Angiotensin Vaccines

By Cardiologist on May 11th, 2011

Overview

Patient compliance is a huge challenge for physicians. Poor compliance with antihypertensive medications is often cited as the single most common cause of resistant hypertension. All plays a pivotal role in the development of hypertension and is often the target of antihypertensive medication. By inducing an immune response to this key component of the renin-angiotensin-aldosterone system, agents in this class are designed to interfere with the endogenous activity of this molecule without the need for daily drug administration.

Mechanism Of Action

An analogue of angiotensin is essentially the key component of angiotensin vaccines. These vaccines are designed to elicit the production of antibodies to angiotensin. The antibodies effectively block the conversion of angiotensin to angiotensin II, an effect analogous to that of angiotensin-converting enzyme inhibitors.

PMD-3117

Protherics is developing a series of angiotensin vaccine candidates. PMD-3117 is in Phase lib trials in the United Kingdom, although Protherics is looking to develop second-generation derivatives with better efficacy.

PMD-3117 is a peptide analogue of angiotensin I. It induces antibodies to angiotensin I, thereby inhibiting its conversion to All and preventing the hypertensive actions associated with AIL

A Phase Ha clinical trial of PMD-3117 investigated patient antibody titers and antibody half-life. In this trial, 27 patients with mild-to-moderate hypertension received three or four doses of PMD-3117. Results revealed that antibody titers were raised compared with titers observed in Phase I trials, but not as high as titers observed in preclinical rat studies. Maximum antibody titers were seen by day 64 for the three-dose and four-dose regimens. Thereafter, the titers declined slowly with a median half-life of 85 days.

Eliciting a sufficiently large immune response to achieve a therapeutic antibody titer will be a key hurdle in the development of such vaccines. To boost the vaccine’s immunogenicity, Protherics has tested a combination of AI peptide and an adjuvant (keyhole limpet cyanogen) in rats and in two human volunteers. Two doses of the vaccine conjugate resulted in a significant immune response to AI in humans. A shift in diastolic blood pressure dose response was also demonstrated following challenge with AI and All in one of the human subjects.

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