A novel long-acting conjugate of the vasodilative hormone, human brain natriuretic peptide (hBNP), to treat resistant hypertension - SUMMARY Hypertension affects one-third of US adults (68-88 million cases), contributing to >500,000 deaths per year and healthcare expenses of $51-131 billion annually. Despite the availability of myriad FDA-approved drugs to lower blood pressure, 15-20% of patients are resistant to treatment, and many more patients are unresponsive because of non-adherence to their medication schedule. With an aging population and the increasing prevalence of hypertension, effective treatment for hypertension is likely to become progressively more critical. Human brain natriuretic peptide (hBNP) potently lowers blood pressure. hBNP is produced by the heart in response to high blood pressure, leading to vasodilation, excretion of salt and water in the urine, and inhibition of certain enzymes that raise blood pressure. The safety and effectiveness of hBNP as a therapeutic (aka nesiritide, Natrecor®) were proven for short-term use, but it must be given by constant intravenous infusion or multiple suboptimal daily injections, because it is rapidly removed from the blood. Sale of Natrecor® was discontinued by the manufacturer in 2018 due to decreasing sales after it was shown that a short-term infusion of the acute-acting endogenous peptide had no beneficial effect on reducing long-term rehospitalization or death. Antlia Bioscience has resolved the issue that previously impeded the long-term effectiveness of Natrecor® Antlia Bioscience has discovered an innovative method to extend the lifespan of hBNP in the blood, while keeping its ability to lower blood pressure without increasing heart rate. Antlia has added a block of 200 units of the three amino acids—Proline-Alanine-Serine, PAS(200)—to the hBNP peptide, creating a large molecule that resists degradation and elimination from the blood. Importantly, dogs treated with PAS(200)-hBNP demonstrated significant and sustained blood pressure lowering after a single injection, with minimal adverse side effects. Subsequently three additional hBNP compounds have been made with 400, 600, and 800 PAS units, which were shown to produce progressively longer and higher plasma exposure in a rat pharmacokinetic study. The PAS(400)-hBNP analog is anticipated to be suitable for up to 2x monthly dosing in humans, while the PAS(600) and PAS(800) analogs could provide once monthly or longer dosing intervals. For first proof-of-concept studies designed to establish safety and efficacy in patients, we will use the PAS(400)-hBNP product with an anticipated >72-hour half-life in humans. In preparation for human studies, this Direct-to-Phase-II proposal will pursue bulk manufacture of clinical-grade PAS(400)-hBNP with formulation and stability studies (Aim 1). The first non-clinical batch of the compound made during manufacturing process development will be used for dose-range-finding PK/PD studies in rats and dogs with the goal of defining the therapeutic range of doses with associated plasma concentrations over time (Aim 2). From the results of Aim 2, the doses and frequency of dosing will be selected for the testing of safety of the clinical grade material in rat and dog GLP-toxicity studies (Aim 3) and in a cardiovascular safety study in dogs (Aim 4).
