Monoclonal antibodies (mAbs) targeting calcitonin gene‐related peptide (CGRP) signaling are being explored as prophylactic treatments for migraine. Erenumab (AMG 334) is the first potent, selective, and competitive human mAb antagonist of the CGRP receptor. We report the data from two phase I studies assessing the safety, pharmacokinetics (PK), and pharmacodynamics of single and multiple administrations of erenumab in healthy subjects and patients with migraine. The results indicate that the PK profile of erenumab is nonlinear from 1 mg to 70 mg and the linear portion of the clearance from 70 mg to 210 mg is consistent with other human immunoglobulin G2 antibodies. Single doses of erenumab resulted in >75% inhibition of capsaicin‐induced dermal blood flow, with no apparent dose‐dependency for erenumab ≥21 mg. Erenumab was generally well tolerated, with an acceptable safety profile, supporting further clinical development of erenumab for migraine prevention.
Transient receptor potential Ankyrin 1 (TRPA1) is an ion channel expressed by sensory neurons, where it mediates pain signaling. Consequently, it has emerged as a promising target for novel analgesics, yet, to date, no TRPA1 antagonists have been approved for clinical use. In the present translational study, we utilized dermal blood flow changes evoked by TRPA1 agonist cinnamaldehyde as a target engagement biomarker to investigate the in vivo pharmacology of LY3526318, a novel TRPA1 antagonist. In rats, LY3526318 (1, 3, and 10 mg/kg, p.o.) dose-dependently reduced the cutaneous vasodilation typically observed following topical application of 10% v/v cinnamaldehyde. The inhibition was significant at the site of cinnamaldehyde application and also when including an adjacent area of skin. Similarly, in a cohort of 16 healthy human volunteers, LY3526318 administration (10, 30, and 100 mg, p.o.) dose-dependently reduced the elevated blood flow surrounding the site of 10% v/v cinnamaldehyde application, with a trend toward inhibition at the site of application. Comparisons between both species reveal that the effects of LY3526318 on the cinnamaldehyde-induced dermal blood flow are greater in rats relative to humans, even when adjusting for cross-species differences in potency of the compound at TRPA1. Exposure-response relationships suggest that a greater magnitude response may be observed in humans if higher antagonist concentrations could be achieved. Taken together, these results demonstrate that cinnamaldehyde-evoked changes in dermal blood flow can be utilized as a target engagement biomarker for TRPA1 activity and that LY3526318 antagonizes the ion channel both in rats and humans.
Montelukast, a cysteinyl leukotriene receptor antagonist, is being developed for the treatment of asthma and related diseases. This study was designed to evaluate whether montelukast at clinically used dosage levels would interfere with the anticoagulant effect of warfarin. In a two‐period, double‐blind, randomized crossover study, 12 healthy male subjects received a single oral dose of 30 mg warfarin on the 7th day of a 12‐day treatment with montelukast, 10 mg daily by mouth, or a placebo. Montelukast had no significant effect on the area under the plasma concentration‐time curves and peak plasma concentrations of either R‐ or S‐warfarin. However, slight but statistically significant decreases in time to peak concentration of both warfarin enantiomers and in elimination half‐life of the less potent R‐warfarin were observed in the presence of montelukast. These changes were not considered as clinically relevant. Montelukast had no significant effect on the anticoagulant effect of warfarin, as assessed by the international normalized ratio (INR) for prothrombin time (AUC 0–144 and INR maximum). The results of this study suggest that a clinically important interaction between these drugs is unlikely to occur in patients requiring concomitant administration of both drugs.
Twelve healthy male subjects participated in a double-blind, placebo-controlled, randomized, three-period, crossover study to investigate the safety, tolerability, biochemical activity and pharmacokinetics of ibuprofen, a cyclooxygenase inhibitor and MK-0591, a 5-lipoxygenase inhibitor, given as single entities and in combination. Each subject received for three consecutive 8-day periods, separated by 1 week washout, each of the following treatments: ibuprofen 600 mg three times a day with 125 mg MK-0591 twice a day, ibuprofen 600 mg three times a day with placebo for MK-0591 and MK-0591 125 mg twice a day with placebo for ibuprofen. Cyclooxygenase inhibition was measured by platelet thromboxane (TxB2) generation test, and 5-lipoxygenase inhibition was measured by urinary leukotriene E4 excretion and ex vivo LTB4 generation in calcium-ionophore-stimulated blood. TxB2 suppression on day 8 by ibuprofen was not affected by concomitant treatment with MK-0591. MK-0591 alone had no effect on TxB2 generation. Leukotriene biosynthesis was inhibited by more than 90% by MK-0591 alone and by combined treatment, while ibuprofen alone had no effect. Coadministration appears to affect the pharmacokinetics of MK-0591 (decrease of area under the plasma concentration-vs-time curve [AUC] and maximum plasma concentrations [Cmax]) and of ibuprofen (increase of AUC and half-lives of elimination (t1/2) of the (S)-enantiomer, increase of t1/2 the (R)-enantiomer). Combined treatment had no effect on creatinine clearance nor on the number and intensity of the reported adverse experiences.
LY2951742, a monoclonal antibody targeting calcitonin gene-related peptide (CGRP), is being developed for migraine prevention and osteoarthritis pain. To support the clinical development of LY2951742, capsaicin-induced dermal blood flow (DBF) was used as a target engagement biomarker to assess CGRP activity in nonhuman primates and healthy volunteers. Inhibition of capsaicin-induced DBF in nonhuman primates, measured with laser Doppler imaging, was dose dependent and sustained for at least 29 days after a single intravenous injection of the CGRP antibody. This information was used to generate a pharmacokinetic/pharmacodynamic model, which correctly predicted inhibition of capsaicin-induced DBF in humans starting at a single subcutaneous 5-mg dose. As expected, the degree of inhibition in capsaicin-induced DBF increased with higher LY2951742 plasma concentrations. Utilization of this pharmacodynamic biomarker with pharmacokinetic data collected in phase I studies provided the dose-response relationship that assisted in dose selection for the phase II clinical development of LY2951742.
Objective: Assess the effects of subcutaneous (SC) sumatriptan alone and concomitant SC sumatriptan and intravenous (IV) erenumab on resting blood pressure (BP) in healthy subjects. Background: Erenumab is an anti-CGRP receptor monoclonal antibody in development for migraine prophylaxis. BP elevation is a known side effect of SC sumatriptan, a commonly used acute migraine medication. Increased BP is a theoretical possibility with CGRP inhibition. Design/Methods: In this one-way, parallel design study, 34 healthy adults were randomized to: Group A (sumatriptan alone, n=12) and Group B (concomitant sumatriptan and erenumab, n=22). Both groups received IV placebo on Day 1 and SC sumatriptan 12mg (Imitrex™) on Day 2 (Part 1). After a 2-day washout, Group A received IV placebo and Group B received IV erenumab 140mg on Day 4, both groups received SC sumatriptan 12mg on Day 5 (Part 2). BP was assessed at 11 time points (Parts 1 and 2). The primary endpoint was time-weighted, resting mean arterial pressure, (MAP) calculated 2.5hrs post-dose on Day 2 and Day 5. For post-hoc analyses, changes in MAP were calculated 2hrs after each dose of investigational product. Results: Mean baseline BP was similar between groups. Overall, baseline mean (SD) systolic BP (SBP), diastolic BP (DBP), and MAP, respectively were 122.8 (6.5), 70.1 (5.6), and 87.5 (5.0) mmHg. No differences in SBP, DBP, or MAP were observed between subjects who received sumatriptan alone and those who received concomitant sumatriptan and erenumab (upper limit of the 90% CI for the treatment difference was Conclusions: Concomitant administration of IV erenumab 140mg with SC sumatriptan had no effect on resting BP compared with SC sumatriptan alone. Study Supported by: Amgen Inc. Disclosure: Dr. De Hoon has received personal compensation for activities with Ablynx, Merck Sharp & Dohme, Galderma, UCB, and Eli Lilly as an advisor and/or consultant. Dr. De Hoon has received research support from Amgen Inc., Abide, Galderma, Genentech, GSK, J&J, Merck Sharp & Dohme, and UCB. Dr. Hecken has nothing to disclose. Dr. Vandermeulen9s institution has received grants from GSK, Sanofi Pasteur, and AdImmune. Dr. Herbots has nothing to disclose. Dr. Kubo has received personal compensation for activities with Amgen Inc as an employee. Dr. Kubo holds stock and/or stock options in Amgen Inc., which sponsored research in which Dr. Kubo was involved as an investigator. Dr. Lee has received personal compensation for activities with Amgen, Inc. as an employee. Dr. Lee holds stock and/or stock options in Amgen, Inc., which sponsored research in which Dr. Lee was involved as an investigator. Dr. Eisele has received personal compensation for activities with Amgen Inc. as an employee. Dr. Eisele holds stock and/or stock options in Amgen Inc. Dr. Vargas has received personal compensation for activities with Amgen as an employee. Dr. Vargas holds stock in Amgen. Employee of Amgen Inc,,,,,,
