PURPOSE: Ensifentrine, a trequinsin analog, is an investigational dual inhibitor of PDE3 and 4 designed to enhance bronchodilator and anti-inflammatory effects locally in the airways and minimize possible adverse systemic effects through direct delivery via inhalation. Ensifentrine has shown bronchodilatory effects in clinical studies in patients with COPD and asthma (Singh 2020, Bjermer 2019). Anti-inflammatory effects including a significant reduction in inflammatory cells (e.g. neutrophils) have been shown with once-daily inhaled ensifentrine (e1mg) in sputum of healthy individuals following LPS challenge (Franciosi 2013). In enzyme activity assays of recombinant PDE3A, PDE3B, and PDE4B2, ensifentrine inhibited PDE activity with IC50s of 0.25, 0.29 and 290nM, respectively. The activity of ensifentrine against PDE4 aligns with positive control rolipram (130nM) and with reported functional activity of ensifentrine on PDE4-mediated inhibition of TNFa production in LPS-stimulated human monocytes (520nM) and proliferation of human mononuclear cells stimulated with PHA (460nM, Boswell-Smith 2006). While ensifentrine appears to be 1000-fold selective for PDE3 over PDE4 in vitro, it is well-recognized that several factors including dimerization, phosphorylation state and cross talk between PDEs limit the interpretation of PDE selectivity in assays using isolated or recombinant PDEs (Francis 2011). As an inhaled therapy delivered topically to the lung ate1mg/mL (e2000uM), pharmacologically relevant local concentrations of ensifentrine for PDE4 inhibition will be readily achieved. METHODS: Studies were conducted to demonstrate that at doses that produced bronchoprotective effects in vivo, ensifentrine could also inhibit antigen-induced inflammatory cell infiltration into the lungs and nose of allergic animals. Study 1 examined the anti-inflammatory effects of ensifentrine in ovalbumin (OVA) sensitized guinea pigs. Animals and were administered 0.3mg/mL inhaled ensifentrine immediately post antigen challenge. Study 2 examined the effect of ensifentrine on cell infiltration in nasal lavage in OVA sensitized guinea pigs. Ensifentrine was dosed 0.1, 0.3 & 0.5mg/mL via snout inhalation prior to antigen challenge. RESULTS: Study 1: ensifentrine produced significant inhibition of the recruitment of total cell numbers to BAL fluid 6 hours post antigen challenge. Study 2: guinea pigs dosed with ensifentrine showed a dose dependent inhibition of OVA-induced eosinophil and total cell recruitment into the nose (>80% inhibition at 1mg/mL dose). CONCLUSIONS: This in-vivo work supplements previously reported work and confirms that, at clinically relevant inhaled doses in animal models of lung inflammation, ensifentrine demonstrates robust anti-inflammatory activity. CLINICAL IMPLICATIONS: This further supports the dual mechanism of action of ensifentrine showing in vivo pharmacology consistent with both inhibition of PDE3 and 4.

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I. Two-week intervals during omalizumab treatment may provide better symptom control in selected patients with chronic urticaria.

Ensifentrine is a novel, potent, and selective dual inhibitor of phosphodiesterase (PDE)3 and PDE4 designed for delivery by inhalation that combines effects on airway inflammation, bronchodilation and ciliary function in bronchial epithelia. In Phase 2 studies in subjects with COPD, ensifentrine demonstrated clinically meaningful bronchodilation and improvements in symptoms and health-related quality of life when administered alone or in combination with current standard of care therapies. Ensifentrine is currently in late-stage clinical development for the maintenance treatment of patients with COPD. This review summarizes non-clinical data as well as Phase 1 and Phase 2 efficacy and safety results of nebulized ensifentrine relevant to the maintenance treatment of patients with COPD.