the reasons of chronic migraine [20] healthy subjects [21,22] or without placebo group [23] .Finally, a total of 11 studies met the inclusion and exclusion criteria [14][15][16][17][18][24][25][26][27][28][29] , and at least 1 outcome could be included in this meta-analysis ( Figure 1).…”

Section: Eligible Studiesmentioning

confidence: 99%

Efficacy and safety of calcitonin-gene-related peptide binding monoclonal antibodies for the preventive treatment of episodic migraine – An updated systematic review and meta-analysis

Deng

Nie

et al. 2019

Preprint

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Background: Migraine is one of the most common neurological disorders that leads to disabilities. However, the conventional drug therapy for migraine is unsatisfactory. Therefore, this meta-analysis aimed to evaluate the efficacy and safety of calcitonin-gene-related peptide binding monoclonal antibody (CGRP mAb) for the preventive treatment of episodic migraine, and provide high-quality clinical evidence for migraine therapy. Methods: A systematic electronic database search was conducted to identify the potentially relevant studies. Two independent authors performed data extraction and quality appraisal. Mean difference (MD) and risk ratio (RR) were pooled for continuous and dichotomous data, respectively. The significance levels, weighted effect sizes and homogeneity of variance were calculated. Results: Eleven high-quality randomized control trials that collectively included 4402 patients were included in this meta-analysis. Compared to placebo group, CGRP mAb therapy resulted in a reduction of monthly migraine days [weighted mean difference (WMD) = −1.44, 95% CI = (−1.68,−1.19)] and acute migraine-specific medication days [WMD = −1.28, 95% CI = (−1.66,−0.90)], with an improvement in 50% responder rate [RR = 1.51, 95% CI =(1.37,1.66)]. In addition, the adverse events (AEs) and treatment withdrawal rates due to AEs were not significantly different between CGRP mAb and placebo groups. Similar efficacy and safety results were obtained for erenumab, fremanezumab, and galcanezumab in subgroup analysis. Conclusions: The current body of evidence reveals that CGRP mAb is an effective and safe preventive treatment for episodic migraine. Keywords: calcitonin gene-related peptide monoclonal antibody, episodic migraine, efficacy, safety, meta-analysis

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Section: Eligible Studiesmentioning

confidence: 99%

Efficacy and safety of calcitonin-gene-related peptide binding monoclonal antibodies for the preventive treatment of episodic migraine – An updated systematic review and meta-analysis

Deng

Nie

et al. 2019

Preprint

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“…The pharmacokinetic parameters of fremanezumab 225, 675 and 900 mg were similar between Japanese and Caucasian healthy volunteers, according to a phase I study [14]. …”

Section: Scientific Summarymentioning

confidence: 99%

Fremanezumab: First Global Approval

Hoy

2018

Drugs

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Fremanezumab-vfrm (hereafter referred to as fremanezumab) [AJOVY™] is a fully humanized monoclonal antibody (IgG2Δa) developed by Teva Pharmaceuticals to selectively target calcitonin gene-related peptide (a vasodilatory neuropeptide involved in the pathophysiology of migraine). Its use has been associated with significant reductions in migraine frequency, the requirement for acute headache medication use and headache-related disability compared with placebo in multinational, phase III studies, and in September 2018 fremanezumab was approved by the US FDA for the preventive treatment of migraine in adults. A regulatory assessment for fremanezumab as a preventive treatment of migraine in adults is underway in the EU. Fremanezumab is also undergoing phase III development for the preventive treatment of cluster headache (although a phase III chronic cluster headache study has been suspended due to the results of a prespecified futility analysis) and phase II development for the preventive treatment of post-traumatic headache disorder. This article summarizes the milestones in the development of fremanezumab leading to this first approval in the USA for the preventive treatment of migraine in adults.

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“…This rapid achievement of C max may provide a pharmacokinetic explanation for the rapid onset of effect observed in clinical trials . The short T max values for eptinezumab are in contrast to the longer median values for single doses of erenumab (4‐11 days), fremanezumab (5‐11 days), and galcanezumab (7‐14 days), which are administered subcutaneously. Delivery by the subcutaneous route of administration requires time for absorption, a process that is also associated with a loss of active drug or reduced bioavailability .…”

Section: Discussionmentioning

confidence: 97%

“…There are currently three mAbs that inhibit CGRP biology (erenumab, fremanezumab, and galcanezumab) approved for prevention of migraine in the United States, with eptinezumab currently under regulatory review. Differences exist between these mAbs in pharmacokinetics and in binding characteristics that have the potential to influence efficacy and tolerability . These pharmacologic differences likely explain the dosing regimens of the available agents.…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetic and exposure‐response analysis of eptinezumab in the treatment of episodic and chronic migraine

Baker

Schaeffler

Béliveau³

et al. 2020

Pharmacology Res & Perspec

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Eptinezumab is a humanized mAb that targets calcitonin gene‐related peptide and is under regulatory review for the prevention of episodic and chronic migraine (EM, CM). It is important to determine whether exposures achieved with intravenous (IV) administration of eptinezumab achieve desired pharmacologic effects. Population pharmacokinetics, including dose‐ and exposure‐response analyses, were performed using patient‐level data from the eptinezumab clinical trial program with IV doses ranging from 10 to 1000 mg in pharmacokinetic analyses or 10 to 300 mg in phase 2/3 clinical studies in patients with EM or CM. Exposure‐response analysis explored the relationship between eptinezumab exposure metrics and efficacy parameters including monthly migraine days. The pharmacokinetic profile of eptinezumab was characterized by rapid attainment of maximum plasma concentration (ie, end of IV administration) and a terminal half‐life of 27 days. Covariate analysis found that patient characteristics had no clinically significant effects on pharmacokinetic parameters and were insufficient to influence dosing. Dose‐ and exposure‐response analyses found exposure with single doses ≥100 mg was associated with greater efficacy compared with doses ≤30 mg and a plateau of effect between 100 and 300 mg. A saturable inhibitory Emax model found the exposure over 12 weeks produced by single‐dose eptinezumab 100 and 300 mg exceeded the exposure estimates required to achieve 90% of the maximal efficacy (EC90). This pharmacokinetic analysis of eptinezumab supports dosing every 12 weeks with no adjustment for patient characteristics, including exposures associated with 100‐ or 300‐mg doses producing optimal efficacy effects. The similar efficacy profiles support 100 mg as the lowest effective dose of eptinezumab.

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A phase 1 study to assess the pharmacokinetics, safety, and tolerability of fremanezumab doses (225 mg, 675 mg and 900 mg) in Japanese and Caucasian healthy subjects

Abstract: The results of the pharmacokinetic exposure parameters and safety measures were similar for Japanese and Caucasians and support the once monthly and once quarterly sc injections of fremanezumab.

Cited by 44 publications

References 22 publications

Efficacy and safety of calcitonin-gene-related peptide binding monoclonal antibodies for the preventive treatment of episodic migraine – An updated systematic review and meta-analysis

Efficacy and safety of calcitonin-gene-related peptide binding monoclonal antibodies for the preventive treatment of episodic migraine – An updated systematic review and meta-analysis

Fremanezumab: First Global Approval

Population pharmacokinetic and exposure‐response analysis of eptinezumab in the treatment of episodic and chronic migraine

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