Afferent Pharmaceuticals Reports Cardiovascular Research Showing P2X3 Antagonism Successfully Reduces Hypertension By Restoring Autonomic Nervous Balance at the 2016 American Thoracic Society Conference

Proof-of-Concept Phase 2 Clinical Trials in Hypertension Planned

SAN FRANCISCO--()--Afferent Pharmaceuticals, a leader in the development of small molecule compounds targeting the P2X3 receptor for the treatment of poorly managed and common neurogenic conditions, today announced data from preclinical research that validates P2X3 as a new therapeutic target for hypertension and supports the company’s plans to evaluate AF-130 in hypertension. AF-130 is an orally available compound that selectively blocks the P2X3 receptor, and is Afferent’s second-generation P2X3 antagonist. Data were presented at the American Thoracic Society (ATS) International Conference, held May 13-18, 2016 in San Francisco.

“Carotid Body Involvement in a Translational Ovine Model of Renovascular Hypertension: Sensitivity to Purinergic P2X3 Receptor Antagonism with AF-130”

In research directed by Afferent collaborator, Julian F. Paton, PhD, professor of physiology at the University of Bristol, UK, data show that aberrant carotid body signaling in two preclinical models of hypertension is caused in part by upregulation and stimulation of P2X3 receptors of the carotid sinus nerve. The carotid body is a small mass of vascular tissue located at the bifurcation of the common carotid artery that critically monitors changes in the blood oxygenation and helps the autonomic (involuntary) nervous system to control cardiovascular and respiratory activity. Researchers then showed that after treatment with Afferent’s selective, proprietary P2X3 inhibitor, they were able to inhibit the aberrant carotid body signaling that leads to hypertension.

“This research validates P2X3 as an important target for the treatment of hypertension, and provides support for Afferent’s planned proof-of-concept Phase 2 clinical trials in patients with hypertension with AF-130,” said Kathleen Glaub, CEO of Afferent Pharmaceuticals. “We recently successfully completed a highly promising Phase 1 trial to assess pharmacokinetics, safety and tolerability of AF-130, and look forward to exploring this drug candidate’s potential in hypertension and potentially other non-respiratory indications.”

Role of P2X3 in Hypertension and Cardiovascular Disease

The autonomic or involuntary nervous system has two functional divisions. The sympathetic branch of this system is the protective branch that functions largely as the fight-or-flight response system, in contrast to the complimentary parasympathetic branch that is more involved in the body’s ongoing maintenance functions. Persistently elevated sympathetic nerve discharge is a common driver of neurogenic hypertension, and morbidity and mortality in heart failure, stroke and cardiac arrhythmia. Recent studies from Dr. Paton and collaborators have shown that increased sympathetic activity may be caused by excessive stimulation (known as “hypertonicity”) of sensory nerve fibers or afferents that receive signals from chemical-sensing structures in the major arteries, such as carotid and aortic bodies. Upregulation and/or persistent stimulation of P2X3 in the carotid body afferents may be a key factor precipitating and maintaining such hypertonicity.

In blocking P2X3 receptors in the carotid body with Afferent’s unique compounds, researchers were able to measure reductions in sympathetic nervous activity and an accompanied reduction in blood pressure in their hypertension models. They deduced that inhibiting P2X3 receptors in patients with a range of cardiovascular diseases may serve to correct chronically imbalanced autonomic nervous function, thereby treating their hypertension.

Research Presentations
Abstract #13194
“Purinergic P2X3 Receptor Signaling in the Carotid Body (CB) Accounts for Its Aberrant Discharge in Hypertension”
Session: B64 – Bop Goes the Heart: Cardiovascular Consequences of SDB
May 16, 2016, 9:00 am-4:15 pm

Abstract #13198
“Carotid Body Involvement in a Translational Ovine Model of Renovascular Hypertension: Sensitivity to Purinergic P2X3 Receptor Antagonism with AF-130”
Session: D29 – Bench to Bedside: Translational Science in SDB
May 18, 2016, 9:00-11:00 am

About P2X3 Receptor-Mediated Sensitization

Afferent’s clinical candidates – AF-219 and AF-130 – are orally available, first-in-class compounds that selectively block P2X3 receptors. P2X3 receptors play a key role in the sensitization of certain sensory nerves, notably C-fiber afferents. These nerves become activated and sensitized under pathological conditions mediated by a common cellular signal, ATP, when it is released in high concentrations due to cellular distress following injury or infection. Afferent’s compounds selectively block ATP activation of P2X3 channels, reducing a range of sensory signs and symptoms.

P2X3 receptor-mediated sensitization has also been implicated in inflammatory, visceral and neuropathic pain states, as well as airways hyperreactivity, hypertension, heart failure, migraine, itch and cancer pain.

About Afferent Pharmaceuticals

Afferent Pharmaceuticals is a clinical-stage biotechnology company and a leader in the development of novel drugs for the treatment of a range of neurogenic conditions. These conditions affect millions of patients who suffer from chronic respiratory and urologic sensory pathologies, as well as chronic pain and cardiovascular disorders, and who have limited, if any, treatment options. These chronic pathologies arise when certain nerves become hyper-sensitized as a result of inflammation, distress, infection or tissue injury, which may remain chronically sensitized for months and even years.

Afferent is developing a portfolio of compounds that selectively block P2X3, which plays a key role in the sensitization of these nerves. Afferent’s lead molecule, AF-219, is in Phase 2 clinical development for the treatment of pathologic cough, including chronic cough and cough in idiopathic pulmonary fibrosis (IPF) patients. A second compound, AF-130, has successfully completed Phase 1 clinical testing and will advance to a number of Phase 2 trials in non-respiratory conditions, including hypertension. For more information on the company, please visit Afferent’s website at www.afferentpharma.com.

Contacts

Contacts
Afferent Pharmaceuticals
Dulce Dizon, 650-286-1276
info@afferentpharma.com
or
Media:
Kinkead Communications, Inc.
Susan Kinkead, 415-509-3610
susan@kinkeadcomm.com
or
Burns McClellan, Inc.
Justin Jackson, 212-213-0006, Ext. 327
jjackson@burnsmc.com