Verona Pharma has notified the success of a phase 3 clinical trial of the experimental drug ensifentrine being studied in the maintenance therapy of chronic obstructive pulmonary disease (COPD).
If another parallel late-phase clinical trial is successful, Verona will submit a New Drug Application (NDA) for ensifentrine to the U.S. Food and Drug Administration (FDA) in the first half of 2023.
The presumptive trademark for ensifentrine is Wynayre or Wynfidra.
Ensifentrine is being studied in the treatment of asthma and cystic fibrosis.
Wynayre/Wynfidra: Mechanism of Action of Ensifentrine
Ensifentrine (RPL554) is a first-in-class inhaled dual inhibitor of phosphodiesterase 3 (PDE3) and phosphodiesterase 4 (PDE4) that improves smooth muscle relaxation and provides anti-inflammatory effects.    The combination of PDE3 and PDE4 inhibition is thought to have an additive or possibly synergistic effect. 
Ensifentrine also activates the cystic fibrosis transmembrane conductance regulator (CFTR), thereby helping to reduce mucus viscosity and stimulate mucociliary clearance. 
The molecule is not characterized by gastrointestinal adverse events that are common with systemic PDE4 inhibition.
The originator of ensifentrine is the UK-based Vernalis, which licensed it to Rhinopharma in February 2005. In August 2006, the latter changed its name to Verona Pharma.
Wynayre/Wynfidra: Clinical Efficacy of Ensifentrine in COPD Treatment
The ENHANCE-2 (NCT04542057) phase 3 (randomized, double-blind, placebo-controlled, multicenter, international) clinical trial invited adult (40–80 years old) patients (n=789) with moderate-to-severe chronic obstructive pulmonary disease (COPD).
Approximately 52% of participants continued to receive standard background maintenance therapy with a long-acting muscarinic antagonist (LAMA) and a long-acting beta-agonist (LABA). Approximately 15% of subjects also received inhaled corticosteroid (ICS).
For 24 weeks, patients were given twice-daily inhaled ensifentrine or placebo.
The primary efficacy endpoint of COPD treatment was stated to be improvement in respiratory function, according to an increase in peak forced expiratory volume in 1 second (FEV1) after 12 weeks of therapy.
The ensifentrine group showed a statistically significant mean area under curve (AUC) increase in FEV1 0–12 hours after drug administration, by 94 mL relative to placebo (p<0.0001).
This was true regardless of subjects’ baseline characteristics such as gender, age, smoker status, COPD severity, background treatment, ICS use, chronic bronchitis, FEV1 reversibility, and geographic region.
The use of ensifentrine was also reflected in improved secondary endpoints of respiratory function after 12 weeks of treatment. Thus, relative to placebo, the increase in peak FEV1 0–4 hours post dose was 146 mL (p<0.0001); the increase in FEV1 in the morning before bronchodilator administration (morning trough) was 49 mL (p=0.0017).
Over 24 weeks, there was a 42% reduction in the incidence of moderate-to-severe COPD exacerbations compared to placebo (p=0.0109). Ensifentrine reduced the risk of such exacerbations by 42% based on delayed time to exacerbation (p=0.0088).
A parallel clinical trial, ENHANCE-1 (NCT04535986) phase 3 (randomized, double-blind, placebo-controlled, multicenter, international), of the same design, has organized a longer 48-week trial of ensifentrine in COPD maintenance therapy. Its results will be available closer to the end of 2022.
The additional bronchodilator effect of ensifentrine achieved in a relatively short course of treatment in patients previously considered to have reached maximum therapeutic response to dual (LAMA/LABA) or triple (LAMA/LABA/ICS) therapy for COPD makes the drug under development positioned as a sought-after medication that is clearly useful in severe forms of this progressive and disabling disease. In an estimated 40% of patients, COPD is not adequately controlled, remaining symptomatic and with risks of exacerbations.
And yet Verona’s position is shaky, because ensifentrine has been being perfected for so long that there is virtually nothing left of its patent protection. The patent weakness explains the lack of partnership agreements with any of the strong pharmaceutical manufacturers for joint development of the molecule. Obviously, it will be necessary to rely on traditional methods of intellectual property protection: for example, patented inhaled formulations of ensifentrine (polymorphs, salts, combinations) may delay the fall of the patent shield until the mid-2030s, and the status of an orphan drug in the United States will confer the right to seven years of market exclusivity.
ENHANCE-2 phase 3 data. August 2022. [PDF]