Highlights
Wynayre/Wynfidra (ensifentrine) is a new drug indicated for the maintenance treatment of chronic obstructive pulmonary disease (COPD).
Inhaled ensifentrine is a dual inhibitor of phosphodiesterase 3 and 4 (PDE3/4).
Verona Pharma is awaiting approval from the U.S. Food and Drug Administration (FDA) for ensifentrine. The FDA is expected to make a decision by the end of June 2024 [1].
If it receives regulatory approval, ensifentrine would be the first COPD maintenance drug with a completely new mechanism of action in over a decade.
Ensifentrine is also currently being investigated for the treatment of asthma, cystic fibrosis, and bronchiectasis.
Wynayre and Wynfidra are hypothetical brand names for ensifentrine. Other proposed trademarks for ensifentrine include Wynzephr, Trinayro, Ohtuvayre, and Zunhayre.
Verona may find some of the brand names useful for its future drugs. For instance, a fixed-dose combination of ensifentrin and glycopyrrolate is being developed for the maintenance treatment of COPD.
Toward the Treatment of COPD
Chronic obstructive pulmonary disease (COPD) is characterized by progressive and partially reversible airflow obstruction, chronic inflammation, airway remodeling, and excessive mucus production. These factors result in daily symptoms and exacerbations that adversely affect quality of life [1] [2].
The standard treatment for COPD has remained unchanged for over 40 years. It includes medications such as inhaled bronchodilators, which are represented by long-acting muscarinic antagonists (LAMA), long-acting beta-agonists (LABA), short-acting muscarinic antagonists (SAMA), and short-acting beta-agonists (SABA). In addition, inhaled corticosteroids (ICS) are also used.
Despite the wide range of drugs available in the above classes and their various double and triple combinations, patients with COPD still experience significant symptoms that affect their daily lives, particularly due to persistent exacerbations [3] [4].
Inhaled corticosteroids are commonly used to prevent COPD exacerbations, despite being associated with an increased risk of pneumonia, including hospitalization [5] [6]. Patients prescribed long-acting inhaled bronchodilators may be at risk of cardiovascular and urinary tract diseases, highlighting the need for personalized alternative therapies based on individual patient characteristics [7] [8].
New therapies for COPD should aim to provide additional bronchodilation, anti-inflammatory effects, symptom reduction, and prevention of exacerbations, while maintaining a favorable safety profile. However, the development of new COPD therapies has been relatively inactive [9] [10] [11].
Wynayre/Wynfidra: Mechanism of Action of Ensifentrine
Phosphodiesterase 3 (PDE3) and phosphodiesterase 4 (PDE4) inhibitors affect a range of respiratory functions [1]. Thus, PDE3 regulates cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in airway smooth muscle, which mediates bronchial tone [2] [3] [4].
PDE4 upregulates cAMP and is involved in the activation and migration of inflammatory cells and in the stimulation of cystic fibrosis transmembrane conductance regulator (CFTR) in bronchial epithelial cells, which helps to reduce mucus viscosity and stimulate mucociliary clearance [5] [6] [7] [8] [9].
Simultaneous inhibition of PDE3 and PDE4 — compared to inhibition of PDE3 or PDE4 alone — has demonstrated enhanced or synergistic effects on airway smooth muscle contraction and suppression of the inflammatory response [10] [11] [12]. Such dual mechanism of action is a promising strategy for the treatment of obstructive and inflammatory airway diseases such as COPD, cystic fibrosis, and asthma.
Ensifentrine (RPL554) is a first-in-class inhaled small-molecule selective dual inhibitor of PDE3 and PDE4 that combines beneficial effects on airway smooth muscle, inflammation, and CFTR stimulation in a single drug [13] [14] [15] [16] [17] [18].
Ensifentrine is not associated with gastrointestinal adverse events common with systemic PDE4 inhibition.
The originator of ensifentrine is the UK’s Vernalis, which licensed it to the UK’s Rhinopharma in February 2005. In August 2006, the latter changed its name to Verona Pharma [19].
Wynayre/Wynfidra: Efficacy and Safety of Ensifentrine in COPD Treatment
The ensifentrine pivotal clinical program is represented by identically designed phase 3 (randomized, double-blind, placebo-controlled, multicenter, international) clinical trials, ENHANCE-1 (NCT04535986) and ENHANCE-2 (NCT04542057), lasting 48 weeks and 24 weeks, respectively.
Adult (40–80 years old) patients (n=760 and n=789) with moderate-to-severe chronic obstructive pulmonary disease (COPD) were invited.
Among the main eligibility requirements were:
- Post-bronchodilator forced expiratory volume in 1 second (FEV1) between 30% and 70% of predicted normal.
- Pre- and post-bronchodilator ratio of FEV1/forced vital capacity (FVC) < 0.7.
- A score of ≥ 2 on the modified Medical Research Council (mMRC) dyspnea scale.
- Current or former cigarette smokers with a cigarette smoking history of ≥ 10 pack years.
The subjects were administered inhaled ensifentrine (3 mg) twice daily or placebo — on the background of continuation of standard COPD treatment, if any.
The primary endpoint of COPD treatment efficacy, assessed after 12 weeks of therapy, was stated by the mean change from baseline in average FEV1 area under the curve (AUC) over 12 hours after drug administration.
The ensifentrine groups demonstrated a statistically significant (p<0.0001) change in the primary endpoint relative to the placebo groups by 87 mL (95% CI [hereafter], 55 to 119) and 94 mL (65 to 124) in ENHANCE-1 and ENHANCE-2, respectively [1].
The improvement in respiratory function was consistent across all subjects, regardless of their baseline characteristics, including gender, age, smoking status, COPD severity, background medications, ICS use, chronic bronchitis status, reversibility of FEV1, and geographic region of residence.
After 12 weeks of treatment, the use of ensifentrine resulted in an improvement in secondary endpoints of respiratory function compared to the use of placebo:
- Increase in peak FEV1 between 0 to 4 hours after drug administration, by 147 ml (111 to 183) and 146 ml (113 to179) [p<0.0001].
- Increase in peak FEV1 in the morning prior to drug administration, by 35 ml (1 to 68) and 49 ml (19 to 80) [p=0.041 and p=0.002].
After 24 weeks of treatment, the ensifentrine groups showed an improvement in symptoms, according to the Evaluating Respiratory Symptoms (E-RS). The difference with placebo was −1.0 points (−1.7 to −0.2) and −0.6 points (−1.4 to 0.2) [p=0.011 and p=0.134].
The use of ensifentrine was found to improve the quality of life, as measured by the St. George’s Respiratory Questionnaire (SGRQ). The difference with placebo was −2.3 points (−4.3 to −0.3) and −0.5 points (−2.7 to 1.7) [p=0.025 and p=0.669].
Ensifentrine reduced the need for rescue medications to manage COPD exacerbations and improved dyspnea symptoms, as measured by the Transition Dyspnea Index (TDI) scale.
Ensifentrine was well-tolerated, with no significant differences in adverse events compared to the placebo groups.
Expert Comments
The additional bronchodilator effect of Wynayre/Wynfidra (ensifentrine) can be achieved in a relatively short course of treatment in patients with chronic obstructive pulmonary disease (COPD), even in those who have previously been considered to have achieved maximum therapeutic response to double (LAMA/LABA) or triple (LAMA/LABA/ICS) standard COPD therapy. This makes ensifentrine a sought-after medicine that is clearly beneficial in severe forms of this progressive and disabling disease.
In approximately 50% of patients, COPD is not effectively managed, resulting in ongoing symptoms and an increased risk of exacerbations. As a result, many patients express dissatisfaction with their treatment [1] [2]. COPD is currently the third leading cause of disease-related deaths worldwide [3].
Given that there are over 390 million COPD patients worldwide [4] and maintenance pharmacotherapy is limited to three mechanisms of action [5], Wynayre/Wynfidra has good prospects for high demand. In 2021, sales of the most sought-after drugs and their combinations in the United States exceeded $10 billion.
However, Verona Pharma’s position is precarious as ensifentrine has been in the process of being finalized for so long that its patent protection is virtually nonexistent. The lack of partnership arrangements with any of the world’s pharmaceutical companies to jointly develop and commercialize the molecule can be attributed to a weakness in the patent.
Verona may need to utilize traditional methods of intellectual property protection, such as patented inhaled formulations of ensifentrine (including polymorphs, suspensions, salts, and combinations), to delay the expiration of the patent until the mid-2030s. Additionally, obtaining orphan drug status in the U.S. would provide seven years of market exclusivity.
In June 2021, Verona granted China’s Nuance Pharma exclusive rights to develop and commercialize ensifentrine in China. Verona received an upfront payment of $40 million from parent Nuance Biotech, with the promise of future payments of up to $179 million as the project progresses, plus royalties from the sale of the finished drug [6].