THE DISCOVERY AND DEVELOPMENT OF ENSIFENTRINE; A NOVEL INHALED DUALl PDE3/4 INHIBITOR HAVING “BIFUNCTIONAL” BRONCHODILATOR AND ANTI-INFLAMMATORY ACTIVITY

THE DISCOVERY AND DEVELOPMENT OF ENSIFENTRINE; A NOVEL INHALED DUALl PDE3/4 INHIBITOR HAVING “BIFUNCTIONAL” BRONCHODILATOR AND ANTI-INFLAMMATORY ACTIVITY | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 25 March 2026 V1 Latest version Share on THE DISCOVERY AND DEVELOPMENT OF ENSIFENTRINE; A NOVEL INHALED DUALl PDE3/4 INHIBITOR HAVING “BIFUNCTIONAL” BRONCHODILATOR AND ANTI-INFLAMMATORY ACTIVITY Author : Clive Page [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.177443754.41708438/v1 167 views 82 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Current treatment of patients with asthma or chronic obstructive pulmonary disease (COPD) predominantly involves the use of inhaled bronchodilators (B2 agonists and muscarinic receptor antagonists)(1) and anti-inflammatory corticosteroids (2). Often these drugs are used in fixed dose combination inhalers, either as dual inhibitors (1) or more recently so called “triple inhalers” (1,3). Whilst in many patients this approach is effective in relieving symptoms and providing maintenance treatment, it is also recognised that many patients remain symptomatic despite such treatment (4). Furthermore, there is ongoing concern about the side effect profile of inhaled corticosteroids, particularly when used in patients with COPD where there is an increased risk of infection (5) and in paediatric patients with asthma (6). Moreover, there are now multiple combinations of bronchodilators and inhaled corticosteroids licenced as medicines and they are delivered in a wide range of inhaler devices which can be bewildering to patients and affect adherence to treatment (1,4). THE DISCOVERY AND DEVELOPMENT OF ENSIFENTRINE; A NOVEL INHALED DUALl PDE3/4 INHIBITOR HAVING “BIFUNCTIONAL” BRONCHODILATOR AND ANTI-INFLAMMATORY ACTIVITY Clive Page, Emeritus Professor of Pharmacology, Institute of Pharmaceutical Science, King’s College London [email protected] Current treatment of patients with asthma or chronic obstructive pulmonary disease (COPD) predominantly involves the use of inhaled bronchodilators (B2 agonists and muscarinic receptor antagonists)(1) and anti-inflammatory corticosteroids (2). Often these drugs are used in fixed dose combination inhalers, either as dual inhibitors (1) or more recently so called “triple inhalers” (1,3). Whilst in many patients this approach is effective in relieving symptoms and providing maintenance treatment, it is also recognised that many patients remain symptomatic despite such treatment (4). Furthermore, there is ongoing concern about the side effect profile of inhaled corticosteroids, particularly when used in patients with COPD where there is an increased risk of infection (5) and in paediatric patients with asthma (6). Moreover, there are now multiple combinations of bronchodilators and inhaled corticosteroids licenced as medicines and they are delivered in a wide range of inhaler devices which can be bewildering to patients and affect adherence to treatment (1,4). Given there remains a considerable unmet need in the treatment of respiratory diseases, not least the need for a safe alternative anti-inflammatory treatment to corticosteroids, some years ago we set out to develop a novel bifunctional molecule that exhibited both bronchodilator and anti-inflammatory activity to complement existing classes of drug used in the treatment of conditions such as asthma and COPD. Our original starting point was based on observations that xanthines such as theophylline were already known to possess both bronchodilator (7) and anti-inflammatory activity (8,9), and were effective in the treatment of both patients with asthma (7,8) or COPD (7). However, as systemically administered drugs, xanthines were recognised as having a narrow therapeutic window and a range of drug/drug interactions which has limited their use (7), and as a consequence today in many countries they are used infrequently. Nonetheless, part of the suggested mechanism of action of xanthines was via non-selective inhibition of phosphodiesterase enzymes (PDEs)(10) and with the discovery of multiple families of PDEs (11) it became plausible to find selective inhibitors of different PDEs which would have an improved therapeutic window. This has been borne out with the introduction of different selective PDE inhibitors entering clinical practice such as PDE5 inhibitors for the treatment of erectile dysfunction (12) and pulmonary hypertension (13), as well as PDE 4 inhibitors for the treatment of COPD (roflumilast)(14) and for skin diseases such as psoriatic arthritis (apremilast)(15). However, the PDE4 inhibitors are still not widely used as they are dose limited by a range of side effects when administered orally, particularly in the gastrointestinal tract (14,15). Furthermore, many other selective PDE 4 inhibitors have failed to enter clinical practice because they have been limited by gastrointestinal side effects which has curtailed their development (16). However, many of these PDE 4 inhibitors are analogues of the archetypal PDE4 inhibitor rolipram, originally developed to be an anti-depressant drug, but which still remains one of the most emetic compounds ever discovered (16). Others have also attempted to develop dual PDE3/4 inhibitors (17-19) (Table 1) as it was recognised that PDE3 was the predominant PDE found in airway smooth muscle (11) and PDE4 was the predominant PDE found in most of the inflammatory cell types considered important in the pathogenesis of asthma and COPD (11). Inhibiting both PDE enzyme classes could therefore provide a novel mechanism to induce bronchodilation and anti-inflammatory activity in a single molecule (18). However, several dual PDE 3/4 inhibitors had to be stopped in early clinical development because of unwanted side effects, notably in the gastrointestinal tract (17,19). For example, zardaverine was shown by inhalation to induce significant bronchodilation in subjects with asthma, but at doses that also caused very significant gastrointestinal side effects (19), presumably due to the swallowed portion of the inhaled medicine. Given the known gastrointestinal side effects associated with many of the PDE inhibitors that have been described as chemical analogues of rolipram, our starting point for the discovery and development of ensifentrine was to start with a different non-emetic pharmacophore. We had made the observation that the PDE inhibitor, trequinsin was able to produce long lasting effects on relaxing airway smooth muscle in comparison to other PDE inhibitors (20) which was of considerable interest as this drug had previously been in early clinical trials for the treatment of cardiovascular diseases and shown no adverse effects in either the cardiovascular or gastrointestinal systems (21,22). It was plausible therefore that analogues of trequinsin may provide a good starting point to produce a bifunctional drug through inhibiting both PDE3 and PDE4 having an improved safety profile. With the collaboration of the late Sir David Jack and Alec Oxford, Dom Spina and I set about investigating new trequinsin analogues with a grant from the former Vanguard Pharmaceuticals. The primary screen used to investigate new analogues of trequinsin was electrical field stimulation (EFS) induced contractions of guinea-pig trachea, a robust and reproducible assay previously used by David Jack and his team at GSK to develop the long acting B2 agonist (LABA) salmeterol (23). Importantly this assay not only allowed the evaluation of the effect of novel drugs on airway smooth muscle relaxation, but also permitted the investigation of the duration of action of the compounds as we were keen to develop a drug with a long duration of action to improve adherence. In total we synthesised and investigated only 182 analogues of trequinsin before choosing RPL554 (24) as our lead compound because it had a good duration of action at relaxing guinea-pig trachea in vitro induced by EFS. RPL554 subsequently became known as ensifentrine and demonstrated selective inhibitory effects against recombinant PDE3 and PDE4 enzymes derived from human cells, with a greater potency against PDE3 in comparison with PDE4 (24,25). Furthermore, RPL554 showed very little inhibitory activity against any other known PDE isoform from the PDE superfamily (24,25). However, in functional cellular assays in vitro, we demonstrated that RPL554 potently inhibited the activation of human inflammatory cells to reduce the release of pro-inflammatory cytokines (24). This effect was mimicked by other selective PDE4 inhibitors, but not by selective PDE3 inhibitors (24) suggesting that this anti-inflammatory effect of RPL 554 was due to PDE4 inhibition, even though it’s effect against the recombinant PDE4 enzyme was less than its ability to inhibit PDE3. It is of course also plausible that the ability to inhibit both PDE3 and PDE4 produces effects greater than inhibiting either PDE alone as has been demonstrated elsewhere in other assay systems (26,27) and this hypothesis may also explain the failure of earlier inhaled PDE4 inhibitors in patients with COPD (28). We also demonstrated that RPL554 administered by inhalation with lactose powder produced long lasting bronchoprotection in vivo in guinea-pigs (24), as well as inhibiting the influx of inflammatory cells into the lung induced by allergen in sensitised animals (24,25). These observations were subsequently confirmed and extended in other experiments in guinea-pigs and in primates naturally allergic to Ascaris suum antigen (25). These observations confirmed our earlier observation that RPL554 exhibited anti-inflammatory properties in vivo (24) in addition to the ability of this drug to produce bronchodilation (24). Importantly these effects of RPL554 were not accompanied by significant changes in the cardiovascular system, including in non-human primates which encouraged us to move the drug into further development (25). The preclinical pharmacology of ensifentrine is summarised in Table 2. After successfully passing through a battery of regulatory safety pharmacology investigations and 28 day toxicology in rats and dogs, we were allowed to proceed to a first in man study. These early clinical studies were carried out in the Centre for Human Drug Research in Leiden in the Netherlands under the supervision of Professor Adam Cohen and Dr Zuzana Diamant. In a placebo controlled study in otherwise healthy subjects with mild asthma, inhalation of RPL554 administered by nebuliser showed a rapid and profound improvement in FEV1 in all subjects (29). RPL554 also demonstrated a good bronchoprotective effect against methacholine induced bronchoconstriction in subjects with asthma (29). Subsequently in collaboration with Professor Mario Cazzola in Tor Vergata University in Rome, we showed that inhalation of RPL 554 also produced long lasting bronchodilation in patients with COPD without eliciting any significant side effects in the cardiovascular system (29). There was also no tolerance to the bronchodilator effects of ensifentrine when it was adminstered twice daily for 7 days (29). In order to confirm the anti-inflammatory effect of this drug in man we also carried out experiments in collaboration with Professor Dave Singh at the Medicines Evaluation Unit in the University of Manchester to investigate the ability of inhaled RPL554 to inhibit lipopolysaccharide (LPS)-induced neutrophil infiltration into the lungs of healthy volunteers. Inhalation of RPL554 at similar doses that we had found produced bronchodilation and bronchoprotection significantly reduced the LPS-induced infiltration of neutrophils into the lung in comparison with placebo treated volunteers (29). Ensifentrine was also demonstrated to have a potentiating effect on the CFTR channel in ciliated epithelial cells which may provide a molecular basis for this drug to also improve mucociliary clearance (30). In addition, ensifentrine has been shown to reduce the release of pro-inflammatory cytokines from epithelial cells obtained from patients with CF (31). As such ensifentrine may also be of value in the treatment of other respiratory diseases with increased mucous production such as cystic fibrosis (CF) and bronchiecstasis. Indeed, a pilot study in patients with CF has already shown this drug to improve lung function (32). However, the formulation used in the early clinical studies with ensifentrine required a long nebulisation period and so for further clinical development a new formulation was developed to allow shorter delivery times for the drug. This new formulation of ensifentrine was subsequently investigated to determine the doses to be used in the phase 3 pivotal trials using increases in FEV1 as the primary endpoint (33,34). In addition we demonstrated that when ensifentrine was added to human airway smooth muscle in vitro (both large and small airways), the relaxation could be enhanced when administered with either a B2 agonist or a muscarinic receptor antagonist, with the interaction with a muscarinic antagonist exhibiting true synergy (35,36). This positive interaction between ensifentrine and other classes of bronchodilator was later confirmed in a phase 2 clinical trial demonstrating that ensifentrine could potentiate the effects of the long acting muscarinic receptor antagonist (LAMA), tiotropium bromide (37). This positive interaction with a muscarinic receptor antagonist has led to the development of a fixed dose combination of ensifentrine with the muscarinic receptor antagonist glycopyrollate, which is currently undergoing phase 2 clinical trials in patients with COPD (38). Finally, ensifentrine was evaluated in two phase 3 randomized double blind, parallel group, placebo controlled clinical studies in patients with COPD, ENHANCE 1 and ENHANCE 2 (39). These pivotal studies demonstrated that ensifentrine (3mg twice daily for 24 weeks) produced rapid bronchodilation, with improvement in lung function measured in a exacerbation rate. Furthermore, patients treated with ensifentrine showed a remarkable 48% in more than 1500 patients with moderate to severe COPD, with or without stable background treatment with a long acting LAMA or a LABA, with or without an inhaled corticosteroid (39). 24 weeks of treatment of ensifentrine also reduced the need for daily reuse medication and improved QoL measurement as improvements in SGRQ (39). Importantly these improvements in lung health were obtained without any major side effects occurring with ensifentrine. This is particularly so with gastrointestinal side effects being similar to the placebo treated patients, vindicating our original choice of selecting an analogue of the non-emetic trequinsin, rather than other groups who had selected analogue of rolipram. Ensifentrine was subsequently approved by the FDA in the summer of 2024 for the maintenance treatment of patients with COPD. The drug is now being increasingly prescribed in the USA as an addition therapy for the treatment of patients with COPD and represents an important “first in class” novel approach. With ongoing studies in patients with asthma and cystic fibrosis, it is anticipated that ensifentrine may well also find clinical utility in the treatment of a broader range of patients with other respiratory diseases. Since approval of ensifentrine, GSK have recently announced they have acquired the drug HRS-9821 from Hengrui Pharma in China, another novel inhaled PDE3/4 inhibitor in Phase 1 clinical trials for the treatment of respiratory diseases (Table 1). This is in addition to other companies developing PDE3/4 inhibitors (42) and suggests that the respiratory field can hopefully expect other “bifunctional drugs” to appear in the not too distant future. Conflicts of Interest No conflict of interest to declare Acknowledgements I would like to dedicate this article to my now deceased colleagues Sir David Jack, Alec Oxford and Dom Spina without whom this drug would have never seen the light of day. I would also like to Acknowledge funding from Vanguard Pharmaceuticals Ltd (now Ligand Pharma) and Verona Pharma (now Merck) that supported the development of Ensifentrine. 1. Matera MG, Page CP, Calzetta L, Rogliani P, Cazzola M. Pharmacology and therapeutics of bronchodilators revisited. Pharmacological reviews. 2020 Jan 1;72(1):218-52. 2. Cazzola M, Hanania NA, Page CP, Matera MG. Novel anti-inflammatory approaches to COPD. International journal of chronic obstructive pulmonary disease. 2023 Dec 31:1333-52. 3. Lipworth B, Kuo CR, Jabbal S. Current appraisal of single inhaler triple therapy in COPD. International Journal of Chronic Obstructive Pulmonary Disease. 2018 Sep 28:3003-9. 4. Dekhuijzen R, Lavorini F, Usmani OS, van Boven JF. 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A dose-ranging study of the novel inhaled dual PDE 3 and 4 inhibitor ensifentrine in patients with COPD receiving maintenance tiotropium therapy. International Journal of Chronic Obstructive Pulmonary Disease. 2021 Apr 22:1137-48. 38. www.veronapharma.com 39. Anzueto A, Barjaktarevic IZ, Siler TM, Rheault T, Bengtsson T, Rickard K, Sciurba F. Ensifentrine, a novel phosphodiesterase 3 and 4 inhibitor for the treatment of chronic obstructive pulmonary disease: randomized, double-blind, placebo-controlled, multicenter phase III trials (the ENHANCE trials). American Journal of Respiratory and Critical Care Medicine. 2023 Aug 15;208(4):406-16. 40. Sciurba FC, Jia S, Subramanian S. Ensifentrine: a novel approach to redefining COPD management and implications for additional respiratory diseases. Expert Opinion on Pharmacotherapy. 2025 May 3;26(7):809-20. 41. Cleary SJ, Page CP. Exploring dual PDE 3/4 inhibitors in the treatment of airway diseases. Drugs of the Future. 2015; 40: 301-310. 42. Ochiai K, Takita S, Kujima A, Eiraku K, Iwase K et al. Phosphodiesterase inhibitors. Part 5: hybrid PDE3/4 inhibitors as dual bronchorelaxant/anti-inflammatory agents for inhaled administration. Bioorganic and Medicinal Chemistry Letters. 2013; 23: 375-381. Table 2. Summary of ensifentrine preclinical data Modified from Sciurba et al. (2025) [40] Information & Authors Information Version history V1 Version 1 25 March 2026 Copyright This work is licensed under a Non Exclusive No Reuse License. Authors Affiliations Clive Page [email protected] King's College London Institute of Pharmaceutical Science View all articles by this author Metrics & Citations Metrics Article Usage 167 views 82 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Clive Page. THE DISCOVERY AND DEVELOPMENT OF ENSIFENTRINE; A NOVEL INHALED DUALl PDE3/4 INHIBITOR HAVING “BIFUNCTIONAL” BRONCHODILATOR AND ANTI-INFLAMMATORY ACTIVITY. Authorea . 25 March 2026. 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