Dr Kathleen Rickard, MD, Chief Medical Officer, Verona Pharma
Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of death worldwide affecting more than 384 million patients. The condition causes progressive loss of lung function leading to debilitating breathlessness, hospitalizations, and death. Patients struggle to perform basic daily activities such as getting up, eating, and walking and often have difficulty sleeping. In addition, it prevents people from socializing and enjoying hobbies resulting in frustration, anxiety, and depression.
The burden of COPD does not only impact patients and caregivers, medical systems are also affected on a daily basis. In the US, direct and in-direct costs associated with the treatment of COPD total a staggering $50 billion per annum. Despite its widespread impact and spiralling medical costs, COPD receives little media coverage and no new classes of therapeutics have been approved in over a decade.
Although the damage COPD causes to the lungs is permanent, treatment can help to alleviate symptoms to improve patients’ quality of life. However, there is no cure for COPD and, eventually, the condition progresses, and patients continue to experience symptoms despite existing medications. Current standard of care is limited to three mechanisms of action, long acting muscarinic agents (LAMAs), long acting beta-adrenoceptor agonists (LABAs) and inhaled corticosteroids (ICS). LAMAs and LABAs are bronchodilators, designed to relieve airway constriction and make it easier to breathe, while ICS act as anti-inflammatory agents designed to prevent exacerbations, periods where symptoms suddenly escalate.
Some COPD patients are treated with the phosphodiesterase (PDE) 4 inhibitor, roflumilast, which received approval from the US Food and Drug Administration in 2011 and reduces the risk of COPD exacerbations. While roflumilast has been shown to reduce exacerbations, its oral delivery results in systemic exposure and its use has been limited by unfavorable gastrointestinal side-effects including nausea, emesis, diarrhea, abdominal pain, loss of appetite and weight loss.
Unfortunately, despite the availability of these treatments, alone or in combination, many patients remain symptomatic with their wellbeing and daily routines severely compromised through restricted activity. In the US alone, over one million patients remain uncontrolled and symptomatic. These patients urgently require novel, alternative treatments to help manage their COPD.
Ensifentrine is a first-in-class, inhaled, dual inhibitor of the enzymes phosphodiesterase (PDE) 3 and 4 with the potential to be an effective maintenance treatment for COPD and other respiratory diseases including asthma and cystic fibrosis. Its therapeutic profile enables it to act as both a bronchodilator and an anti-inflammatory and potentially differentiates ensifentrine from available therapies. Currently, no dual PDE3 and PDE4 inhibitor is on the market or in clinical development.
Ensifentrine was co-invented by Sir David Jack, former head of research at GlaxoSmithKline, who made many significant contributions to respiratory medicine including pioneering the development of salbutamol, still one of the most widely prescribed bronchodilators for asthma today, and the first inhaled steroid, beclomethasone. After Sir Jack left GSK, he focused on seeking a single molecule that would combine both bronchodilator and anti-inflammatory activity, leading to the discovery of ensifentrine. Patents on the work were assigned to Vernalis plc and later acquired by Rhinopharma Ltd. In 2006, Rhinopharma was recapitalized and renamed Verona Pharma.
In Phase 2 clinical studies in subjects with moderate-to-severe COPD, ensifentrine has demonstrated statistically significant and clinically meaningful improvements in both lung function and symptoms, including breathlessness. These benefits have been observed with or without background therapy. Importantly, ensifentrine has been well tolerated with an adverse event profile similar to placebo in clinical trials involving over 1,400 subjects.
Ensifentrine is currently in two randomized, double-blind, place-controlled Phase 3 trials (ENHANCE-1 and ENHANCE-2) designed to evaluate safety and efficacy for the maintenance treatment of COPD. Each trial has enrolled approximately 800 moderate to severe, symptomatic COPD patients, across sites in the US, Europe, and Asia. The trials will replicate measurements of efficacy and safety data over 24 weeks, with ENHANCE-1 also evaluating longer-term safety in approximately 400 patients over 48 weeks. The primary endpoint is improvement in lung function at week 12 and key secondary endpoints are improvements in symptoms and quality of life. Exacerbations will be assessed in pooled analysis.
We are excited about reporting results from the Phase 3 trials with top-line data expected in the third quarter of 2022 and around the end of 2022. COPD patients and their caregivers have been waiting a long time for a novel class of therapy that has the potential to enable a more enjoyable and active lifestyle. Our hope is that ensifentrine will help to alleviate patient symptoms and contribute to raising the profile of this neglected respiratory disease.
Dr Katheen Rickard, MD, is Chief Medical Officer at Verona Pharma (NASDAQ: VRNA), a clinical-stage biopharmaceutical company focused on respiratory diseases, and a specialist in pulmonary and critical care, with more than 25 years of experience in developing respiratory therapeutics.
Prior to joining Verona Pharma, Dr Rickard served in multiple roles at Aerocrine and subsequently Circassia, where she was instrumental in directing clinical and regulatory strategies for NIOX VERO, an airway inflammation test for managing asthma, across key markets such as the US, China, and Japan, as well as the rest of the world. Previously, Dr Rickard was Vice President Clinical Development and Medical Affairs of GlaxoSmithKline’s Respiratory Medicines Development Centre and, over a period of 15 years, held a number of other leadership positions in clinical development across GlaxoSmithKline’s global respiratory franchise. Dr Rickard received an MD from Hahnemann University Hospital, Philadelphia.