Abstract/Summary: We propose the investigation of slow-release formulations of a Calcitonin Gene- Related Peptide (CGRP) antagonist for the treatment of migraine. We identified a series of peptides, designed on the salmon calcitonin backbone, which due to a slow receptor off-rate have an extended duration of action in vivo. In a rodent model measuring CGRP-induced vasodilation, at the middle meningeal artery, our lead peptide antagonist ACX101 was far superior, at a low dose of 20 mcg/kg, to a small molecule inhibitor dosed at 300 mcg/kg. While a challenging assay to accomplish, it is a more relevant CGRP-related readout than the typical assay where vasodilation was caused by capsaicin to study the effect of a CGRP antagonist or antibody. Due to a complicated physiology, it is important to note that there is no generally accepted assay for migraine that is clinically predictive. Small molecule antagonists from Boehringer Ingelheim and Merck were dropped from the clinic due to compound-related toxicity. Small molecule inhibitors are thus dose-limited, resulting in marginal benefits over placebo control. Since ACX101 is composed of natural amino acids it will be cleared by the kidneys, as small peptide fragments, thus circumventing the liver. ACX101 has also demonstrated superior potency to a CGRP antibody in the same rodent assay where the antibody was about 50% effective. Incidentally, clinical data from CGRP antibodies have demonstrated reductions in migraine-related pain symptoms averaging 50%. ACX101 is fully effective within 30 minutes and neutralizes CGRP-related vasodilation sustainably for over 90 minutes (the assay duration). Since peptide therapeutics are rapidly metabolized and cleared physiologically, we propose slow-release formulations that extend drug efficacy from a few days to two weeks. This would primarily address the needs of patients who suffer from low to medium frequency migraine episodes (less than 15 days/month). The proposed formulation choices have been clinically validated, resulting in a number of slow-release drugs with efficacy extended to four months from a single dose form. The resulting therapeutic will substantially benefit unserved patients if the preclinical efficacy and formulation choices translate in the clinic. Benefitting from widely used manufacturing processes, both for peptide synthesis and formulations, the cost of a peptide-based therapeutic will be substantially lower than antibodies which are currently priced at close to $7000/year. Additionally, the proposed formulations could be dosed as needed thus avoiding antibody therapeutics with substantially longer half-lives that result in physiological effects of greater than 3 months.