What are the Available and Emerging Phosphodiesterase 4 Inhibitors for COPD Treatment?

Introduction
Chronic obstructive pulmonary disease (COPD) is a lung condition that is characterized by abnormalities of the airways that result in persistent and progressive airflow obstruction.¹ It is a leading cause of morbidity and mortality worldwide and imposes considerable economic and social burdens (e.g., disability and mortality). The global prevalence of COPD is around 10.3% and it is estimated to be responsible for roughly 3 million deaths annually. Studies also indicate that COPD morbidity rises with age and individuals with COPD experience increasing comorbid condition development earlier in life which can be influenced by concomitant chronic conditions (e.g., cardiovascular disease, musculoskeletal impairment) that are related to smoking.

Regarding its pathobiology, COPD is characterized by increased levels of macrophages, activated neutrophils, and lymphocytes within the lungs, peripheral airways, and pulmonary vessels.¹ These inflammatory agents have the capacity to secrete various mediators that attract more inflammatory cells from the bloodstream, which amplify the inflammatory reaction through proinflammatory cytokines, and induce structural changes via growth factors. Patients with COPD have limited emptying of the lungs during forced expiration, thus having decreased forced expiratory volume (FEV1) and a FEV1/FVC [forced vital capacity] ratio, which can contribute to gas trapping and lung hyperinflation.² The FEV1 is reduced by the inflammatory response and airway blockage, while airflow restriction and decreased gas exchange are brought on by tissue damage. Imaging studies also frequently reveal hyperinflation of the lungs, which results from air getting trapped when the airways collapse during exhalation. Acute exacerbations of COPD are also common and can be brought on by a trigger (e.g., bacterial or viral pneumonia, environmental irritants).

Individuals who have dyspnea, have a chronic cough or sputum production, and have previously been exposed to risk factors for COPD, should be evaluated for COPD.¹ Following spirometry-confirmed COPD diagnosis, 4 key factors need to be established in order to guide therapy: degree of airflow restriction, type and intensity of current symptoms, history of moderate and severe exacerbations, and presence of other conditions (multimorbidity).

Currently Available Therapies
Both pharmacological and nonpharmacological therapy options for COPD exist.¹ According to the 2024 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, the goal for pharmacological therapy for COPD is to reduce symptoms, reduce the frequency and severity of exacerbations, and improve exercise tolerance and health status. Beta2-agonists, anticholinergics, methylxanthines, inhaled corticosteroids (ICS), phosphodiesterase-4 (PDE-4) inhibitors, systemic glucocorticoids, mucolytic medicines, and combination therapies are among the drug classes that are frequently used to treat COPD.

Phosphodiesterase-4 inhibitors reduce inflammation by preventing the degradation of intracellular cyclic adenosine monophosphate (cAMP).² The only PDE-4 inhibitor currently approved for the treatment of COPD in the US is roflumilast. Its FDA-labeled indication is to treat individuals with severe COPD who also have chronic bronchitis and a history of exacerbations.³ Roflumilast is not recommended for the treatment of acute bronchospasm because it is not a bronchodilator. Because it selectively inhibits PDE-4, it causes intracellular cAMP to accumulate and aids in the regulation of inflammatory processes. Roflumilast is available in an oral tablet formulation and patients begin treatment with a dose of 250 mcg once daily for the first 4 weeks of treatment, and then increase to 500 mcg once daily for maintenance.

The safety and efficacy of roflumilast was evaluated and established in 8 key randomized controlled trials (RCTs) in adult patients aged 40 years and older with COPD (N=9394).³ The 8 trials included 2 placebo-controlled dose selection trials (Trials 1 and 2) that assessed the effectiveness of roflumilast 250 mcg and 500 mcg once daily, 4 placebo-controlled 1-year trials (Trials 3, 4, 5, and 6) that evaluated the efficacy of roflumilast on COPD exacerbations, and two 6-month efficacy trials (Trials 7 and 8) that evaluated the impact of roflumilast as an add-on therapy to a long-acting beta agonist or long-acting anti-muscarinic. An additional trial (Trial 9) evaluated the effect of roflumilast 500 mcg on COPD exacerbations when added to a fixed-dose combination product containing an inhaled corticosteroid and long-acting beta agonist. The tolerability of roflumilast was also evaluated in a 12-week trial in patients with severe COPD associated with chronic bronchitis (Trial 10).

Emerging Therapies
The emerging development of inhaled PDE-4 inhibitors may lessen the adverse effects currently seen with systemic inhibition of PDE-4 from oral therapies, such as gastrointestinal and class- related adverse effects (e.g, diarrhea, nausea, decreased appetite, weight loss, psychiatric symptoms), which could improve the medication’s overall tolerability.⁴ Recently, a number of drugs that exhibit either combination inhibition of PDE-3/PDE-4 or monotherapy PDE-4 inhibition have entered the development pipeline.⁵ Ensifentrine is a novel dual PDE-3/PDE-4 inhibitor indicated to treat COPD and asthma; it is intended to reduce airway inflammation, increase bronchial relaxation, and increase ciliary beat frequency in bronchial epithelial cells, and is thought to work synergistically to decrease COPD symptoms because it is a dual PDE-3/PDE-4 inhibitor with both bronchodilatory and anti-inflammatory activities.⁶ Ensifentrine is currently in late-stage clinical development for the maintenance treatment of patients with COPD and has completed two phase 3 trials (ENHANCE Trials) where eligible patients were randomized to receive either twice-daily ensifentrine 3 mg or placebo.

Tanimilast, another PDE-4 inhibitor, is under development to treat psoriasis, chronic bronchitis, and COPD.⁷ It is a dry powder inhaler. Its strong pulmonary anti-inflammatory profile, limited systemic exposure, and minimal adverse effects are all part of its design.⁴ In two phase 3 RCTs, 800 and 1,600 μg of tanimilast given twice daily are being tested for 52 weeks to evaluate safety and efficacy using the NEXThaler device (PILASTER and PILLAR studies).

Conclusion
In conclusion, the management of COPD involves a multifaceted approach encompassing both pharmacological and nonpharmacological therapies. The current pharmacological approach includes various drug classes such as PDE-4 inhibitors, with roflumilast being the only PDE-4 inhibitor approved in the US. Emerging therapies like ensifentrine and tanimilast hold promise in offering potential improvements in tolerability and efficacy through their novel mechanisms of action. Further clinical trials are underway to validate the safety and efficacy profiles of these agents, providing hope for enhanced management strategies in COPD patients.

References

1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the prevention, diagnosis, and management of chronic obstructive pulmonary disease (GOLD 2024 report). Global Initiative for Chronic Obstructive Lung Disease website. https://goldcopd.org/2024-gold-report/. Accessed February 19, 2024.
2. Agarwal AK, Raja A, Brown BD. Chronic obstructive pulmonary disease. In: StatPearls. Treasure Island (FL): StatPearls Publishing; August 7, 2023.
3. Roflumilast [package insert], Piscataway, NJ: Camber Pharmaceuticals, Inc.; March 2023
4. Facchinetti F, Civelli M, Singh D, Papi A, Emirova A, Govoni M. Tanimilast, a novel inhaled PDE4 inhibitor for the treatment of asthma and chronic obstructive pulmonary disease. Front Pharmacol. 2021;12:740803. doi:10.3389/fphar.2021.740803
5. Li G, He D, Cai X, et al. Advances in the development of phosphodiesterase-4 inhibitors. Eur J Med Chem. 2023;250:115195. doi:10.1016/j.ejmech.2023.115195
6. Donohue JF, Rheault T, MacDonald-Berko M, Bengtsson T, Rickard K. Ensifentrine as a novel, inhaled treatment for patients with COPD. Int J Chron Obstruct Pulmon Dis. 2023;18:1611-1622. doi:10.2147/COPD.S413436
7. Tanimilast by Chiesi Farmaceutici for chronic obstructive pulmonary disease (COPD): likelihood of approval. pharmaceutical technology. Published July 31, 2023. Accessed February 20, 2024. https://www.pharmaceutical-technology.com/data-insights/tanimilast-chiesi-farmaceutici-chronic-obstructive-pulmonary-disease-copd-likelihood-of-approval/

Prepared by:
Faria Munir, PharmD, MS, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

The information presented is current as February 19, 2024. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.