Verona Pharma's Ohtuvayre (Ensifentrine), First Novel COPD Therapy in Nearly Two Decades, Receives FDA Approval

Recently, Nasdaq-listed Verona Pharma announced that Ohtuvayre (ensifentrine), developed by the company, has received FDA approval for marketing as a maintenance treatment for adult patients with chronic obstructive pulmonary disease (COPD). Previously, the overseas industry media Evaluate had listed ensifentrine as one of the ten blockbuster therapies expected to be approved in 2024.

In recent years, the global market for respiratory drugs has gained increasing momentum. According to a report by Precedence Research, global sales of chronic obstructive pulmonary disease (COPD) medications reached $18.1 billion in 2022. The market is projected to grow at a compound annual growth rate (CAGR) of 5.14% from 2023 to 2032, with sales expected to reach approximately $29.88 billion. Prior to the approval and launch of ensifentrine, there were few blockbuster drugs with novel mechanisms of action in the global COPD treatment landscape.

Globally, chronic respiratory diseases—including chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, and interstitial lung diseases—are recognized as one of the four major chronic conditions, alongside hypertension, diabetes, and cancer. According to incomplete statistics, COPD alone affects up to 600 million people worldwide, making it the third leading cause of death globally, with approximately 2.5 deaths per minute attributed to this condition. Furthermore, China is among the countries with the highest burden of COPD, with an estimated 100 million patients.

Chronic Obstructive Pulmonary Disease (COPD) is a chronic airway disease characterized by persistent airflow limitation, primarily affecting the human airways and alveoli. Typically, COPD causes symptoms such as chronic cough, sputum production, and progressive dyspnea, thereby reducing patients' quality of life. Clinically, the management of COPD remains challenging.

On the one hand, there is no specific cure available for chronic obstructive pulmonary disease (COPD).At present, the disease progression of chronic obstructive pulmonary disease (COPD) is irreversible and incurable. Mainstream treatment regimens are based on traditional multi-drug therapies, including the use of bronchodilators (such as β2-agonists and anticholinergics) and anti-inflammatory agents (such as inhaled corticosteroids). For most patients, these regimens can alleviate symptoms to some extent but struggle to slow the progression of the disease and the decline in lung function. Furthermore, even when well-controlled, patients require long-term continuous medication due to the recurrent nature of COPD. In addition, traditional multi-drug therapies for COPD involve complex combinations of multiple medications, which are relatively cumbersome, often resulting in suboptimal patient adherence during long-term treatment. During medication, exposure to irritant gases, colds, or bacterial and viral infections may trigger acute exacerbations of COPD.

On the other hand, the pace of new drug development for chronic obstructive pulmonary disease (COPD) is relatively slow.For a long time, the development of new drugs for chronic obstructive pulmonary disease (COPD) has been frequently hindered because its complex pathogenesis has not yet been fully elucidated. Over the past few decades, only a few drugs with novel mechanisms of action have been approved for the treatment of COPD. Among them, the approval of oral phosphodiesterase-4 (PDE4) inhibitors has provided more options for anti-inflammatory therapy in COPD. The mechanism of action of PDE4 inhibitors involves inhibiting the hydrolysis of cyclic adenosine monophosphate (cAMP), thereby suppressing inflammatory signaling pathways and reducing the release of downstream cytokines and chemokines, which ultimately alleviates airway inflammation. However, patients taking oral P4 inhibitors may experience adverse effects such as nausea, vomiting, diarrhea, headache, and weight loss.

As the world’s first novel inhaled dual phosphodiesterase 3/4 (PDE3/4) inhibitor, ensifentrine builds upon PDE4 inhibition by adding targeting of PDE3. PDE3 hydrolyzes both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), whereas PDE4 hydrolyzes only cAMP. Inhibition of PDE3 and PDE4 leads to intracellular accumulation of cAMP and/or cGMP, thereby triggering various downstream signaling effects. At the cellular level, cAMP is involved in multiple processes within airway and vascular tissues. PDE3 inhibition results in bronchial smooth muscle relaxation (leading to bronchodilation), vascular smooth muscle relaxation, positive inotropic effects, and reduced platelet aggregation. PDE4 inhibition exerts anti-inflammatory effects (Torphy TJ, 1998; Schmidt DT, 2000) and has the potential to stimulate mucociliary clearance, partly through activation of the cystic fibrosis transmembrane conductance regulator (CFTR) in epithelial cells.

In the United States, the approval and market launch of ensifentrine were based on data from two pivotal Phase III clinical studies, ENHANCE-1 and ENHANCE-2, conducted by Verona Pharma. In the ENHANCE-1 and ENHANCE-2 clinical trials, after 24 weeks of treatment, the annualized rate of moderate or severe acute exacerbations in the experimental group was reduced by 36% and 43%, respectively, while the risk of acute exacerbations of chronic obstructive pulmonary disease (COPD) was reduced by 38% and 42%, respectively. Furthermore, according to data from ENHANCE-1, the risk of moderate or severe acute exacerbations was reduced by 52% in patients who continued treatment for 48 weeks.

In terms of safety, ensifentrine inhalation may offer better efficacy and tolerability compared to oral formulations of similar products. Based on data from 24 weeks of continuous patient observation in the ENHANCE-1 and ENHANCE-2 studies, as well as data from up to 48 weeks of continuous patient observation in the ENHANCE-1 extension study, no significant differences in adverse reactions were observed between the ensifentrine group and the placebo group.

Studies have shown that ensifentrine can also be used in patients who have already received conventional medications. For instance, ensifentrine may be considered for patients whose condition remains unrelieved after treatment with inhaled corticosteroids, anticholinergics, and β2-adrenergic agonists. Furthermore, according to Verona Pharma’s official website, clinical trials of ensifentrine for indications such as cystic fibrosis and asthma have advanced to Phase II. In the future, ensifentrine may be utilized in a broader population of patients with respiratory diseases.

In China, chronic obstructive pulmonary disease (COPD) also imposes a substantial disease burden. According to statistics, as of 2022, COPD had become one of the most prevalent chronic respiratory diseases in the country, with 100 million existing patients.

In 2021, UroGen Pharma, an innovative Chinese pharmaceutical company, licensed from Verona Pharma the rights to develop and commercialize ensifentrine for chronic obstructive pulmonary disease (COPD) and other potential indications in the Greater China region (Mainland China, Hong Kong, Macao, and Taiwan). Founded in 2014, UroGen Pharma focuses on the licensing and development of drugs in the fields of respiratory and critical care, having established a product portfolio that includes multiple commercially available drugs and late-stage clinical candidates, thereby accumulating extensive clinical resources. After obtaining approval for the Phase III clinical trial of ensifentrine, UroGen Pharma rapidly initiated its domestic research and development process. In April 2023, the ENHANCE–China Phase III clinical trial of ensifentrine announced the dosing of the first patient.

According to Mr. Mark Lotter, Founder and CEO of Verona Pharma, the Phase III clinical trial of ensifentrine in China, led by Academician Zhong Nanshan, is progressing smoothly. As the global development of ensifentrine advances, Verona Pharma will seek to further explore the drug’s potential clinical value.

Furthermore, Mark pointed out that, benefiting from the pilot policies implemented in certain domestic medical special zones, some patients in China may gain earlier access to ensifentrine. In recent years, Chinese regulatory authorities have issued a series of documents encouraging pilot programs and accelerating the domestic market approval process for urgently needed innovative drugs and medical devices already approved overseas. Under the impetus of these innovative policies, the pace of ensifentrine’s market launch in China is expected to further accelerate.

Ensifentrine, as the inaugural commercial product of YouRui’s respiratory pipeline, also marks the launch of the company’s strategic initiative to become a leading enterprise in the field of respiratory disease treatment in China. The company is currently registering and developing two additional products in its respiratory pipeline, targeting neonatal respiratory distress and allergy-related diseases.

Notably, over the past decade since its founding, YouRui Pharma has adopted a dual-drive strategy combining commercialization and clinical development. This approach has successfully accelerated the rapid commercial adoption and market penetration of several licensed overseas originator drugs in China, enabling the company to build extensive commercial resources and clinical experience. Among these achievements, Ferinject Polysaccharide Iron Complex Capsules, acquired from UCB, have seen their single-product revenue double to exceed RMB 500 million, becoming a star product in its category. Currently, YouRui Pharma’s sales network—spanning both hospital and non-hospital channels, as well as online and offline platforms—covers all key provinces and cities across China. These accomplishments undoubtedly provide a critical foundation for YouRui Pharma to efficiently advance the future commercialization of ensifentrine and other products in its respiratory pipeline.

With the approval and market launch of ensifentrine, a potential blockbuster drug for respiratory diseases, YouRui Pharma has drawn industry attention for its robust market access capabilities. Over the past decade, under its dual-drive strategy, YouRui Pharma has focused on addressing significant unmet patient needs, building strengths in the vertical sectors of respiratory and critical care. By efficiently introducing globally leading clinical treatment regimens to patients in China, the company has established a pharmaceutical innovation model with substantial clinical value. We also look forward to more drugs that fill clinical gaps entering patient diagnosis and treatment pathways more efficiently, thereby providing urgently needed innovative therapeutic options for both patients and physicians.