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. Public Health Relevance Statement Narrative: The application relates to slow-release formulations of a peptide Calcitonin Gene-Related Peptide (CGRP) antagonist that would primarily benefit episodic migraine sufferers. We propose the use of readily available FDA-approved biodegradable polymers, with proven degradation kinetics, that will sustain drug exposure ranging from 3 to 15 days.
Project Terms: Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Liver ; hepatic body system ; hepatic organ system ; Meningeal Arteries ; Methods ; nervous system disorder ; Nervous System Diseases ; Neurologic Disorders ; Neurological Disorders ; neurological disease ; Pain ; Painful ; Legal patent ; Patents ; Patients ; Peptide Fragments ; Peptides ; Pharmacology ; Physiology ; Rodent ; Rodentia ; Rodents Mammals ; Safety ; Salmon ; Vertebral column ; Spinal Column ; Spine ; backbone ; Testing ; Toxicology ; Translating ; Vasodilation ; Vasodilatation ; Vasorelaxation ; Measures ; Price ; pricing ; Drug Delivery Systems ; Drug Delivery ; Injectable ; Migraine ; Migraine Headache ; analytical method ; base ; Acute ; Chronic ; Clinical ; Physiological ; Physiologic ; Series ; Evaluation ; Hepatotoxicity ; Hepatotoxic effect ; Liver Toxicity ; Toxic effect on liver cells ; hepatic toxicity ; hepatoxicity ; analog ; Therapeutic ; Rivers ; programs ; Investigation ; Frequencies ; Event ; Clinic ; Treatment Period ; treatment days ; treatment duration ; Degenerative Neurologic Diseases ; Degenerative Neurologic Disorders ; Nervous System Degenerative Diseases ; Neural Degenerative Diseases ; Neural degenerative Disorders ; Neurodegenerative Diseases ; Neurologic Degenerative Conditions ; degenerative diseases of motor and sensory neurons ; degenerative neurological diseases ; neurodegenerative illness ; Neurodegenerative Disorders ; experience ; Receptor Protein ; receptor ; success ; bioresorbable polymer ; degradable polymer ; biodegradable polymer ; drug efficacy ; Toxicities ; Toxic effect ; novel ; disorder model ; Disease model ; Drug Exposure ; Property ; LC/MS ; liquid chromatography mass spectrometry ; Drops ; small molecule ; Address ; Dose ; in vivo ; Clinical Data ; Peptide Synthesis ; Rodent Model ; Process ; Development ; developmental ; Placebo Control ; cost ; design ; designing ; manufacturing process ; Therapeutic antibodies ; Peptide antibodies ; FDA approved ; patient population ; preclinical efficacy ; pre-clinical efficacy ; clinical predictors ; Formulation ; peptide drug ; therapeutic peptide ; small molecule inhibitor ; pain symptom ; painful symptom ; Injections ; Amino Acids ; aminoacid ; Antibodies ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Biological Availability ; Bioavailability ; Biologic Availability ; Physiologic Availability ; Blood ; Blood Reticuloendothelial System ; Calcitonin ; Calcitrin ; Thyrocalcitonin ; Calcitonin Gene-Related Peptide ; Capsaicin ; Delayed-Action Preparations ; slow release drug ; time release medication ; Family ; Freedom ; Liberty ; Goals ; Half-Life ; Kidney ; Kidney Urinary System ; renal ; Kinetics ; Laboratories ;
