Phase I, Randomized, Double‐blind, Placebo‐controlled, Single‐dose, and Multiple‐dose Studies of Erenumab in Healthy Subjects and Patients With Migraine

Monoclonal antibodies targeting the calcitonin gene-related peptide pathway represent a new class of mechanism-specific, migraine-targeted therapies available for migraine prevention. To date, four monoclonal antibodies have demonstrated efficacy in phase II and III trials, significantly reducing migraine days per month versus placebo with rapid onset of action. While their efficacy may be considered similar to existing preventive options, their true value may lie in an improved tolerability profile, with high specificity and selectivity for the calcitonin gene-related peptide receptor or ligand reducing the potential for off-target binding and toxicity. The infrequent parenteral administration of these therapeutic proteins, and lack of requirement for dose titration, has potential to simplify treatment selection and use for clinicians and patients. However, the treatments have not yet been tested in real-world settings in patients with the range of comorbid conditions encountered in routine clinical practice, and longer-term data on safety, efficacy, and treatment persistence are required. If data from real-world settings can confirm the initial clinical trial findings, it is hoped that antibodies antagonizing the calcitonin gene-related peptide pathway will be able to improve quality of life for patients with episodic and chronic migraine, and help relieve the huge patient and societal burden of migraine. Novel treatments designed to target the specific pathophysiology of migraine could have an important place in future migraine management.

Section: Role Of Novel Targeted Treatments In Meeting Goals Of Prevementioning

confidence: 99%

A Review of Monoclonal Antibody Therapies and Other Preventative Treatments in Migraine

Reuter

2018

“…The average amino acid is 0.11 kDa, sumatriptan 0.295 kDa, gepants under 0.603 kDa, but less orally bioavailable dihydroergotamine (DHE) mesylate 0.680 kDa and non-oral olcegepant 0.87 kDa. 80,107 Based on available data from various and numerous IgG studies, it is unlikely that statistical clinically meaningful differences can be established between any of the 4 anti-CGRP mAbs based on half-life. 106 MAb administration seemed limited to injection, making long half-life desirable or a necessity, and limiting choices to IgG1, 2, or 4.…”

Section: Anti-cgrp Mabs Pharmacokinetics: Half-life Issuesmentioning

confidence: 99%

“…These variations are likely based on the aforementioned factors and probable industry manipulation of FcRn and hinge held proprietary information. 80,107 Based on available data from various and numerous IgG studies, it is unlikely that statistical clinically meaningful differences can be established between any of the 4 anti-CGRP mAbs based on half-life. 89 An advantage of prolonged mAb PK half-life is that daily dosing, as for all extant oral preventives, is not needed.…”

Section: Anti-cgrp Mabs Pharmacokinetics: Half-life Issuesmentioning

confidence: 99%

CGRP, Amylin, Immunology, and Headache Medicine

Taylor

2018

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.

“…By 2014 INN standards erenumab is fully human; all 3 ligand agents are zumabs described as >90% homologous to Homo sapiens or humanized. Specifics attributed to individual agents are as follows: Erenumab is an IgG2 lambda receptor mAb produced in transgenic XenoMouse ® , administered subcutaneously, with 3‐14 day Tmax, and T1/2 21 days . Eptinezumab is an IgG1 kappa mAb produced in yeast, with 100% bioavailability due to IV delivery, has a Tmax of 4.8 hours and average T1/2 of 28 days .…”

Section: Cgrp Antagonismmentioning

confidence: 99%

“…Specifics attributed to individual agents are as follows: Erenumab is an IgG2 lambda receptor mAb produced in transgenic XenoMouse ® , administered subcutaneously, with 3-14 day Tmax, and T1/2 21 days. 30,31 Eptinezumab is an IgG1 kappa mAb produced in yeast, with 100% bioavailability due to IV delivery, has a Tmax of 4.8 hours and average T1/2 of 28 days. 30,32 Galcanezumab is an IgG4 mAb, administered subcutaneously, with unreported bioavailability, Tmax and T1/2 between 25 and 30 days.…”

Section: Cgrp Antagonismmentioning

confidence: 99%

Antigens and Antibodies in Disease With Specifics About CGRP Immunology

Taylor

2018

Growth in knowledge about calcitonin gene-related peptide (CGRP) in the pathophysiology of migraine brought CGRP antagonism to headache medicine. Failures in development of small molecule CGRP receptor antagonists and increasing knowledge and use of monoclonal antibodies (mAbs) in medicine led to the breakthrough development of large molecule anti-CGRP mAbs: eptinezumab, erenumab, fremanezumab, and galcanezumab. This specifics about CGRP immunology aims to outline: (1) knowledge needed for CGRP antagonism and (2) developmental issues of specific CGRP antagonists for provider use. This clinically oriented review documents IgG structure and function; state of the art of monoclonal IgG production and ligand-antigen-antibodies in migraine therapeutics contributing to immunogenic risks and off-target toxicities. Specifics to CGRP ligand, receptor, antagonism, and molecules, small and large, complete this review. Completion will facilitate assessment of the similarities, differences, and application of the forthcoming anti-CGRP receptor and ligand antagonists for patients.