Afferent Pharmaceuticals announced the results from the first cohort of a two-cohort Phase 2b study, revealing that the company’s AF-219, an orally available antagonist of the P2X3 receptors, significantly reduced cough frequency in patients with chronic cough, a commonly experienced symptom in people with idiopathic pulmonary fibrosis (IPF).
P2X3 receptors are activated by ATP, a common cellular signal, and play an important role in the sensitization of sensory nerves. Cellular distress caused by injury or infection often lead to the release of high concentrations of ATP, inducing hyper-sensitization of these nerves, and causing chronic or debilitating symptoms, such as chronic cough. Afferent’s AF-219 is a selective P2X3 inhibitor that works by blocking its ATP-mediated activation, and has already shown promising results in pathological cough management.
Afferent’s randomized, double-blind, placebo-controlled, Phase 2 crossover study enrolled 29 patients with cough for a mean duration of 15 years, and a mean awake cough average of almost 60 times per hour. Patients randomized to the AF-219 group received a 50 mg dose, followed by dose escalation up to 100 mg, 150 mg, and 200 mg. Each dose was given two times a day for four days. This first treatment period was followed by a three-to-seven day washout period, after which patients crossed over to the study’s alternate arm and were treated for 16 more days with either AF-219 or placebo.
Following each AF-219 treatment, a cough recording device was used to objectively measure cough frequency in patients. The results demonstrated that the lowest dose had a similar efficacy to that of higher doses — including a previously evaluated 600 mg dose — with about 50 percent of patients having their cough frequency reduced to at least half, and 35 percent demonstrating at least a 70 percent reduction in cough frequency.
A few patients experienced altered taste perception upon 50 mg treatment of AF-219, but the number reporting this side effect was half that of the previous 600 mg dose study. One serious adverse event was recorded, a urinary tract infection.
Patients were also asked to record treatment outcomes in a cough severity diary, based on two questionnaires, and revealed consistent results with the objective measure of cough frequency, although effects were in a dose- and time-dependent manner.
“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,” Mandel Sher, MD, clinical professor of medicine and pediatrics, Morsani College of Medicine, University of South Florida, and an allergist and head of Center for Cough in Tampa Bay, said in a press release.
Data from the second cohort, evaluating lower doses of AF-219, are to be presented in mid-2016 in a medical/scientific conference, and the company expects to begin registration for a Phase 3 trial early in 2017.
Afferent is also evaluating AF-219 efficacy in IPF patients with bothersome cough and breathlessness in an ongoing Phase 2b study. In addition, a 12-week Phase 2b study, evaluating lower AF-219 doses (7.5, 20, or 50 mg) or matching placebo, given twice a day, was started in December 2015 and is expected to finish this year.
“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.”