PMID- 36111429 OWN - NLM STAT- MEDLINE DCOM- 20221031 LR - 20230110 IS - 1526-4610 (Electronic) IS - 0017-8748 (Print) IS - 0017-8748 (Linking) VI - 62 IP - 9 DP - 2022 Oct TI - A phase IV clinical trial of gastrointestinal motility in adult patients with migraine before and after initiation of a calcitonin gene-related peptide ligand (galcanezumab) or receptor (erenumab) antagonist. PG - 1164-1176 LID - 10.1111/head.14390 [doi] AB - OBJECTIVE: To compare effects of an initial dose of calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) antagonists on gastrointestinal (GI) motility in patients with migraine and to explore if the mechanistic difference contributes to GI adverse events (AEs). BACKGROUND: Different frequencies of constipation have been observed between CGRP mAbs that target the ligand (galcanezumab [GMB]) or receptor (erenumab [ERE]). METHODS: Patients (n = 65) with migraine without significant GI symptoms were enrolled in a multi-center, single-blind phase IV clinical trial (NCT04294147) and randomized 1:1 to receive GMB (240 mg; n = 33) or ERE (140 mg; n = 32). GI whole and regional transit times were assessed using a wireless motility capsule 1 week before and 2 weeks after mAb administration. The primary endpoint was change from baseline in colonic transit time (CTT) within each treatment group. Other measures included GI Symptom Rating Scale (GSRS), Bristol Stool Form Scale (BSFS), and spontaneous bowel movement (SBM) evaluation. AEs were monitored throughout the study. RESULTS: Baseline characteristics indicated significant GI transit time variability with minimal GI reported symptoms. While not statistically significant, a numerical mean increase in CTT was observed in ERE patients (n = 28, mean [SD] at baseline: 33.8 [29.4] h; least square [LS] mean [SE] change: 5.8 [5.7] h, 95% confidence interval [CI] -5.7 to 17.2, p = 0.320), while GMB decreased CTT (n = 31, mean [SD] at baseline: 29.3 [24.5] h; LS mean [SE] change: -5.4 [5.4] h, 95% CI -16.2 to 5.5, p = 0.328) compared to baseline. No meaningful changes were observed in other regional transit times. ERE significantly reduced BSFS (LS mean [SE] score -0.5 [0.2], p = 0.004) and SBM (LS mean [SE] -1.2 [0.5], p = 0.0120), and increased GSRS-constipation compared to baseline (LS mean [SE] score 0.3 [0.1], p = 0.016). GMB increased GSRS-constipation (LS mean [SE] score 0.4 [0.1], p = 0.002). There were no discontinuations due to or serious AEs. A higher percentage of treatment-emergent AEs were reported with ERE than GMB (ERE: nine of 32 [28.1%] versus GMB: three of 33 [9.1%]), with constipation the most frequently reported (ERE: five of 32 [15.6%] versus GMB one of 33 [3.0%]). CONCLUSION: While the primary endpoint of this study was not met, secondary and tertiary endpoints support a within- and between-treatment change in GI effects suggesting possible mechanistic differences between ligand (GMB) and receptor (ERE) antagonism. CI - (c) 2022 Eli Lilly and Company and The Author. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society. FAU - Kudrow, David AU - Kudrow D AD - California Medical Clinic for Headache, Santa Monica, California, USA. FAU - Nguyen, Linda AU - Nguyen L AD - Division of Gastroenterology, Stanford University, Palo Alto, California, USA. FAU - Semler, Jack AU - Semler J AD - Medtronic, Minneapolis, Minnesota, USA. FAU - Stroud, Chad AU - Stroud C AUID- ORCID: 0000-0002-8374-1212 AD - Eli Lilly and Company, Indianapolis, Indiana, USA. FAU - Samaan, Karen AU - Samaan K AD - Eli Lilly and Company, Indianapolis, Indiana, USA. FAU - Hoban, Deirdre B AU - Hoban DB AUID- ORCID: 0000-0002-9608-8398 AD - Eli Lilly and Company, Indianapolis, Indiana, USA. FAU - Wietecha, Linda AU - Wietecha L AD - Eli Lilly and Company, Indianapolis, Indiana, USA. FAU - Hsu, Hai-An AU - Hsu HA AD - Eli Lilly and Company, Indianapolis, Indiana, USA. FAU - Pearlman, Eric AU - Pearlman E AD - Eli Lilly and Company, Indianapolis, Indiana, USA. LA - eng PT - Clinical Trial, Phase IV PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial DEP - 20220916 PL - United States TA - Headache JT - Headache JID - 2985091R RN - JHB2QIZ69Z (Calcitonin Gene-Related Peptide) RN - I5I8VB78VT (erenumab) RN - 0 (Ligands) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 55KHL3P693 (galcanezumab) RN - 0 (Calcitonin Gene-Related Peptide Receptor Antagonists) SB - IM MH - Adult MH - Humans MH - Calcitonin Gene-Related Peptide MH - *Constipation/chemically induced MH - Double-Blind Method MH - *Gastrointestinal Motility MH - Ligands MH - *Migraine Disorders/drug therapy MH - Single-Blind Method MH - Treatment Outcome MH - *Antibodies, Monoclonal, Humanized/adverse effects/therapeutic use MH - Calcitonin Gene-Related Peptide Receptor Antagonists/adverse effects/therapeutic use PMC - PMC9826055 OTO - NOTNLM OT - calcitonin gene-related peptide OT - colonic transit time OT - constipation OT - gastrointestinal motility OT - migraine OT - monoclonal antibodies COIS- David Kudrow has received grants and/or contracts as a clinical trial investigator from AbbVie, Teva, Amgen, Eli Lilly and Company, Biohaven, Axsome, Satsuma and Lundbeck; consulting fees for advisory boards from Eli Lilly and Company, Amgen, Biohaven, AbbVie, Lundbeck, Axsome, BioDelivery Science International and Satsuma; and payment for speaker's bureaus from AbbVie, Biohaven, Lundbeck, Eli Lilly and Company, Amgen and Teva. Linda Nguyen has received research grants and/or contracts from KateFarm, Vanda and Bold Health; and consulting fees from Eli Lilly and Company, Impel, Ironwood, Phathom, Gemelli, Alnylam, Takeda and Pendulum. Jack Semler has received consulting fees from Eli Lilly and Company, Medtronic, GI Windows, Axial Biotherapeutics and SV Health Partners and holds stock/stock options in Medtronic. Chad Stroud, Karen Samaan, Linda Wietecha, Eric Pearlman are full-time employees and minor shareholders at Eli Lilly and Company. Deirdre B. Hoban has received research and equipment grants from The Swedish Parkinson Foundation (Parkinsonfonden) and The Thorsten and Elsa Segerfalk Foundation; consulting fees from Novo Nordisk; support for attending meetings from International Society for Stem Cell Research (ISSCR), MultiPark at Lund University, Network of European CNS Transplantation and Repair (NECTAR) and The Swedish Parkinson Foundation (Parkinsonfonden); is a former employee of Lund University and a former board member of Network of European CNS Transplantation and Repair (NECTAR) and is a full-time employee of Eli Lilly and Company. Hai-An Hsu is a statistical contractor to Eli Lilly and Company. EDAT- 2022/09/17 06:00 MHDA- 2022/10/29 06:00 PMCR- 2023/01/08 CRDT- 2022/09/16 04:02 PHST- 2021/12/17 00:00 [received] PHST- 2022/07/06 00:00 [accepted] PHST- 2022/09/17 06:00 [pubmed] PHST- 2022/10/29 06:00 [medline] PHST- 2022/09/16 04:02 [entrez] PHST- 2023/01/08 00:00 [pmc-release] AID - HEAD14390 [pii] AID - 10.1111/head.14390 [doi] PST - ppublish SO - Headache. 2022 Oct;62(9):1164-1176. doi: 10.1111/head.14390. Epub 2022 Sep 16.