PDE4 Inhibitors and their Potential Combinations for the Treatment of Chronic Obstructive Pulmonary Disease: A Narrative Review

All published articles of this journal are available on ScienceDirect.

REVIEW ARTICLE

PDE4 Inhibitors and their Potential Combinations for the Treatment of Chronic Obstructive Pulmonary Disease: A Narrative Review

Rakesh Kumar1 Mohd Imran Khan1 Amit Panwar1 Bhavishya Vashist1 Santosh Kumar Rai1 , * Open Modal iD Anil Kumar1
Authors Info & Affiliations
The Open Respiratory Medicine Journal • 13 Nov 2024 • REVIEW ARTICLE • DOI: 10.2174/0118743064340418241021095046
Previous Article | Next Article

Abstract

Chronic Obstructive Pulmonary Disease (COPD) is associated with cough, sputum production, and a reduction in lung function, quality of life, and life expectancy. Currently, bronchodilator combinations (β2-agonists and muscarinic receptor antagonists, dual therapy) and bronchodilators combined with inhaled corticosteroids (ICS), triple therapy, are the mainstays for the management of COPD. However, the use of ICS in triple therapy has been shown to increase the risk of pneumonia in some patients. These findings have laid the foundation for developing new therapies that possess both anti-inflammatory and/or bronchodilation properties. Phosphodiesterase-4 (PDE4) inhibitors have been reported as an effective therapeutic strategy for inflammatory conditions, such as asthma and COPD, but their use is limited because of class-related side effects. Efforts have been made to mitigate these side effects by targeting the PDE4B subtype of PDE4, which plays a pivotal role in the anti-inflammatory effects. Unfortunately, no selective oral PDE4B inhibitors have progressed to clinical trials. This has led to the development of inhaled PDE4 inhibitors to minimize systemic exposure and maximize the therapeutic effect. Another approach, the bronchodilation property of PDE3 inhibitors, is combined with anti-inflammatory PDE4 inhibitors to develop dual inhaled PDE4/PDE3 inhibitors. A few of these dual inhibitors have shown positive effects and are in phase 3 studies. The current review provides an overview of various PDE4 inhibitors in the treatment of COPD. The possibility of studying different selective PDE4 inhibitors and dual PDE3/4 inhibitors in combination with currently available treatments as a way forward to increase their therapeutic effectiveness is also emphasized.

Keywords: COPD, Bronchodilators, ICS, PDE4 inhibitors, Dual PDE4/PDE3 inhibitors, Anti-inflammatory.

1. INTRODUCTION

Chronic Obstructive Pulmonary Disease (COPD) is a common and treatable disease that is characterized by an abnormal inflammatory response in the lungs [1]. Around 11.7% of the global population is estimated to be affected by COPD, although these figures could be underestimated due to the rapid increase in COPD prevalence [2-4]. According to the Fixed Ratio (FR) criteria, the highest COPD prevalence was found in the American region (22.93%), followed by the Southeast Asian region (19.48%), which was followed by Europe (13.09%), Western Pacific (11.17%), and Eastern Mediterranean regions (7.95%) [5]. The prevalence of COPD was 10.43% in the 2016-2019 period and increased to 15.17% in the 2020-2022 period [5]. Although COPD can be prevented and treated, it is still among the top 10 causes of mortality worldwide [6], the sixth leading cause of death in the United States [7], and is a major reason for morbidity and healthcare expenditures. COPD is predicted to be the leading cause of death worldwide in future years [8].

COPD is considered a systemic disease, which is more common in individuals with a history of tobacco smoking [5, 8]. Smoking tobacco is the most common contributing factor in developed and developing countries [5, 9, 10]. Besides smoking, various comorbidities and risk factors are reported to be associated with this disease, including genetics, infections, malnutrition, aging, occupational exposures, indoor and outdoor air pollutants, asthma, and low socioeconomic status [8, 10]. In COPD, a large population of patients suffers from exacerbations, which are described as an acute worsening of respiratory signs. Severe exacerbations are always related to a significantly worse survival outcome [11].

It is estimated that COPD contributes approximately $40 billion annually in US healthcare expenditures [12]. Most of the contributing factors to the economic burden of COPD are frequent or severe exacerbations, which require frequent visits to the emergency department or may require hospitalization. Hence, current objectives to treat COPD patients should be changed towards symptom reduction, exacerbation prevention, and reducing the risk of premature death.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD, 2023) has recommended maintenance therapy based on COPD severity, symptoms assessment, and exacerbation history [13]. Long-acting bron- chodilators, such as Long-Acting Muscarinic Antagonists (LAMAs) and long-acting β2-agonists (LABAs), are the basis of maintenance therapy for COPD patients (Table 1) [13, 14].

LAMA or LABA monotherapy has not always been found satisfactory, while combination therapy has been reported to have superior effects (Table 1) [15]. The combination of LABAs and LAMAs maximized bronchodilation with an insignificant increase in the side effects compared to increasing the dose of a single bronchodilator [13]. Since the COPD mechanism is related to inflammation, treatments like Inhaled Corticosteroids (ICSs) have been evaluated in combination with existing therapies. The addition of an Inhaled Corticosteroid (ICS) to LABAs and/or LAMAs is recommended for patients with frequent exacerbations and high blood eosinophil levels [13, 16]. The recommended triple combination therapies for the treatment of COPD are mentioned in (Table 2).

Table 1.
Approved fixed-dose combinations of LABAs and LAMAs for COPD treatment [116].
LABA/LAMA Device Approved Dose Frequency of Administration
Indacetrol/glycopyrronium Breezhaler 110/50 µga Once daily
Neohaler 27.5/15.6 µgb Twice daily
Vilanterol/umeclidinum Ellipta 22/55 µga Once daily
25/62.5 µgc Once daily
Formoterol/aclidinum Genuair 12/340 µg Twice daily
Olodaterol/tiotropium Respimat 2.5/2.5 µgd Once daily
Note: aApproved dose in Europe and Asia.
bApproved dose in the USA.
cApproved dose in USA and Japan.
dTwo puffs once daily.
Table 2.
Current triple fixed-dose combinations of LABAs, LAMAs and ICS for COPD treatment.
Study Name Triple Combination Used
(ICS+LABA+LAMA) 		No. of Subjects Outcome
KRONOS
NCT02497001
(2018) 		Budesonide 640 µg
Glycopyrronium 36 µg
Formoterol 19.2 µg
(Fixed inhaler)		 639 The Phase III KRONOS trial proved the efficacy and tolerability of triple
therapy relative to dual combination in patients with moderate to severe
COPD irrespective of exacerbation history.
IMPACT
NCT02164513
(2018) 		Fluticasone
furoate 100 µg
Umeclidinium 62.5 µg
Vilanterol 25 µg
(Fixed inhaler)		 4151 The Phase III IMPACT trial showed that treatment with triple therapy
significantly reduced the rate of moderate or severe COPD
exacerbations and hospitalizations compared to LABA/LAMA
TRIBUTE
NCT02579850
(2018) 		Beclometasone 174 µg
Glycopyrronium 18 µg
Formoterol 10 µg
(Fixed inhaler)		 764 Phase III TRIBUTE trial showed that BDP/FF/G significantly reduced the rate of moderate-to-severe
exacerbations compared to LABA/LAMA, without increasing the risk of pneumonia.
ETHOS
NCT02465567
(2020) 		Budesonide 640 µg
Glycopyrronium 36 µg
Formoterol 19.2 µg
(Fixed inhaler)		 2144 Phase III ETHOS trial showed that triple therapy resulted in a lower rate of moderate or severe exacerbations than
dual therapy in COPD patients.

Inflammatory diseases like asthma, COPD, rheumatoid arthritis (RA), or psoriasis can be treated by inhibiting phosphodiesterase-4 (PDE4) [17]. The PDE4 inhibition suppresses airway inflammation and relaxes smooth muscle via an elevation of cAMP (cyclic adenosine monophosphate) levels [17]. Roflumilast is the only PDE4 inhibitor approved for the treatment of patients with severe COPD. A major problem with oral PDE4 inhibitors is the mechanism-based side effects, i.e., nausea, emesis, diarrhea, and headache, which have restricted their use to lower doses only [18]. Thus, there is still considerable room for the development of more efficacious and safe PDE inhibitors for the treatment of asthma and COPD. To date, different strategies have been adopted to enhance the efficacy and safety of PDE4 inhibitors, as mentioned below [18]:

(1) One of the approaches to increase the efficacy of oral PDE4 inhibitors is to selectively target one of the PDE4 subtypes, PDE4B, which is responsible for most of the anti-inflammatory effects [19]. A PDE4D selective inhibitor, like cilomilast, caused emesis and demonstrated a poor therapeutic index compared to the non-selective roflumilast and cilomilast [20-22].

(2) Another approach could be the development of inhaled PDE4 inhibitor formulations to deliver them directly to the lungs in order to avoid systemic exposure. Among several inhaled PDE4 inhibitors, a few have progressed to clinical trials for the treatment of asthma and COPD [18, 23-27].

(3) PDE3 inhibition causes bronchodilation, and selective PDE4 inhibitors are anti-inflammatory but lack acute bronchodilator activity [28, 29]. Therefore, several researchers have tried to develop dual inhibitors of PDE3 and PDE4 to achieve cumulative effects. It has also been proposed that dual PDE3/PDE4 inhibitors may enhance the effects of LABA/ICS combination therapies in asthma or COPD patients [30, 31].

(4) Another approach is to study PDE4 inhibitors in combination with available bronchodilators (LABA/LAMA) or triple therapy for COPD. Roflumilast has demonstrated improvement in lung function in patients with asthma or COPD when combined with ICS or LABA/LAMA [30, 31].

(5) Based on the above-mentioned different app- roaches to improve the therapeutic index, this review lays out future goals for research focused on the basis of efficacy and safety of PDE4 inhibitor combinations/FDC (Fixed-Dose Combination) and dual inhibitors of PDE3/4 as drugs for the treatment of patients with asthma or COPD.

1.1. Chronic Inflammation in COPD and the Role of PDEs

Inflammation and structural modifications in the lungs are major causes of airflow limitation and the decline in forced expiratory volume in 1 second (FEV1) in COPD patients. Inflammatory cells like neutrophils, macro- phages, and T cells are mainly involved in COPD pathophysiology. Structural cells (e.g., epithelial cells, fibroblasts, and smooth muscle cells) also contribute by releasing cytokines, chemokines, and growth factors (e.g., IL-8 and TNF-α) [32, 33]. PDEs are divided into 11 families (PDE1 to PDE11) and are expressed in different cell types of the lungs [34]. PDEs hydrolyze cAMP and cGMP, and these second messengers play important roles in asthma or COPD by regulating the Airway Smooth Muscle (ASM) tone via the β2-adrenergic (β2-AR)-soluble adenylyl cyclase (sAC)-cAMP signaling pathway. A higher level of cAMP in ASM is responsible for its relaxation and prevents various inflammatory responses, which play a fundamental role in the pathophysiology of COPD [35]. cAMP-specific PDEs are PDE4, PDE7, and PDE8, while PDE5, PDE6, and PDE9 are cGMP-specific PDEs. PDE1, PDE2, PDE3, PDE10, and PDE11 can hydrolyze both cAMP and cGMP [31].

All PDE4 isoenzymes are mainly expressed in T-cells, B-cells, eosinophils, neutrophils, airway epithelial cells, and endothelial cells [36]. PDE4 is also expressed in ASM cells, but its inhibition has not exhibited bronchodilator effects in humans [31]. Predominant PDE4 activity is also found in the ciliary epithelia [37]. The PDE4 family of enzymes has been gaining attention in asthma and COPD because PDE4 inhibitors have shown anti-inflammatory effects (Fig. 1).

2. PDE4 INHIBITORS: MONOTHERAPY

2.1. Oral PDE4 Inhibitors

Theophylline or 1,3-dimethylxanthine inhibits PDE and is used to treat COPD or asthma. Being a PDE inhibitor, theophylline exerts anti-inflammatory and immuno- modulatory effects through inhibition of cAMP degra- dation [38-41], although the mechanism of action of theophylline is not fully understood [42]. Theophylline is not a selective PDE inhibitor and inhibits all PDEs in different tissues and organs, including the cardiovascular, gastrointestinal, and central nervous systems (Fig. 2) [41, 42].

Roflumilast was approved for COPD patients suffering from severe airflow obstruction and a history of previous exacerbations, although it was associated with side effects [43]. Oral roflumilast was found to improve lung function and reduce the frequency of exacerbations in COPD patients in two large Phase 3 trials [44]. In a double-blind, placebo-controlled, multicentre, phase 4 trial (NCT013- 29029), roflumilast was tested to reduce exacerbations and hospitalizations in patients with severe chronic obstructive pulmonary disease and chronic bronchitis. It was reported that roflumilast decreased exacerbations by 13.2% lower than the placebo group; however, adverse events were observed in 67% of patients in the roflumilast group and 59% in the placebo group. Patient withdrawals related to adverse events were higher in the roflumilast group (11%) than in the placebo group (5%). The most commonly reported serious adverse events were exacerbations of chronic obstructive pulmonary disease and pneumonia, with 17 (1.8%) deaths in the roflumilast group versus 18 (1.9%) in the placebo group. Weight loss was higher in the roflumilast group (9%) compared to the placebo group (3%) [45].

Fig. (1).

Anti-inflammatory effects of PDE4 inhibitors in COPD patients. (ROS, Reactive Oxygen Species; LTC4, Leukotriene C4; IL2, Interleukin-2; IL4, Interleukin-4; IL5, Interleukin-5; IL8, Interleukin-8; IFNγ, Interferon‐gamma; TNFα, Tumor necrosis factor alpha; LTB4, Leukotriene B4; MMP-1, Matrix metalloproteinase-1; MMP-2, Matrix metalloproteinase-2; MAPK, Mitogen-activated protein kinase; MUC5B, Mucin 5B; MUC5AC, Mucin 5AC).

Fig. (2).

Mechanism of action of phosphodiesterase 4 inhibitors. PDE4 inhibitors inhibit the degradation of cAMP and increase cAMP levels, which relaxes smooth muscle and inhibits inflammation and fibrosis.

Another orally available second-generation PDE4 inhibitor, Cilomilast, significantly improved lung function and quality of life in Phase I and Phase II clinical trials [46]. However, dose-limiting adverse effects were a major concern in the Phase III clinical study and attributed to interactions with PDE4 expressed in “non-target” tissues [46]. Higher side effects were produced by cilomilast in comparison to other systemically delivered PDE4 inhibitors due to selective inhibition of the PDE4D subtype [21]. Hence, a better therapeutic index of roflumilast was speculated because of its pan inhibition of all PDE4 subtypes by roflumilast [18].

2.2. PDE4 Subtypes (PDE4A-D) Selective Inhibitors

Serious side effects (nausea and headache) associated with most of the oral PDE4 inhibitors led to their elimination from clinical trials because of higher systemic exposure. The development of PDE4B subtype-specific inhibitors was one of the strategies adopted to avoid such side effects since these side effects are thought to be associated with the inhibition of the PDE4D isoenzyme [20].

Four isotypes of PDE4 are expressed by four genes (PDE4A-D), and each gene contains various transcripts to produce long, short, and super-short protein isoforms. Long forms of PDE4 contain two upstream regions, UCR1 and UCR2. Phosphorylation of UCR1 by Protein Kinase A (PKA) is known to form a negative regulatory module. Negative regulation of UCR2 results in closing the active site, hence preventing access to cAMP [47]. All PDE4 isoforms also contain a C-terminal Control Region (CR3) shown to close over the active site by weakly engaging inhibitors. PDE4B accounts for most of the anti-inflammatory effects [19], and PDE4D is related to emesis [20]; therefore, developing PDE4B-specific inhibitors could be a useful strategy to treat COPD. PDE4D and PDE4B are required for neutrophil recruitment to the lung after exposure to endotoxin [19]. A single amino acid polymorphism in CR3 is responsible for PDE4B selectivity, i.e., a leucine in place of glutamine in PDE4B-CR3 causes a 70-80-fold shift in selectivity for any inhibitor. A series of arylpyrimidine-based PDE4 inhibitors have been reported by Naganuma et al., which showed >100-fold selectivity for PDE4B over PDE4D [48]. Highly selective triazine-based PDE4B inhibitors have been developed and reported by Hagen et al. [49]. High similarity in catalytic domains of PDE4B and PDE4D made it difficult to design PDE4 subfamily selective inhibitors. Unfortunately, no oral PDE4B-selective inhibitor has progressed to clinical trials [31].

2.3. Inhaled PDE4 Inhibitors

Roflumilast use has been reduced because of adverse effects, such as nausea, diarrhea, weight loss, and abdominal pain, which led to significant treatment discontinuation and withdrawal from clinical trials. Higher systemic exposure to roflumilast caused these adverse effects and led to the development of inhaled PDE4 inhibitors to get maximum exposure in the lungs only [24-27, 50]. Several PDE4 inhibitors have been synthesized for inhaled administration, and very few of them have progressed to clinical trials for the treatment of asthma and COPD [18]. Several companies have disclosed data on inhaled PDE4 inhibitors (Fig. 3). AWD-12-281 was a potent inhaled PDE4 inhibitor (IC50 = 9.7 nM) [51, 52] and showed preclinical efficacy in different species [53]. Poor efficacy led to the discontinuation of AWD-12-281. Tofimilast is a less potent (IC50 = 140 nM) inhaled PDE4 inhibitor [54] and has been found inefficacious in various clinical trials, i.e., in mild asthma [55], persistent asthma [56], GOLD stage II and III COPD patients, and LPS-challenged healthy subjects [57]. Therefore, the development of this compound was discontinued.

UK-500,001, an inhaled isotype-nonspecific but selective PDE-4 inhibitor (IC50 = 1 nM), was tested at three different doses in COPD patients. However, it did not demonstrate efficacy at any dose and was discontinued [18, 58]. GSK256066 (IC50 = 3 pM) is a PDE4B selective inhibitor and is claimed to be the most potent of all known PDE4 inhibitors [59, 60]. GSK256066 exhibited anti-inflammatory effects in LPS-stimulated human peripheral blood monocytes and whole blood, as well as in preclinical rat models of pulmonary inflammation [59, 60]. GSK256066 demonstrated a protective effect in mild asthma patients challenged with an inhaled allergen [61]. GSK256066 did not cause substantial changes in inflammatory markers, although it was well-tolerated in patients with moderate COPD [62].

Another effective PDE4 inhibitor is SCH900182 (IC50 = 0.07 nM), but this compound is in preclinical development and has not progressed to clinical studies [63, 64]. AstraZeneca has developed another inhaled PDE4 inhibitor, 12b (IC50 = 0.02 nM), with high potency [65]. 12b exhibited anti-inflammatory activity in the lungs of LPS-induced rats, and a very low predicted effective dose (1 μg/kg) may not cause emesis in humans [65]. Gilead synthesized a bifunctional compound, GS-5759, by linking a PDE4 inhibitor to a b2-agonist. This molecule moderately inhibited PDE4 (IC50 = 5 nM) [66, 67] and demonstrated in-vivo preclinical efficacy [68]. No clinical development has been reported for GS-5759. Two potent chemical series, the naphthyridinones (IC50 = 0.17 nM) [69] and pyridazinones (IC50 = 0.05 nM) [70], have been published, but compounds have not advanced to clinical development.

CHF 6001/Tanimilast is a highly potent but non-isotype selective PDE4 inhibitor (IC50 = 0.026 nM) and inhibited all isoforms (PDE4A-D) with equal potency [71]. CHF 6001 exhibited preclinical efficacy in various species and was also well tolerated in humans [71-73]. In a phase 2 clinical study, patients with COPD or chronic bronchitis (receiving inhaled triple therapy for ≥2 months) were treated with CHF6001 (800 or 1600 μg) twice daily via multi-dose dry powder inhaler for 32 days. This study confirmed that inhaled CHF6001 is capable of showing anti-inflammatory effects in the lungs of COPD patients already treated with triple inhaled therapy [74]. In another randomized, double-blind, placebo-controlled study, CHF6001 effects for moderate-to-severe exacerbations were non-significant in patients with a chronic bronchitis phenotype. These effects were further increased in patients with chronic bronchitis and eosinophil count ≥150 cells/μL [75, 76], indicating that a specific patient population (eosinophil count ≥150 cells/μL) may be more beneficial from CHF6001 treatment. Overall, both doses of CHF6001 were well-tolerated with no gastrointestinal adverse event (due to minimal systemic exposure) compared to placebo [74, 75]. These findings provided beneficial information for patients with chronic bronchitis, indicating that tanimilast could have additional beneficial effects in patients who are still symptomatic even after the regular use of ICS, LABA, and LAMA [57]. The benefits of tanimilast in this particular patient population are still under investigation in two large phase-III trials [PILASTER (NCT04636801); PILLAR (NCT04636814)] (Table 3).

Fig. (3).

The chemical structures of roflumilast and inhaled PDE4 inhibitors.

Table 3.
Ongoing Phase III studies of tanimilast [57].
Study ID Main Objectives Study Design Device, Dosing Regimen, Duration Treatments (Number of Subjects) Population (N randomized) Primary Measures
PILASTER
(NCT04636801) 		Efficacy, safety, and tolerability Multicenter, Randomised, Double-blind, Placebo-controlled, Parallel-group NEXThaler Twice-daily (BID) 24 weeks Tanimilast: Dose 1: 800µg BID Dose 2: 1,600 µg BID Matched placebo BID N= 2,985 moderate to very severe COPD patients with chronic bronchitis and a history of exacerbation on maintenance with triple therapy (ICS, LABA and LAMA) Primary efficacy variable: Rate of moderate and severe exacerbations, Main secondary variables: Time to 1st moderate or severe exacerbations, predose FEV1 PROs, Safety variables: AEs, AEs of special interests, vital signs, body weight, 12-lead ECGs, routine laboratory values
PILLAR
(NCT04636814) 		Efficacy, safety, and tolerability Multicenter, Randomised, Double-blind, Placebo-controlled, Parallel-group NEXThaler Twice-daily (BID) 24 weeks Tanimilast: Dose 1: 800µg BID DOSE 2: 1,600 µg BID Roflumilast 500µg OD Matched placebo N= 3,980 severe to very severe COPD patients with chronic bronchitis and a history of exacerbation on maintenance with triple therapy (ICS, LABA and LAMA) Primary efficacy variable: Rate of moderate and severe exacerbations, Main secondary variables: Time to 1st moderate or severe exacerbations, predose FEV1 PROs, Safety variables: AEs, AEs of special interests, vital signs, body weight, 12-lead ECGs, routine laboratory values

As discussed above, a significant effect of tanimilast was found in chronic bronchitis patients with higher eosinophil counts, where tanimilast reduced eosinophils and other key type-2 mediators in sputum [76, 77]. Also, a reduction in the exacerbation rate was significant in patients with chronic bronchitis and blood eosinophils ≥150 cells/μL [75]. This clinical data showed that the effect of tanimilast on type-2 inflammation is responsible for its clinical outcomes; however, further confirmation is needed [57].

2.4. Dual PDE4 and PDE3 Inhibitors

It has been well understood that a single molecule having bronchodilation and anti-inflammatory effects or a combination of a molecule having bronchodilation effects with an anti-inflammatory molecule could be a potential approach to dealing with COPD. However, selective PDE4 inhibitors (e.g., roflumilast) are anti-inflammatory but lack acute bronchodilation activity. Therefore, airway inflammation may not be resolved by targeting PDE4 alone. As already mentioned, different PDE isozymes selectively regulate cAMP or cGMP signaling, and PDEs are involved in specific locations at certain time points based on different stimulations/activations [34, 78, 79]. Hence, simultaneous targeting of different PDE enzymes with bifunctional drugs may be essential to have optimal anti-inflammatory and/or bronchodilation effects in asthma and COPD patients [80, 81].

Currently, particular emphasis has been given to the PDE3 since this isozyme can hydrolyze both cAMP and cGMP, with 5-10-fold higher catalytic rates for cAMP [82]. PDE3 is mainly expressed in airway smooth muscle, along with PDE4B and PDE4D [83]. PDE3 inhibition is responsible for bronchodilation through airway smooth muscle relaxation, whereas PDE4 inhibition is associated with an anti-inflammatory effect [27, 82]. Therefore, the development of dual PDE3/4 inhibitors could have better therapeutic effects in patients with COPD and asthma [80, 81, 84]. Very few dual PDE3/4 inhibitors have been published as well as reached in clinical trials to date (Table 4).

Table 4.
Dual PDE3/4 inhibitors entered into clinical trials for airway diseases.
Compound Chemical Structures Clinical Trial Updates for the Treatment of Airway Diseases Current Status
Zardaverine Inhaled zardaverine did not cause lung function improvements in COPD patients Clinical trials discontinued
Benafentrine Benafentrine showed dose-dependent bronchodilation after methacholine challenge in healthy volunteers Clinical trials discontinued
ORG-20241 Tested in Phase I trials for Asthma but data not published Clinical trials discontinued
Tolafentrine Caused decrease in FEV1 >10% in phase II asthma trials Clinical trials discontinued
Pumafentrine Pumafentrine entered in Phase II asthma trials but lacked efficacy Clinical trials discontinued
RPL-554 Inhibition of pulmonary leukocyte recruitment in healthy volunteers treated with aerolized LPS. Acute increase in FEV1 in patients with asthma and patients with COPD. Completed Phase II trials and currently in Phase III trials (clinicaltrials.gov; NCT04542057)

Zardaverine is a 6-phenyl-2H-pyridazin-3-one, having IC50 values of 110 nM and 210 nM, respectively, for human PDE3 and PDE4 [85] and has shown bronchodilation [86, 87] and anti-inflammatory [88] activity in animal models. Clinical trials using oral and intravenous delivery demonstrated that zardaverine caused bronchodilation but also showed dose-limiting adverse effects, including emesis. Although the compound was better tolerated and retained bronchodilator efficacy by inhalation in asthmatics [89], inhaled zardaverine still did not cause lung function improvements in a trial in COPD patients [90]. Zardaverine trials in airway diseases were abandoned due to its short duration of action [91].

Benafentrine is a benzonaphthyridine derivative that inhibited PDE3 from guinea-pig platelets (IC50 1.74 mM) and PDE4 from guinea-pig neutrophils (IC50 1.76 mM) [92]. Although this compound is a relatively weak inhibitor of PDE3 and PDE4 enzymes, it was still tested in humans. Normal human subjects challenged with methacholine did not show bronchodilator activity after treatment with benafentrine at oral doses of up to 90 mg. However, benafentrine exhibited dose-dependent bronchodilation when administered by inhalation. Benafentrine has been discontinued as a drug, probably because of its short duration of action and modest efficacy [82]. Pumafentrine is a compound that has entered clinical trials and is reported to have IC50 values of 28 nM and 7 nM for PDE3 and PDE4, respectively [93]. This compound was expected to be in Phase-II clinical trials for the treatment of asthma but was discontinued due to failure to meet the expected duration of action. Tolafentrine is reported as a dual PDE3/4 inhibitor, but little preclinical data has been published. In a phase-II asthma trial, inhaled tolafentrine did not affect airway responses to histamine challenge, and in four patients, it caused a decrease in FEV1 greater than 10% [94], and trials for asthma were subsequently terminated [91]. ORG-30029 and ORG-20241, two compounds, were published as dual PDE3/4 inhibitors [95, 96]. Among these two, ORG-20241 inhibited pulmonary leukocyte recruitment in allergen-challenged rats [94] and was found bronchoprotective in guinea pigs when delivered by inhalation [97]. ORG-20241 was reported to have entered Phase-I trials for asthma [98], although the outcome of these trials has not been made public. Kyorin Pharmaceutical and Scottish Biomedical collaborated to develop dual PDE3/4 inhibitors, and a lead compound, KCA-965, was synthesized by coupling the pyrazo- lopyridine core of ibudilast to a PDE3-inhibitor pyrida- zinone [99]. KCA-965 was abandoned due to cardio- vascular side effects noted in dogs [100], but structure-activity relationship studies refined this molecule to design novel compounds with a range of IC50 values for PDE3 and PDE4. Several of these lead compounds inhibited leukocyte recruitment to the lungs after methacholine-induced airway obstruction in guinea pigs [101].

Lately, two preclinical PDE3/4 dual inhibitors (RPL554 and RPL565) have been reported, which are trequinsin analogues [102] (Fig. 4). Both compounds inhibited eosinophil recruitment in ovalbumin-sensitized guinea pigs at an oral dose of 10 mg/kg [102]. RPL554/Ensifentrine is a moderately potent PDE3 inhibitor (IC50 = 0.4 nM) and a weak PDE4 inhibitor (IC50 = 1479 nM) [102]. In a preclinical guinea pig model, inhaled RPL554 has demonstrated bronchoprotective and anti-inflammatory activities [102]. RPL554 was evaluated in two different clinical trials in patients with asthma [103] and COPD [104]. RPL554 demonstrated dose-dependent broncho- dilation in asthma patients and was well tolerated without any significant systemic adverse effects [103]. When evaluated in patients with COPD, RPL554 showed significant bronchodilator and anti-inflammatory effects [104]. Verona Pharma evaluated nebulized ensifentrine in a Phase 3 (NCT04542057) clinical study ENHANCE (Ensifentrine as a Novel Inhaled Nebulized COPD Therapy) for COPD maintenance treatment. Ensifentrine demonstrated significant improvements in lung function and reduced the rate of exacerbations in the ENHANCE-2 (NCT04542057) clinical study in patients with COPD. Another study, ENHANCE-1 (NCT04535986), successfully achieved primary and secondary endpoints, demonstrating significant improvements in lung function and reducing the rate and risk of COPD exacerbations.

Fig. (4).

Trequinsin and its analogues (RPL554/Ensifentrine and RPL565).

RPL554 (Ohtuvayre or ensifentrine) was approved by the US Food and Drug Administration (FDA) on June 26, 2024, for the maintenance treatment of COPD in adult patients. Ohtuvayre approval was based on Phase 3 ENHANCE trials data (Verona Pharma website, June 2024).

2.5. PDE4 Inhibitors: Combination Therapy

In a meta-analysis, the efficacy/safety impact of triple combination ICS/LABA/LAMA with dual LABA/LAMA and ICS/LBA combinations was assessed in COPD patients after administration via the same inhaler device [16]. It has been well demonstrated that the addition of ICS to LABA/LAMA causes a higher incidence of pneumonia than LAMA/LABA in patients with COPD and a history of exacerbations, but it is still the preferred treatment due to the lower incidence of exacerbations and better QOL (Quality of Life) score. It has also been reported that triple therapy is superior to the LAMA/LABA combination due to the lower mortality and better dyspnea score in patients. To date, triple therapy with LAMA/LABA in patients with COPD has been reviewed in five systematic reviews [105-109]. All these reviews showed that triple therapy has a risk of pneumonia (because of ICS), but it is superior to LAMA/LABA therapy. From the safety point of view, these reviews also showed that serious adverse events were similar between triple and dual LAMA/LABA therapy. These clinical data open opportunities for combining PDE4 inhibitors or PDE3/PDE4 dual inhibitors with LAMA/LABA therapy or ICS/LAMA/LABA triple therapy since these therapies are associated with serious adverse effects, including pneumonia.

Two different clinical trials have been reported where the effect of roflumilast in addition to LABA (salmetrol) or LAMA (tiotropium) was evaluated on patients with COPD (Table 5) [110]. The patient population included in these trials consisted of either chronic smokers or ex-smokers not using ICS at the time of randomization. In both studies, roflumilast demonstrated improvements in pre- and post-bronchodilation. The roflumilast combination with salmeterol or tiotropium exhibited an increase in pre-bronchodilator FEV1 in comparison to placebo; however, the increase was higher when combined with tiotropium (a LAMA). In both studies, a high number of withdrawals were reported in the roflumilast arm due to adverse effects.

Table 5.
A summary of the most important clinical trials with PDE4 inhibitors and long-acting bronchodilators in COPD.
Duration of Treatment Treatment Groups Severity Endpoints Results
24 Weeks (M2-127) Placebo (467/385) Roflumilast 0.5mg OD (466/359) Salmeterol both groups 50% Exacerbations: (GOLD IV) Prebroncodilator FEV1 Postbroncodialtors FEV1 Mean rate of exacerbations (mild, moderate, severe) Dyspnea index 36% Lower 49ml increase over placebo/salmeterol
60ml increase over placebo/salmeterol NS vs placebo/salmeterol
NS vs placebo/salmeterol
24 Weeks (M2-128) Placebo (372/333) Roflumilast 0.5mg OD (371/309) Tiotropium both groups 50% Prebroncodilator FEV1 Postbroncodialtors FEV1 Mean rate of exacerbations (mild, moderate, severe) Dyspnea index (TDI focal score/change in SOBQ) 80ml increase over placebo/tiotropium 81ml increase over placebo/tiotropium NS vs placebo/tiotropium

0.4units/2.6 units significantly better
with roflumilast

Two more clinical studies (M2-124 and M2-125) have been reported for roflumilast. These studies aimed to investigate the effect of roflumilast on exacerbation rate and pulmonary function in patients with COPD, along with safety and tolerability evaluation [44]. In both studies, oral administration of roflumilast (500 μg, daily) reduced exacerbation frequency and improved lung function. However, 14% of patients in the roflumilast group discontinued because of class-related adverse effects.

As mentioned earlier, RPL554/Ensifentrine is a novel inhaled dual PDE3/4 inhibitor that has bronchodilator and anti-inflammatory properties. Singh et al. studied the short-term bronchodilator effects of RPL554 in combi- nation with other bronchodilators in COPD patients in two different clinical studies [111].

The purpose of both studies was to find out the additional bronchodilation effects of RPL554 over and above a β2-agonist or a muscarinic antagonist. In study 1, RPL554 showed clinically relevant bronchodilation, as similar effects were found after salbutamol (a SABA) and ipratropium (a SAMA) administration. The combination of RPL554 with short-acting bronchodilators (salbutamol or ipratropium) showed additional effects in terms of FEV1 when compared to monotherapies. Study 1 laid the foundation for further investigation of RPL554 in combination with long-acting bronchodilators. Therefore, tiotropium, a long-acting bronchodilator (a LAMA), was selected for study 2. Study 2 also demonstrated an additional effect of RPL554 on bronchodilation when combined with a LAMA. Overall, both studies demons- trated additional bronchodilation, reduced gas trapping, and improved airway conductance when RPL554 was administered alongside either a β2-agonist or muscarinic antagonists [111].

2.6. Future Prospective

Although there are hopes regarding the potential of PDE4 inhibitors for the treatment of asthma and COPD, further improvements are needed. Since PDE4 inhibitors are associated with class-related adverse effects, careful designing of compounds is required to improve the risk-to-benefit ratio. The dose-limiting toxicity of oral PDE4 inhibitors cilomilast or roflumilast has limited their use in COPD. Class-related adverse events led the researchers to develop inhaled PDE4 inhibitors to apply them directly to the site of action (lungs) to minimize systemic exposure and maximize the therapeutic effects [18]. Therefore, several PDE4 inhibitors have been developed for inhaled administration and tested in various respiratory diseases [17]. Among all tested inhaled PDE4 inhibitors, tanimilast exhibited more promising preclinical and clinical results so far. Tanimilast has shown ∼2000-fold higher drug levels in the lungs compared to the levels found in the systemic circulation. Moreover, tanimilast did not show PDE4 inhibitor class-related adverse effects and was tolerated well in a Single Ascending Dose (SAD) study. Inhaled tanimilast administration, along with ICS, LABA, and LAMA, steadily decreased inflammation in the lungs of patients with chronic bronchitis [74, 112]. These findings proved that patients with chronic bronchitis, after treatment with tanimilast, could have additional beneficial effects if they are still symptomatic even after the regular use of ICS, LABA, and LAMA [57]. Two large randomized, phase III trials (PILASTER and PILLAR) are currently going on to assess the effects of tanimilast in COPD patients [57].

Dual inhibitors of both PDE3 and PDE4 showed promise as a novel class of drugs with both anti-inflammatory and bronchodilator effects exerted by a single molecule [113]. FDA approval of RPL554 has proved that dual PDE3/4 inhibitors have additive or synergistic effects on cells involved in inflammation and broncho- dilation beyond those that an inhibitor selective for each PDE isozyme alone can achieve. Furthermore, it is now evident that inhaled RPL-554 displays synergism with muscarinic receptor antagonists in the relaxation of human airways [114-116], suggesting that the combination of a PDE3/4 inhibitor with an existing class of broncho- dilator may provide further clinical benefits than using any of these drug classes alone. Suppose synergistic effects can be optimized to improve efficacy and minimize side effect profiles without compromising duration of action. In that case, these observations are cause for optimism that dual PDE3/4 inhibitors could still emerge as a novel class of drugs for the treatment of airway diseases.

CONCLUSION

Additional efforts are still necessary to develop more effective inhaled PDE4 inhibitors and dual PDE3/4 inhibitors. Also, more clinical data are needed to evaluate their therapeutic efficacy and safety in COPD patients in combination approaches. The data reported so far has come from shorter studies; however, longer-duration studies with a larger sample size are needed to evaluate the effect of PDE4 inhibitors (alone or in combination) on key clinical endpoints and safety parameters. The recent approval of the dual PDE3/4 inhibitor RPL554/ensifentrine sparked new hope for developing more such inhibitors. We anticipate that effective inhaled PDE4 inhibitors and dual PDE3/4 inhibitors have the potential to replace or reduce ICS and its side effects.

AUTHOR’ CONTRIBUTION

S.K.R.: Study conception and design; R.K.: Writing the paper; M.I.K.: A.P., B.V.: Data collection; A.K.: Supporting the idea.

LIST OF ABBREVIATIONS

COPD = Chronic Obstructive Pulmonary Disease
ICS = Inhaled Corticosteroids
FR = Fixed Ratio

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

None.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

REFERENCES

1
Global Strategy for Prevention. Diagnosis and management of COPD 2023. Available from https://goldcopd.org/ 2023-gold-report-2/
2
British Lung Foundation. British Lung Foundation. Chronic obstructive pulmonary disease (COPD) statistics. Available from https://statistics.blf.org.uk/copd
3
Adeloye D, Chua S, Lee C, et al. Global and regional estimates of COPD prevalence: Systematic review and meta–analysis. J Glob Health 2015; 5(2): 020415.
4
Bednarek M, Maciejewski J, Wozniak M, Kuca P, Zielinski J. Prevalence, severity and underdiagnosis of COPD in the primary care setting. Thorax 2008; 63(5): 402-7.
5
AL Wachami N, Guennouni M, Iderdar Y, et al. Estimating the global prevalence of chronic obstructive pulmonary disease (COPD): A systematic review and meta-analysis. BMC Public Health 2024; 24(1): 297.
6
World Health Organization. The top 10 causes of death. Available from https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death
7
Centers for Disease Control and Prevention. What is COPD? Available from https://www.nhlbi.nih.gov/health/copd
8
Quaderi SA, Hurst JR. The unmet global burden of COPD. Glob Health Epidemiol Genom 2018; 3(e4): e4.
9
Soriano JB, Kendrick PJ, Paulson KR, et al. Prevalence and attributable health burden of chronic respiratory diseases, 1990–2017: A systematic analysis for the global burden of disease study 2017. Lancet Respir Med 2020; 8(6): 585-96.
10
Huertas A, Palange P. COPD: A multifactorial systemic disease. Ther Adv Respir Dis 2011; 5(3): 217-24.
11
Soler-Cataluña JJ, Martínez-García MA, Román Sánchez P, Salcedo E, Navarro M, Ochando R. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax 2005; 60(11): 925-31.
12
Foster TS, Miller JD, Marton JP, Caloyeras JP, Russell MW, Menzin J. Assessment of the economic burden of COPD in the U.S.: A review and synthesis of the literature. COPD 2006; 3(4): 211-8.
13
13. The global strategy for the diagnosis, management and prevention of COPD. Global initiative for chronic obstructive lung disease (GOLD). 2017. Available from https://goldcopd.org/wp-content/uploads/2017/02/wms-GOLD-2017-FINAL.pdf
14
Petite SE. Role of long-acting muscarinic antagonist/long-acting b2-agonist therapy in chronic obstructive pulmonary disease. Ann Pharmacother 2017; 51(8): 696-705.
15
Tashkin DP, Ferguson GT. Combination bronchodilator therapy in the management of chronic obstructive pulmonary disease. Respir Res 2013; 14(1): 49.
16
Calzetta L, Ritondo BL, de Marco P, Cazzola M, Rogliani P. Evaluating triple ICS/LABA/LAMA therapies for COPD patients: A network meta-analysis of ETHOS, KRONOS, IMPACT, and TRILOGY studies. Expert Rev Respir Med 2021; 15(1): 143-52.
17
Li H, Zuo J, Tang W. Phosphodiesterase-4 inhibitors for the treatment of inflammatory diseases. Front Pharmacol 2018; 9: 1048.
18
Phillips JE. Inhaled phosphodiesterase 4 (PDE4) inhibitors for inflammatory respiratory diseases. Front Pharmacol 2020; 11: 259.
19
Ariga M, Neitzert B, Nakae S, et al. Nonredundant function of phosphodiesterases 4D and 4B in neutrophil recruitment to the site of inflammation. J Immunol 2004; 173(12): 7531-8.
20
Robichaud A, Stamatiou PB, Jin SLC, et al. Deletion of phosphodiesterase 4D in mice shortens α2-adrenoceptor–mediated anesthesia, a behavioral correlate of emesis. J Clin Invest 2002; 110(7): 1045-52.
21
Baillie GS, Tejeda GS, Kelly MP. Therapeutic targeting of 3′,5′-cyclic nucleotide phosphodiesterases: Inhibition and beyond. Nat Rev Drug Discov 2019; 18(10): 770-96.
22
Fox D III, Burgin AB, Gurney ME. Structural basis for the design of selective phosphodiesterase 4B inhibitors. Cell Signal 2014; 26(3): 657-63.
23
Page C. New drugs and targets for asthma and chronic obstructive pulmonary disease (CDPD). Br J Clin Pharmacol 2010; 71(6): 969.
24
Tenor H, Hatzelmann A, Beume R, Lahu G, Zech K, Bethke TD. Pharmacology, clinical efficacy, and tolerability of phosphodiesterase-4 inhibitors: Impact of human pharmacokinetics. Handb Exp Pharmacol 2011; 204(204): 85-119.
25
Matera MG, Rogliani P, Calzetta L, Cazzola M. Phosphodiesterase inhibitors for chronic obstructive pulmonary disease: What does the future hold? Drugs 2014; 74(17): 1983-92.
26
Mulhall AM, Droege CA, Ernst NE, Panos RJ, Zafar MA. Phosphodiesterase 4 inhibitors for the treatment of chronic obstructive pulmonary disease: A review of current and developing drugs. Expert Opin Investig Drugs 2015; 24(12): 1597-611.
27
Spina D, Page CP. Xanthines and phosphodiesterase inhibitors. Handb Exp Pharmacol 2016; 237: 63-91.
28
Cazzola M, Page CP, Calzetta L, Matera MG. Pharmacology and therapeutics of bronchodilators. Pharmacol Rev 2012; 64(3): 450-504.
29
Grootendorst DC, Gauw SA, Baan R, et al. Does a single dose of the phosphodiesterase 4 inhibitor, cilomilast (15mg), induce bronchodilation in patients with chronic obstructive pulmonary disease? Pulm Pharmacol Ther 2003; 16(2): 115-20.
30
BinMahfouz H, Borthakur B, Yan D, George T, Giembycz MA, Newton R. Superiority of combined phosphodiesterase PDE3/PDE4 inhibition over PDE4 inhibition alone on glucocorticoid- and long-acting β2-adrenoceptor agonist-induced gene expression in human airway epithelial cells. Mol Pharmacol 2015; 87(1): 64-76.
31
Matera MG, Ora J, Cavalli F, Rogliani P, Cazzola M. New avenues for phosphodiesterase inhibitors in asthma. J Exp Pharmaco 2021; 291-302.
32
Jeffery PK. Remodeling in asthma and chronic obstructive lung disease. Am J Respir Crit Care Med 2001; 164(10 Pt 2)(Suppl. 2): S28-38.
33
Saetta M, Turato G, Maestrelli P, Mapp C, Fabbri LM. Cellular and structural bases of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 163(6): 1304-9.
34
Zuo H, Cattani-Cavalieri I, Musheshe N, Nikolaev VO, Schmidt M. Phosphodiesterases as therapeutic targets for respiratory diseases. Pharmacol Ther 2019; 197: 225-42.
35
Page CP, Spina D. Selective PDE inhibitors as novel treatments for respiratory diseases. Curr Opin Pharmacol 2012; 12(3): 275-86.
36
Mokry J, Mokra D. Immunological aspects of phosphodiesterase inhibition in the respiratory system. Respir Physiol Neurobiol 2013; 187(1): 11-7.
37
Joskova M, Mokry J, Franova S. Respiratory cilia as a therapeutic target of phosphodiesterase inhibitors. Front Pharmacol 2020; 11: 609.
38
Spina D, Landells LJ, Page CP. The role of theophylline and phosphodiesterase4 isoenzyme inhibitors as anti-inflammatory drugs. Clin Exp Allergy 1998; 28(Suppl. 3): 24-34.
39
Peleman RA, Kips JC, Pauwels RA. Therapeutic activities of theophylline in chronic obstructive pulmonary disease. Clin Exp Allergy 1998; 28(Suppl. 3): 53-6.
40
Culpitt SV, de Matos C, Russell RE, Donnelly LE, Rogers DF, Barnes PJ. Effect of theophylline on induced sputum inflammatory indices and neutrophil chemotaxis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002; 165(10): 1371-6.
41
Barnes PJ. Theophylline. Am J Respir Crit Care Med 2003; 167(6): 813-8.
42
Torphy TJ, Undem BJ. Phosphodiesterase inhibitors: New opportunities for the treatment of asthma. Thorax 1991; 46(7): 512-23.
43
Cazzola M, Calzetta L, Rogliani P, Matera MG. The discovery of roflumilast for the treatment of chronic obstructive pulmonary disease. Expert Opin Drug Discov 2016; 11(7): 733-44.
44
Calverley PMA, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ. Roflumilast in symptomatic chronic obstructive pulmonary disease: Two randomised clinical trials. Lancet 2009; 374(9691): 685-94.
45
Martinez FJ, Calverley PMA, Goehring UM, Brose M, Fabbri LM, Rabe KF. Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): A multicentre randomised controlled trial. Lancet 2015; 385(9971): 857-66.
46
Giembycz MA. An update and appraisal of the cilomilast Phase III clinical development programme for chronic obstructive pulmonary disease. Br J Clin Pharmacol 2006; 62(2): 138-52.
47
Burgin AB, Magnusson OT, Singh J, et al. Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety. Nat Biotechnol 2010; 28(1): 63-70.
48
Naganuma K, Omura A, Maekawara N, et al. Discovery of selective PDE4B inhibitors. Bioorg Med Chem Lett 2009; 19(12): 3174-6.
49
Hagen TJ, Mo X, Burgin AB, Fox D III, Zhang Z, Gurney ME. Discovery of triazines as selective PDE4B versus PDE4D inhibitors. Bioorg Med Chem Lett 2014; 24(16): 4031-4.
50
Hansel TT, Barnes PJ. New drugs and targets for asthma and COPD. Progr Respir Res 2010; 39: 269-78.
51
Draheim R, Egerland U, Rundfeldt C. Anti-inflammatory potential of the selective phosphodiesterase 4 inhibitor N-(3,5-dichloro-pyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyoxylic acid amide (AWD 12-281), in human cell preparations. J Pharmacol Exp Ther 2004; 308(2): 555-63.
52
Gutke HJ, Guse JH, Khobzaoui M, Renukappa-Gutke T, Burnet M. AWD-12-281 (inhaled) (elbion/GlaxoSmithKline). Curr Opin Investig Drugs 2005; 6(11): 1149-58.
53
Kuss H, Hoefgen N, Johanssen S, Kronbach T, Rundfeldt C. In vivo efficacy in airway disease models of N-(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyoxylic acid amide (AWD 12-281), a selective phosphodiesterase 4 inhibitor for inhaled administration. J Pharmacol Exp Ther 2003; 307(1): 373-85.
54
Duplantier AJ, Bachert EL, Cheng JB, et al. SAR of a series of 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridines as potent inhibitors of human eosinophil phosphodiesterase. J Med Chem 2007; 50(2): 344-9.
55
Danto S, Wei GC, Gill J. A randomized, double-blind, placebo-controlled, parallel group, six-week study of the efficacy and safety of tofimilast dry powder for inhalation (DPI) in adults with COPD. Am J Respir Crit Care Med 2007; 175(Abstracts Issue): A131.
56
Fregonese L, Grootendorst D, Gaum S, et al. The inhaled PDE4 inhibitor tofimilast does not inhibit airway responses to allergen and histamine. Am J Respir Crit Care Med 2007; 175: A486.
57
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.
58
Vestbo J, Tan L, Atkinson G, Ward J. A controlled trial of 6-weeks’ treatment with a novel inhaled phosphodiesterase type-4 inhibitor in COPD. Eur Respir J 2009; 33(5): 1039-44.
59
Nials AT, Tralau-Stewart CJ, Gascoigne MH, Ball DI, Ranshaw LE, Knowles RG. In vivo characterization of GSK256066, a high-affinity inhaled phosphodiesterase 4 inhibitor. J Pharmacol Exp Ther 2011; 337(1): 137-44.
60
Tralau-Stewart CJ, Williamson RA, Nials AT, et al. GSK256066, an exceptionally high-affinity and selective inhibitor of phosphodiesterase 4 suitable for administration by inhalation: In vitrokinetic, and in vivo characterization. J Pharmacol Exp Ther 2011; 337(1): 145-54.
61
Singh D, Petavy F, Macdonald AJ, Lazaar AL, O’Connor BJ. The inhaled phosphodiesterase 4 inhibitor GSK256066 reduces allergen challenge responses in asthma. Respir Res 2010; 11(1): 26.
62
Watz H, Mistry SJ, Lazaar AL. Safety and tolerability of the inhaled phosphodiesterase 4 inhibitor GSK256066 in moderate COPD. Pulm Pharmacol Ther 2013; 26: 588-95.
63
Chapman RW, House A, Richard J, et al. Pharmacology of a potent and selective inhibitor of PDE4 for inhaled administration. Eur J Pharmacol 2010; 643(2-3): 274-81.
64
Ting PC, Lee JF, Kuang R, et al. Discovery of oral and inhaled PDE4 inhibitors. Bioorg Med Chem Lett 2013; 23(20): 5528-32.
65
De Savi C, Cox RJ, Warner DJ, et al. Efficacious inhaled PDE4 inhibitors with low emetic potential and long duration of action for the treatment of COPD. J Med Chem 2014; 57(11): 4661-76.
66
Tannheimer SL, Sorensen EA, Cui ZH, et al. The in vitro pharmacology of GS-5759, a novel bifunctional phosphodiesterase 4 inhibitor and long acting β2-adrenoceptor agonist. J Pharmacol Exp Ther 2014; 349(1): 85-93.
67
Joshi T, Yan D, Hamed O, et al. GS-5759, a bifunctional b2-adrenoceptor agonist and phosphodiesterase 4 inhibitor for chronic obstructive pulmonary disease with a unique mode of action: effects on gene expression in human airway epithelial cells. J Pharmacol Exp Ther 2017; 360(2): 324-40.
68
Salmon M, Tannheimer SL, Gentzler TT, et al. The in vivo efficacy and side effect pharmacology of GS ‐5759, a novel bifunctional phosphodiesterase 4 inhibitor and long‐acting β2 ‐adrenoceptor agonist in preclinical animal species. Pharmacol Res Perspect 2014; 2(4): e00046.
69
Roberts RS, Sevilla S, Ferrer M, et al. 4-Amino-7,8-dihydro-1,6-naphthyridin-5(6H)-ones as inhaled phosphodiesterase type 4 (PDE4) inhibitors: Structural biology and structure-activity relationships. J Med Chem 2018; 61(6): 2472-89.
70
Gràcia J, Buil MA, Castro J, et al. Biphenyl pyridazinone derivatives as inhaled PDE4 inhibitors: Structural biology and structure-activity relationships. J Med Chem 2016; 59(23): 10479-97.
71
Moretto N, Caruso P, Bosco R, et al. CHF6001 I: a novel highly potent and selective phosphodiesterase 4 inhibitor with robust anti-inflammatory activity and suitable for topical pulmonary administration. J Pharmacol Exp Ther 2015; 352(3): 559-67.
72
Villetti G, Carnini C, Battipaglia L, et al. CHF6001 II: A novel phosphodiesterase 4 inhibitor, suitable for topical pulmonary administration--in vivo preclinical pharmacology profile defines a potent anti-inflammatory compound with a wide therapeutic window. J Pharmacol Exp Ther 2015; 352(3): 568-78.
73
Mariotti F, Govoni M, Lucci G, Santoro D, Nandeuil MA. Safety, tolerability, and pharmacokinetics of single and repeat ascending doses of CHF6001, a novel inhaled phosphodiesterase-4 inhibitor: Two randomized trials in healthy volunteers. Int J Chron Obstruct Pulmon Dis 2018; 13: 3399-410.
74
Singh D, Beeh KM, Colgan B, et al. Effect of the inhaled PDE4 inhibitor CHF6001 on biomarkers of inflammation in COPD. Respir Res 2019; 20(1): 180.
75
Singh D, Emirova A, Francisco C, Santoro D, Govoni M, Nandeuil MA. Efficacy and safety of CHF6001, a novel inhaled PDE4 inhibitor in COPD: The PIONEER study. Respir Res 2020; 21(1): 246.
76
Singh D, Bassi M, Balzano D, et al. COPD patients with chronic bronchitis and higher sputum eosinophil counts show increased type‐2 and PDE4 gene expression in sputum. J Cell Mol Med 2021; 25(2): 905-18.
77
Singh D, Watz H, Beeh KM, et al. COPD sputum eosinophils: Relationship to blood eosinophils and the effect of inhaled PDE4 inhibition. Eur Respir J 2020; 56(2): 2000237.
78
Johnstone TB, Smith KH, Koziol-White CJ, et al. PDE8 is expressed in human airway smooth muscle and selectively regulates cAMP signaling by β2-adrenergic receptors and adenylyl cyclase 6. Am J Respir Cell Mol Biol 2018; 58(4): 530-41.
79
Cazzola M, Rogliani P, Matera MG. The future of bronchodilation: Looking for new classes of bronchodilators. Eur Respir Rev 2019; 28(154): 190095.
80
Page C, Cazzola M. Bifunctional drugs for the treatment of asthma and chronic obstructive pulmonary disease. Eur Respir J 2014; 44(2): 475-82.
81
Page C, Cazzola M. Bifunctional drugs for the treatment of respiratory diseases. Handb Exp Pharmacol 2016; 237: 197-212.
82
Abbott-Banner KH, Page CP. Dual PDE3/4 and PDE4 inhibitors: Novel treatments for COPD and other inflammatory airway diseases. Basic Clin Pharmacol Toxicol 2014; 114(5): 365-76.
83
Page CP. Phosphodiesterase inhibitors for the treatment of asthma and chronic obstructive pulmonary disease. Int Arch Allergy Immunol 2014; 165(3): 152-64.
84
Giembycz MA, Maurice DH. Cyclic nucleotide-based therapeutics for chronic obstructive pulmonary disease. Curr Opin Pharmacol 2014; 16: 89-107.
85
Pitts WJ, Vaccaro W, Huynh T, et al. Identification of purine inhibitors of phosphodiesterase 7 (PDE7). Bioorg Med Chem Lett 2004; 14(11): 2955-8.
86
Hoymann HG, Heinrich U, Beume R, Kilian U. Comparative investigation of the effects of zardaverine and theophylline on pulmonary function in rats. Exp Lung Res 1994; 20(3): 235-50.
87
Underwood DC, Kotzer CJ, Bochnowicz S, et al. Comparison of phosphodiesterase III, IV and dual III/IV inhibitors on bronchospasm and pulmonary eosinophil influx in guinea pigs. J Pharmacol Exp Ther 1994; 270(1): 250-9.
88
Schudt C, Winder S, Eltze M, Kilian U, Beume R. Zardaverine: A cyclic AMP specific PDE III/IV inhibitor. Agents Actions Suppl 1991; 34: 379-402.
89
Brunnée T, Engelstätter R, Steinijans VW, Kunkel G. Bronchodilatory effect of inhaled zardaverine, a phosphodiesterase III and IV inhibitor, in patients with asthma. Eur Respir J 1992; 5(8): 982-5.
90
Ukena D, Rentz K, Reiber C, Sybrecht GW. Effects of the mixed phosphodiesterase III/IV inhibitor, zardaverine, on airway function in patients with chronic airflow obstruction. Respir Med 1995; 89(6): 441-4.
91
Schudt C, Hatzelmann A, Beume R, Tenor H. Phosphodiesterase inhibitors: History of pharmacology. Handb Exp Pharmacol 2011; 204(204): 1-46.
92
Hatzelmann A, Engelstaetter R, Morley J, Mazzoni L. Enzymic and functional aspects of dual-selective PDE3/4 inhibitors. In: Schudt C, Dent G, Rabc KF, Eds. Phosphodiesterase Inhibitors 1996; 147-60.
93
Dony E, Lai Y-J, Dumitrascu R, et al. Partial reversal of experimental pulmonary hypertension by phosphodiesterase-3/4 inhibition. Eur Respir J 2008; 31(3): 599-610.
94
Nicholson CD, Shahid M, Bruin J, et al. Characterization of ORG 20241, a combined phosphodiesterase IV/III cyclic nucleotide phosphodiesterase inhibitor for asthma. J Pharmacol Exp Ther 1995; 274(2): 678-87.
95
Evans DJ, Aikman SL, Kharitanov SA. Inhaled tolafentrine, a PDE III/IV inhibitor: acute effect on histamine- and AMP-induced bronchoconstriction and exhaled NO in mild asthma. Am J Respir Crit Care Med 1996; 153: A347. [Abstract issue.].
96
de Boer J, Philpott AJ, van Amsterdam RGM, Shahid M, Zaagsma J, Nicholson CD. Human bronchial cyclic nucleotide phosphodiesterase isoenzymes: Biochemical and pharmacological analysis using selective inhibitors. Br J Pharmacol 1992; 106(4): 1028-34.
97
Elwood W, Sun J, Barnes PJ, Giembycz MA, Chung KF. Inhibition of allergen-induced lung eosinophilia by type-III and combined type III- and IV-selective phosphodiesterase inhibitors in Brown-Norway rats. Inflamm Res 1995; 44(2): 83-6.
98
Santing RE, de Boer J, Rohof A, van der Zee NM, Zaagsma J. Bronchodilatory and anti-inflammatory properties of inhaled selective phosphodiesterase inhibitors in a guinea pig model of allergic asthma. Eur J Pharmacol 2001; 429(1-3): 335-44.
99
Allcock RW, Blakli H, Jiang Z, et al. Phosphodiesterase inhibitors. Part 1: Synthesis and structure–activity relationships of pyrazolopyridine–pyridazinone PDE inhibitors developed from ibudilast. Bioorg Med Chem Lett 2011; 21(11): 3307-12.
100
Ochiai K, Takita S, Kojima A, et al. Phosphodiesterase inhibitors. Part 5: Hybrid PDE3/4 inhibitors as dual bronchorelaxant/anti-inflammatory agents for inhaled administration. Bioorg Med Chem Lett 2013; 23(1): 375-81.
101
Kojima A, Takita S, Sumiya T, et al. Phosphodiesterase inhibitors. Part 6: Design, synthesis, and structure–activity relationships of PDE4-inhibitory pyrazolo[1,5-a]pyridines with anti-inflammatory activity. Bioorg Med Chem Lett 2013; 23(19): 5311-6.
102
Boswell-Smith. The pharmacology of two novel long-acting phosphodiesterase 3/4 inhibitors, RPL554 [9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-(n-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one] and RPL565 [6,7-dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-a]isoquinolin-4-one]. J Pharmacol Exp Ther 2006; 318(2): 840-8.
103
Bjermer L, Abbott-Banner K, Newman K. Efficacy and safety of a first-in-class inhaled PDE3/4 inhibitor (ensifentrine) vs salbutamol in asthma. Pulm Pharmacol Ther 2019; 58: 101814.
104
Franciosi LG, Diamant Z, Banner KH, et al. Efficacy and safety of RPL554, a dual PDE3 and PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive pulmonary disease: Findings from four clinical trials. Lancet Respir Med 2013; 1(9): 714-27.
105
Cazzola M, Rogliani P, Calzetta L, Matera MG. Triple therapy versus single and dual long-acting bronchodilator therapy in COPD: A systematic review and meta-analysis. Eur Respir J 2018; 52(6): 1801586.
106
Zheng Y, Zhu J, Liu Y, et al. Triple therapy in the management of chronic obstructive pulmonary disease: Systematic review and meta-analysis. BMJ 2018; 363: k4388.
107
Lai CC, Chen CH, Lin CYH, Wang CY, Wang YH. The effects of single inhaler triple therapy vs single inhaler dual therapy or separate triple therapy for the management of chronic obstructive pulmonary disease: A systematic review and meta-analysis of randomized controlled trials. Int J Chron Obstruct Pulmon Dis 2019; 14: 1539-48.
108
Zayed Y, Barbarawi M, Kheiri B, et al. Triple versus dual inhaler therapy in moderate‐to‐severe COPD: A systematic review and meta‐analysis of randomized controlled trials. Clin Respir J 2019; 13(7): 413-28.
109
Mammen MJ, Lloyd DR, Kumar S, et al. Triple therapy versus dual or monotherapy with long-acting bronchodilators for COPD: A systematic review and meta-analysis. Ann Am Thorac Soc 2020; 17(10): 1308-18.
110
Fabbri LM, Calverley PMA, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with long acting bronchodilators: Two randomised clinical trials. Lancet 2009; 374: 695-703.
111
Singh D, Abbott-Banner K, Bengtsson T, Newman K. The short-term bronchodilator effects of the dual phosphodiesterase 3 and 4 inhibitor RPL554 in COPD. Eur Respir J 2018; 52(5): 1801074.
112
Govoni M, Bassi M, Vezzoli S, et al. Sputum and blood transcriptomics characterisation of the inhaled PDE4 inhibitor CHF6001 on top of triple therapy in patients with chronic bronchitis. Respir Res 2020; 21(1): 72.
113
Cleary SJ, Page CP. Exploring dual PDE3/4 inhibition in the treatment of airway diseases. Drugs Future 2015; 40(5): 0301.
114
Banner KH, Press NJ. Dual PDE3/4 inhibitors as therapeutic agents for chronic obstructive pulmonary disease. Br J Pharmacol 2009; 157(6): 892-906.
115
Calzetta L, Page CP, Spina D, et al. Effect of the mixed phosphodiesterase 3/4 inhibitor RPL554 on human isolated bronchial smooth muscle tone. J Pharmacol Exp Ther 2013; 346(3): 414-23.
116
Rhee CK, Yoshisue H, Lad R. Fixed-Dose Combinations of Long-Acting Bronchodilators for the Management of COPD: Global and Asian Perspectives. Adv Ther 2019; 36(3): 495-519.