SAN FRANCISCO--(BUSINESS WIRE)--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 that AF-219 significantly reduced cough frequency in the first cohort of a two cohort-Phase 2b study dose-escalation clinical trial in chronic cough patients. Results demonstrated that all AF-219 doses, including the lowest dose of 50 mg twice daily, demonstrated a statistically significant reduction in awake cough frequency compared to placebo (p≤0.002). AF-219 is a selective, non-centrally-acting and orally administered P2X3 antagonist that targets the mechanism by which certain nerve fibers become hyper-sensitized and can lead to chronic and debilitating symptoms, such as chronic cough. Chronic cough is defined as a cough lasting more than eight weeks. Data were presented at the American Thoracic Society (ATS) International Conference, held May 13-18, 2016 in San Francisco.
Data from the second cohort of the Phase 2b study, which evaluates lower doses of AF-219 (as low as 7.5 mg BID), are expected to be presented at a medical/scientific conference in the second half of 2016.
These data support continued clinical development of AF-219 and complement the initial proof-of-concept study showing similar efficacy results in this unmet condition. The company anticipates beginning a Phase 3 registration program in early 2017.
Study Design and Results
The 29-patient randomized, double-blind, placebo-controlled, Phase 2b crossover study was conducted at 10 clinical sites in the U.S. Patients, with a mean awake cough average of almost 60 times per hour and a mean duration of cough of 15 years, were randomized to either AF-219 or placebo arms. Those in the treatment group received AF-219 50 mg, followed by dose escalation up to 100 mg, 150 mg and 200 mg, with each dose given twice daily for four days sequentially. Treatment period one was followed by a three-to-seven day washout period. Patients were then crossed over to the alternate arm of the study and treated with either AF-219 or placebo for 16 more days. Cough frequency was measured objectively utilizing a cough recording device, following each AF-219 treatment and compared to a baseline recording. Nearly 300, 24-hr cough recordings were collected from this study.
All doses demonstrated significant reduction in cough frequency, including at the lowest dose of 50 mg twice daily. The lowest dose of 50 mg BID was shown to have similar efficacy as the previously evaluated dose of 600 mg BID (published in The Lancet, March 2015; online November 2014). An analysis of responders on the 50 mg dose showed nearly half of patients had at least a 50% reduction in cough frequency, and 35% of patients had at least a 70% reduction in cough frequency.
AF-219 was generally well tolerated. The incidence of dysgeusia (altered taste perception), was much lower at the 50 mg twice daily dose compared to higher doses, as well as compared to the first study at 600 mg twice daily, and a clear dose-dependent effect was demonstrated. Specifically, at the 50 mg dose, 57% of patients noted the taste effect, even if only transiently, at any point in time during the four days of treatment. Only one patient discontinued treatment in the current study due to the taste effect. In the previous high-dose study, 100% of patients noted the taste acuity and 25% discontinued due to taste effect. There was one serious adverse event due to a urinary tract infection.
A number of patient-reported outcomes (PROs) were also collected, including a cough severity visual analog scale (VAS), in which patients indicate severity of cough, the Leicester cough questionnaire (a quality-of-life measure), and a cough severity diary. PRO findings were consistent with the objective measure of cough frequency, though patient perception lagged behind the objective measurement. The study data show that the effect of AF-219, in terms of patient-reported outcomes, is both dose and time dependent.
“We are extremely pleased that this study validates the efficacy we had seen in our previous cough study, and provides critical guidance for Phase 3 dose selection. In addition to presenting the second cohort lower-dose results, we look forward to results from our ongoing 12-week chronic cough study with AF-219 later this year,” said Kathleen Sereda Glaub, CEO of Afferent Pharmaceuticals. “As we advance development of AF-219, we also plan to evaluate non-respiratory indications in which P2X3 has been implicated, with our next candidate, AF-130.”
Jacky Smith, MB, ChB, MRCP, PhD, professor and honorary consultant in Respiratory Medicine, University of Manchester and University Hospital Manchester NHS Foundation Trust, and a leading investigator in the field of chronic cough who presented the study results, said, “With millions of adults suffering from poorly controlled or treatment-resistant chronic cough, it is imperative that we find new options for this significant unmet medical need. AF-219 has clear promise as an efficacious, safe and well-tolerated treatment that could significantly improve the quality of life of these patients, who may also experience chest pain, vomiting, incontinence, sleep disturbances, work disruption and social isolation due to their cough.”
Mandel Sher, MD, clinical professor of medicine and pediatrics, Morsani College of Medicine, University of South Florida, as well as an allergist and head of Center for Cough in Tampa Bay, said, “No new treatment for cough has been approved by the FDA in 50 years. The efficacy, safety and tolerability of AF-219 demonstrated in clinical studies to date are impressive, and potentially offer new hope for chronic cough patients who frequently suffer in isolation without adequate treatment—sometimes for many years.”
Twelve-week and Idiopathic Pulmonary Fibrosis (IPF) Phase 2b Studies Ongoing
In December 2015, Afferent initiated a 12-week, Phase 2b study of AF-219 in chronic cough patients, which is expected to be complete by the end of 2016. This is a randomized, double-blind, placebo-controlled, parallel group study in which 200 chronic cough patients are treated for 12 weeks with 7.5, 20 or 50 mg, or matching placebo, twice daily. In addition, the company is evaluating AF-219 in an ongoing Phase 2b study in idiopathic pulmonary fibrosis patients (IPF) with bothersome cough and breathlessness.
ATS Clinical Data Presentations
Profound Antitussive Response to P2X3 Blockade with AF-219 Permits Correlation of Objective Measure of Cough with Improvement in Patient Reported Outcomes
Session: B14: High-Impact Late-Breaking Clinical Trials (Mini-symposium)
Date and time: Monday, May 16, 2016 10-10:15 am
A Phase 2 Dose-Escalation Study with AF-219, a P2X3 Antagonist for the Treatment of Chronic Cough
Session: D23-Symptoms Matter: Cough, Dyspnea, Fatigue and Quality of Life (Poster discussion)
Date and time: Wednesday, May 18, 2016, 9:00-11:00 am
About the AF-219 Proof-of-Concept Chronic Cough Study
Afferent’s initial high-dose proof-of-concept trial demonstrated a 75% reduction in cough frequency (Intent-to-treat population) in 24 refractory chronic cough patients with AF-219 treatment 600 mg twice daily for two weeks. In this first study, all 24 patients noted the change in taste acuity and 25% of these patients discontinued treatment as a result
Chronic Cough – Debilitating Neurogenic Condition Affects Millions
Cough is the symptom for which patients most often seek medical attention. Cough can occur following an upper respiratory infection. In most patients, this cough manifests itself as an acute cough lasting a few days to weeks. However, in some patients, sensitized nerve fibers fail to return to a normal quiescent state, resulting in sub-acute or chronic cough lasting months to years. The prevalence of chronic cough is estimated to be over 10% of adults in the U.S. While an underlying etiology may contribute to cough in some of these patients (such as gasto-intestinal reflux disease or GERD, asthma, or chronic obstructive pulmonary disease), many patients are not well-controlled for their cough even with treatment for such underlying etiology, or with the addition of currently available cough medications.
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, treatment-resistant 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 completed Phase 1 clinical testing and will be evaluated in a number of non-respiratory conditions. For more information on the company, please visit Afferent’s website at www.afferentpharma.com.