Tanimilast, A Novel Inhaled Pde4 Inhibitor for the Treatment of Asthma and Chronic Obstructive Pulmonary Disease

Abstract

Chronic respiratory diseases are the third leading cause of death, behind cardiovascular diseases and cancer, affecting approximately 550 million of people all over the world. Most of the chronic respiratory diseases are attributable to asthma and chronic obstructive pulmonary disease (COPD) with this latter being the major cause of deaths. Despite differences in etiology and symptoms, a common feature of asthma and COPD is an underlying degree of airways inflammation. The nature and severity of this inflammation might differ between and within different respiratory conditions and pharmacological anti-inflammatory treatments are unlikely to be effective in all patients. A precision medicine approach is needed to selectively target patients to increase the chance of therapeutic success. Inhibitors of the phosphodiesterase 4 (PDE4) enzyme like the oral PDE4 inhibitor roflumilast have shown a potential to reduce inflammatory-mediated processes and the frequency of exacerbations in certain groups of COPD patients with a chronic bronchitis phenotype. However, roflumilast use is dampened by class related side effects as nausea, diarrhea, weight loss and abdominal pain, resulting in both substantial treatment discontinuation in clinical practice and withdrawal from clinical trials. This has prompted the search for PDE4 inhibitors to be given by inhalation to reduce the systemic exposure (and thus optimize the systemic safety) and maximize the therapeutic effect in the lung. Tanimilast (international non-proprietary name of CHF6001) is a novel highly potent and selective inhaled PDE4 inhibitor with proven anti-inflammatory properties in various inflammatory cells, including leukocytes derived from asthma and COPD patients, as well as in experimental rodent models of pulmonary inflammation. Inhaled tanimilast has reached phase III clinical development by showing promising pharmacodynamic results associated with a good tolerability and safety profile, with no evidence of PDE4 inhibitors class-related side effects. In this review we will discuss the main outcomes of preclinical and clinical studies conducted during tanimilast development, with particular emphasis on the characterization of the pharmacodynamic profile that led to the identification of target populations with increased therapeutic potential in inflammatory respiratory diseases.

The PDE4 Inhibitor Tanimilast Blunts Proinflammatory Dendritic Cell Activation by SARS-CoV-2 ssRNAs

“…Similarly, also the myelomonocyte-attracting chemokine CCL3 and the Th1-attracting chemokines CXCL9 and CXCL10 were dose-dependently reduced ( Figure 1B ). Figures 1A, B show the calculated IC50s that, in most cases, lie in the nanomolar range, a result consistent with previously published data and indicating a high potency of Tanimilast ( 12 , 14 , 15 ). However, in the case of IFN-β and CXCL10, Tanimilast at a concentration of 10 -7 M (representing the maximal concentration of solubility in our system) could inhibit less than 50% of the secreted cytokine.…”

“…However, this aspect could not be investigated using our system of moDCs stimulation by SCV2-RNA. Overall, the data presented in this study suggest that the PDE4 inhibitor Tanimilast could be a promising inhaled immunomodulator in the scenario of COVID-19, given its remarkable safety demonstrated in healthy subjects as well as in asthma and COPD patients ( 14 ) and its mechanism of action non redundant with corticosteroids. Nevertheless, further studies are needed to evaluate the benefits of this agent in clinical settings.…”

“…Tanimilast is a novel inhaled PDE4 inhibitor currently undergoing phase III clinical development for COPD which shows promising pharmacodynamic results associated with a good tolerability and safety profile ( 14 , 24 ). Tanimilast was previously shown to act as a potent anti-inflammatory agent in several cell-based models ( 23 ), including leukocytes derived from asthma ( 26 ) and COPD patients ( 27 ) and rhinovirus-infected human bronchial epithelial cells ( 12 ), as well as in experimental rodent models of pulmonary inflammation ( 13 ).…”

“…Nevertheless, side effects such as gastrointestinal disturbances, particularly nausea and emesis as well as headache and weight loss are typically associated with oral PDE4 inhibitors ( 10 ). Tanimilast (international non-proprietary name of CHF6001) is an inhaled, selective inhibitor of PDE4 isoforms A-D ( 11 ) endowed with anti-inflammatory properties in several in vitro and in vivo models ( 12 , 13 ) which is particularly well tolerated as compared to oral PDE4 inhibitors ( 13 ) given its high lung retention coupled with low systemic exposure ( 14 ). Published data by our group highlighted that Tanimilast can reduce the secretion of inflammatory and Th1/Th17 polarizing cytokines by fine tuning the activity of the master inflammatory transcription factor NF-κB, which could be useful to control Th-1 and Th-17 driven pathologies without inducing a global repression of the inflammatory and immune responses ( 15 ).…”

Dexmedetomidine alleviates airway hyperresponsiveness and allergic airway inflammation through the TLR4/NF‑κB signaling pathway in mice

“…Patients with asthma undergoing surgery are at great risk of perioperative morbidity and mortality due to bronchospasms and hypoxemia ( 5 ). Although medical treatment that can relax bronchial smooth muscle ( 6 ) or inhibit leukotriene production ( 7 ) is available, the development of additional approaches to relieve these life-threatening symptoms during the perioperative period may be beneficial for patients with asthma.…”