Experimental and investigational phosphodiesterase inhibitors in development for asthma

ABSTRACT

Introduction: Severe, inadequately-controlled asthma remains a clinical challenge. For this reason, clinical trials and preclinical experimental studies on novel agents as an add-on therapies continue emerge. Phosphodiesterases (PDEs) are enzymes that regulate the function of immune cells by hydrolyzing cyclic guanosine monophosphate/cGMP and cyclic adenosine monophosphate/cAMP. PDEs are divided into subfamilies [PDE3, PDE4, PDE5 and PDE7] which are mainly found in the respiratory tract. Inhibitors of PDEs have already been approved for COPD and pulmonary hypertension.

Areas covered: The role of PDE inhibitors in asthma treatment and the possible mechanism of action via their anti-inflammatory and/or bronchodilating effect are discussed.

Expert opinion: Novel PDE inhibitors exhibiting fewer adverse events may have a role as add-on therapies in asthma treatment in the future. More clinical trials are necessary to prove their efficacy and evaluate their safety profile before approval by regulatory bodies is granted.

KEYWORDS:

• Asthma
• novel agents
• PDE inhibitors
• neutrophilic asthma

Article highlights

• High levels of cAMP and cGMP lead to bronchodilation and inhibition of inflammatory pathways in asthma.

• There are lots of novel agents administered orally or via inhalation with encouraging results in asthma under investigation.

• The inhaled agents present satisfactory tolerability and safety profile with fewer systematic adverse events.

• Lots of clinical studies and experimental models have been designed for PDEs inhibitors and are presented in this review.

• PDE inhibitors could be an effective add-on treatment option for severe asthmatics with less T_H2 profile.

• A multicenter, randomized clinical trial with severe asthma patients characterized by low T_H2 inflammation is needed.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewer has equity in Verona Pharma, UK, who are developing the dual PDE3/4 inhibitor RPL554. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded.