LJPC-501 is La Jolla’s proprietary formulation of synthetic human angiotensin II. Angiotensin II, the major bioactive component of the renin-angiotensin system, serves as one of the body’s central regulators of blood pressure. LJPC‑501 is the first synthetic human angiotensin II product candidate to be tested in a Phase 3 study.
The ATHOS‑3 study ( https://www.ncbi.nlm.nih.gov/pubmed/28215131 ) was a multicenter, randomized, double-blind, placebo-controlled, Phase 3 clinical study of LJPC-501 in patients with catecholamine resistant hypotension. A total of 344 patients were randomized across nine countries, 321 of whom received study treatment and are included in the primary analysis. Patients were randomized 1:1 to receive either LJPC‑501 or placebo on a background of standard‑of‑care vasopressors selected by the investigators. Randomized patients received their assigned treatment via continuous intravenous infusion.
The study was conducted under a Special Protocol Assessment (SPA) agreed to with the U.S. Food and Drug Administration (FDA) in 2015. The SPA stipulates that a study of this size and design could provide sufficient safety and efficacy signals and an adequate evaluation of the risk/benefit to the patients to support FDA review and consideration for marketing approval.
Mode of Action
Angiotensin II (ANGII), the major bioactive component of the renin-angiotensin-aldosterone system (RAAS System), serves as one of the body’s central regulators of blood pressure. The RAAS system along with the arginine-vasopressin system and the sympathetic nervous system make up the three major counter-regulatory systems the human body utilizes to manage blood pressure. ANGII is a naturally occurring peptide hormone that regulates blood pressure through activation of the ANGII type 1 receptor (AT1R). Through the AT1R, ANGII induces peripheral vasoconstriction, increases sodium and water retention, aldosterone release, and vasopressin release leading to increase in blood pressure.
ANGII has been shown to raise blood pressure in animal models of hypotension. Additionally, a randomized placebo-controlled clinical pilot study in patients with CRH demonstrated catecholamine sparing providing proof of concept that ANGII may be a therapeutic target for improvement in MAP.
Catecholamine Resistant Hypotension
Catecholamine resistant hypotension (CRH) is a life-threatening syndrome in patients with distributive shock (dangerously low blood pressure with adequate cardiac function) who cannot achieve target mean arterial pressure (MAP) despite adequate fluid resuscitation and treatment with currently available vasopressors (catecholamines and/or vasopressin). There are approximately 500,000 distributive shock cases in the United States per year, an estimated 200,000 of which develop CRH. More than 50% of CRH patients die within 30 days.