Roflumilast: a Novel Phosphodiesterase 4 Inhibitor for the Treatment of Inflammatory Airways Disease

DRUG EVALUATION Roflumilast: a novel phosphodiesterase 4 inhibitor for the treatment of inflammatory airways disease

Victoria Boswell-Smith Isoenzyme phosphodiesterase 4 inhibitors are novel therapeutic agents in late clinical & Clive P Page† development for the treatment of chronic obstructive pulmonary disease and asthma, both †Author for correspondence diseases with significant unmet treatment needs. Roflumilast is one such isoenzyme The Sackler Institute of Pulmonary Pharmacology, phosphodiesterase 4 inhibitor that is undergoing Phase III clinical development. It is an School of Biomedical & orally active compound that owes part of its efficacy and long duration of action to its Health Sciences, 5th Floor, primary metabolite roflumilast N-oxide. Preclinical and clinical studies have indicated that Hodgkin Building, Kings College London, Guys its probable mechanism of action is anti-inflammatory, although it may also have the Campus, London SE1 1UL, ability to relax airway smooth muscle. Its relatively low incidence of class-associated UK gastrointestinal events and long duration of action may account for its improved Tel.: +44 207 848 6097; Fax: +44 207 848 6096; therapeutic profile over other agents in its class. E-mail: [email protected]

Inflammatory airways diseases, including asthma of patients with COPD [1]. Another drug regu- and chronic obstructive pulmonary disease larly prescribed for COPD is theophylline, (COPD), are currently two of the most prevalent which is a nonspecific phosphodiesterase (PDE) diseases worldwide and the incidence of both inhibitor with proven anti-inflammatory and conditions is on the increase. In 2000, it was esti- bronchodilator activity [1]. In addition, sodium mated that 2.74 million people died of COPD cromoglycate and the orally active cysteinyl-leu- and that by 2020, COPD will be the sixth lead- kotriene receptor antagonist montelukast are ing cause of death worldwide. In industrialized regularly prescribed for asthma [3]. Nonetheless, countries, this represents the fastest growing there remain a significant number of unmet cause of mortality [1,2]. It is also evident that the medical needs in the treatment of asthma and economic burden of COPD will rise exponen- COPD, which will be discussed. tially as the prevalence of COPD increases, owing to an aging population. With respect to asthma, Unmet needs with current drugs in the it has been estimated that at least 150 million treatment of COPD people suffer from the condition worldwide, with COPD is generally poorly managed because the disease contributing to approximately there are no drugs that can modify disease pro- 180,000 deaths annually. Again, the incidence of gression and the current drugs only provide, at this disease is rising, although the precise reasons best, symptomatic relief and/or reduced exacer- behind the explosion in diagnosed cases of bations of the disease. Furthermore, many of asthma remain to be determined. the drugs used are administered via inhalation There is an urgent need for the development and the success of these compounds depends on of new therapies to aid the management of the ease of use of the delivery devices, of which COPD as there are no existing treatments that there are many and which are likely to increase can modify disease progression. β2-agonists, further with the introduction of generic ver- such as salbutamol and salmeterol, and mus- sions of β2-agonists and inhaled glucocorticos- carinic antagonists, such as tiotropium bro- teroids in the not too distant future. This is mide, which provide symptomatic relief, are the particularly relevant in patients with COPD, current drugs of choice [1]. Long-acting β2-ago- who are generally elderly and may have Keywords: anti-inflammatory, nists are used alone or increasingly in combina- impaired coordination skills that limit the effec- asthma, chronic obstructive pulmonary disease, tion with inhaled glucocorticosteroids and tiveness of these devices. In addition, to obtain phosphodiesterase, roflumilast combination therapy is now considered ‘gold optimal benefit from these devices, patients standard’ therapy for the treatment of asthma, need ongoing training and education, which is part of although there is little evidence to suggest that both time consuming and expensive. Conse- glucocorticosteroids are effective in the majority quently, for the effective management of

COPD, there is an urgent need for the develop- improved in tandem with the loss of many of ment of orally active disease-modifying drugs, the unacceptable side effects of this drug. As a and several studies have revealed a patient pref- consequence of these early studies, several erence for oral therapy, even if the drugs have isoenzyme-selective PDE4 inhibitors are in side effects [4]. Dosing regime is also important clinical development, including roflumilast as evidence shows that once-daily dosing (Daxas®), which is being developed by increases compliance in all patient groups. Nycomed (formally Altana).

Unmet needs with current drugs in the Introduction to roflumilast treatment of asthma Roflumilast is an isoenzyme-selective PDE4 The major goal of asthma management is to inhibitor with an inhibitory concentration minimize exacerbations of the disease while 50% (IC50) of 0.8 nM against the PDE4 maintaining good lung function and, although enzyme and represents a novel class of drug for the use of inhaled glucocorticosteroids and the treatment of inflammatory airways disease. bronchodilators have revolutionized treatment Thus far, roflumilast has progressed furthest in of this disease, there are still many patients who clinical studies of all the PDE4 inhibitors in achieve poor disease management with the avail- development. It has been formulated as a once- able drugs. These include patients whose under- daily oral tablet and is rapidly absorbed and lying inflammation is not controlled by the use metabolized to its primary metabolite roflumi- of inhaled glucocorticosteroids and young chil- last N-oxide, which is only two- to threefold dren and the elderly who have trouble using less potent than roflumilast itself, but has a pro- inhalation devices. Consequently, compounds longed half-life (∼15 h) following ingestion of a that are orally active, efficacious, tolerable and 500-µg tablet of roflumilast [7,8]. As a result, improve compliance would all be desirable in this metabolite is highly likely to be a major the management of asthma. contributor to the pharmacological efficacy of A number of compounds are in develop- roflumilast [8]. ment that have the potential to address some of these unmet needs in the treatment of air- Chemistry ways disease. One of the most promising new Roflumilast, (3-cyclopropylmethoxy-4-diflurome- class of drugs undergoing clinical development thoxy-N-[3,5-di-chloropyrid-4-yl]-benzamide; for the treatment of airways diseases are the molecular weight 403.2) is a benzamide deriva- PDE4 inhibitors. tive [7]. The primary metabolite of roflumilast, known as roflumilast N-oxide, results from Phosphodiesterase 4 inhibitors N-oxidation of the dichloro-pyridyl moiety. The There are now known to be 11 families of structure of both these compounds is shown enzymes called phosphodiesterases that hydro- in Figure 1. lyze the cyclic nucleotides cyclic AMP (cAMP) and/or cyclic GMP (cGMP), to their inactive Pharmacokinetic & pharmacodynamic monophosphates, 5´-AMP and 5´-GMP, properties of roflumilast respectively [5]. Physiologically, elevation of The pharmacokinetic characteristics of roflumi- cAMP has been shown to be broadly anti- last after oral (500 µg) and intravenous inflammatory, mediate smooth muscle relaxa- (150 µg) administration were investigated in a tion and modulate sensory nerve activity in the randomized, two-period, crossover study of 12 lung. Consequently, inhibition of certain PDE healthy male volunteers. From these studies, it isoenzymes has been targeted as a novel treat- was determined that the absolute bioavailability ment for inflammatory disease. Attention has of orally administrated roflumilast is 79% [9]. focused on the PDE4 isoenzyme, which is pre- Maximum plasma concentrations (Cmax) of rof- dominant in inflammatory cells since the dis- lumilast peak approximately 3 h after adminis- covery that experimentally, a number PDE4 tration and then decline rapidly. Plasma levels inhibitors have profound anti-inflammatory of roflumilast N-oxide peak approximately 6 h effects [6]. Furthermore, by selectively targeting after administration and remain elevated for PDE4, it has been anticipated that the clinical up to 24 h. Consequently, the extent of expo- efficacy of the nonselective PDE inhibitor theo- sure, assessed as area under the curve (AUC), is phylline (a drug that has been used in the treat- 12-fold higher for roflumilast N-oxide than ment of airways disease for many years) can be roflumilast [9]. This exposure and prolonged

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Figure 1. Chemical structures of (A) roflumilast and (B) roflumilast N-oxide.

A B F F F F

O O

O O O O Cl Cl N N

N N Cl Cl O+

duration of action of roflumilast N-oxide is roflumilast is required in patients with kidney believed to allow once-daily administration problems [17]. These data demonstrate that rof- of roflumilast. lumilast appears to be safe and efficacious in all There were no significant difference in phar- patient groups. macokinetic parameters in morning or evening administration of roflumilast [10]. Upon com- Preclinical data parison of the pharmacokinetics in young and A wide range of preclinical studies have been middle-aged subjects, apart from an increased undertaken with roflumilast, investigating both Cmax in middle-aged subjects, reflecting a higher its bronchodilator and anti-inflammatory mech- rate of absorption, there was no major differ- anism of actions. In cellular assays, roflumilast, ence between the two populations [11]. Food alongside other PDE4 inhibitors, has been intake [8], smoking [12], salbutamol [13], budeso- shown to suppress cytokine synthesis [18], lym- nide [14] and warfarin [15] do not significantly phocyte proliferation [7], protease release [19], air- alter the pharmacodynamics of roflumilast. In way smooth muscle proliferation [20] and addition, roflumilast has, thus far, not been leukocyte adhesion to endothelial cells [19]. Fur- shown to adversely influence cardiovascular thermore, particularly pertinent to asthma, function, unlike the nonselective PDE inhibitor PDE4 inhibitors have been shown to reduce theophylline [16]. It has been approximated that eosinophil survival and inhibit eosinophil chem- 70% of orally administered roflumilast is elimi- otaxis [21]. In addition, both roflumilast and rof- nated via the kidneys and therefore the effect of lumilast N-oxide can suppress electrical field roflumilast in patients with severe renal impair- stimulation-induced, nonadrenergic, noncholin- ment has also been evaluated. Patients with ergic contraction of isolated guinea pig bron- severe renal impairment were assessed with chus, implicating a potential role for roflumilast matched pairs of healthy subjects. Subjects were in modulating sensory nerve activity in the lung. given roflumilast 500 µg once daily in an open- The effect of roflumilast has also been examined label study and pharmacokinetic parameters in a wide range of classical in vivo models and were measured, as well as creatinine clearance as has been shown to inhibit both spasmogen and an assessment of renal impairment. Although antigen-induced bronchoconstriction in allergic the plasma concentrations of both roflumilast guinea pigs, rats and mice; although, in guinea and its active metabolite roflumilast N-oxide pigs, roflumilast was far more potent at inhibit- were slightly lower in patients with renal failure ing allergen rather than histamine-induced bron- than healthy subjects, this was not statistically choconstriction, suggesting that this drug may significant and therefore no dose adjustment of be inhibiting mast cell degranulation rather than

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directly causing smooth muscle relaxation [22–24]. study, the effect of roflumilast was examined on In addition, roflumilast reduced eosinophil and the allergen-induced early and late asthmatic neutrophil accumulation in allergen-challenged responses of 23 asthmatics (FEV1 ≥70% pre- Brown Norway rats, a model for the late asth- dicted, aged 18–50 years) in a double-blind, pla- matic response, and tumor necrosis factor cebo-controlled, three-period, cross-over study. (TNF)-α release in a rat model of lipopolysaccha- None of these patients were taking any other ride (LPS)-induced pulmonary neutrophilia [23]. asthma medication, except bronchodilators for In models of chronic remodeling of the airways, symptomatic relief. Each patient was treated roflumilast has also been shown to suppress with placebo or roflumilast (250 or 500 µg) for development of emphysema-like morphology 7–10 days, followed by a 2–5-week washout in mice exposed to chronic cigarette smoke [25] period. On the last day of each treatment period, and in a chronic remodeling murine model of allergen provocation was undertaken. In this inflammation, induced by ovalbumin, roflumi- design, all patients received placebo and both last-suppressed subepithelial collagen deposi- doses of roflumilast. Patients were assessed by tion, epithelial thickening and reduced spirometry prior to, and at standard time points inflammatory cell accumulation [26]. These after, allergen or methacholine provocation. Rof- data suggest that, in animal models, roflumi- lumilast (250 and 500 µg) was found to suppress last possesses significant anti-inflammatory both the early asthmatic response (EAR) and late activity and remodeling with some capacity to asthmatic response (LAR), although this was far influence airway smooth muscle tone. more pronounced with respect to LAR (43 vs 28%, roflumilast 500 µg vs placebo) [29], sug- Clinical profile gesting that roflumilast has an anti-inflamma- A wide variety of Phase II and III clinical stud- tory mechanism of action. In support of this, in ies have now been undertaken with roflumilast another double-blind, placebo-controlled study and its active metabolite roflumilast N-oxide (n = 15, FEV1 50–90% predicted) that directly in patients with asthma, COPD and allergic assessed the bronchodilator actions of roflumi- rhinitis. These studies are now discussed in last (1000 and 500 µg once daily), roflumilast, more detail. in direct contrast to salbutamol, was found to have no direct bronchodilator activity, support- Asthma ing the notion that the predominant mechanism Dose-ranging studies (100–500 µg) were con- of action of roflumilast in improving lung func- ducted in asthmatic patients (total 690 patients, tion is as an anti-inflammatory agent [30]. This is forced expiratory volume [FEV]1 50–85% of further evident from a double-blind, placebo- predicted) taking no concomitant medication controlled study of 421 patients with asthma except the β2-agonist salbutamol. Patients were (FEV1 50–85% predicted, aged 12–70 years) in assessed by FEV1, morning and evening peak which the effects of roflumilast (500 µg once expiratory flow (PEF), lack of efficacy and inci- daily) were directly compared with the inhaled dence of adverse events. After a run-in period of glucocorticosteroid beclomethasone dipropion- 1–3 weeks, roflumilast (100, 250 or 500 µg) was ate (200 µg twice daily). After a 1–3-week run- administered once-daily for 12 weeks. In these in period in which patients were solely adminis- studies, there was a dose-dependent improve- tered placebo compounds, patients were either ment in FEV1 and PEF with clinically signifi- administered a roflumilast tablet once daily and cant improvements observed at the highest two given placebo via an MDI or beclomethasone doses, 250 and 500 µg, respectively dipropionate twice daily via an MDI and a pla- (p < 0.0001). The improvements in lung func- cebo tablet for a further 12 weeks. Both drugs tion parameters observed with the 500 µg were significantly improved lung function (FEV1, significantly superior to those seen with the forced vital capacity [FVC] and morning PEF) 100-µg dose (p = 0.0017). Furthermore, a dose- and, although the improvements were superior dependent reduction in the dropout rate, as a in the patients taking beclomethasone dipropri- result of lack of efficacy, was also observed [27]. onate, this was not significant. In addition, both Significantly, roflumilast demonstrated an early drugs reduced the need for rescue medicine to a onset of action with significant improvements in comparable degree [31]. morning PEF noted just 24 h after the first dose, Studies have also been conducted in patients although the underlying mechanisms behind who experience exercise-induced asthma. In a this remain unclear [28]. In another Phase II randomized, placebo-controlled, double-blind,

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two-period, crossover study, patients either roflumilast (250 or 500 µg) or placebo for received roflumilast for 28 days, followed by a 24 weeks, there was a statistically significant, 14-day washout period before being adminis- dose-dependent (p < 0.0001) improvement in tered placebo for a further 28 days, or this was FEV1, whereas a significant fall in FEV1 was reversed with patients receiving placebo prior to observed in the placebo-treated group. Further- roflumilast. Roflumilast 500 µg caused a signif- more, roflumilast significantly reduced the icant reduction (28%) in FEV1 after exercise by exacerbation rate of patients with COPD. day 28. Furthermore, ex vivo studies demon- When compared with placebo, the patients strated a significant reduction in TNF-α treated with roflumilast (500 µg) experienced release, following stimulation with LPS, from 34% fewer exacerbations. The patients evalua- peripheral blood mononuclear cells of patients tion of their health-related quality of life was treated with roflumilast [32]. This suggests that assessed using the St George’s Respiratory roflumilast may be exerting an anti-inflamma- Questionnaire (SGRQ) and a positive change in tory effect in these patients. Further exploration this score was greatest in the group treated with of this is necessary. roflumilast 500µg (3.51unit decrease vs In studies to assess the long-term efficacy of 1.79 unit decrease in the placebo group). These roflumilast, patients (n = 456) who had previ- data demonstrate that as well as lung function ously been administered roflumilast (100, 250 improvements, roflumilast improved quality of and 500 µg) in a 12-week dose-ranging study life in COPD patients [35]. were enrolled for a further 40 weeks in an open- In another randomized, double-blind, pla- label follow-up trial. All patients received 500 µg cebo-controlled trial (n = 581), patients once daily. Patients who were given 500 µg for received either roflumilast or placebo for the first 12 weeks maintained their improve- 24 weeks or roflumilast for 12 weeks followed ment in lung function over the further 40 weeks by placebo for the remaining 12 weeks. Roflu- of the study. Patients who had previously taken milast significantly improved FEV1 compared the lower doses of roflumilast significantly with placebo (p = 0.0003). In patients admin- improved FEV1 over the course of the study. istered continuous roflumilast, these improve- Collectively, these studies have demonstrated ments were maintained throughout the that roflumilast (500 µg) can significantly 24 weeks of study. In the patients where roflu- improve lung function in asthmatics, which is milast was withdrawn after 12 weeks, FEV1 most likely to be via an anti-inflammatory slowly declined, but remained above placebo mechanism of action. [33] levels, supporting a likely anti-inflammatory mechanism of action. In a third study of 1513 COPD severe/very severe COPD patients, there was a A large body of clinical trial data has now been significant improvement in FEV1. Total mod- collected on the effects of roflumilast in patients erate and severe exacerbations were 7% less with COPD. with roflumilast treatment than placebo, which The first major trial of roflumilast in patients was not statistically significant. However, upon with COPD was undertaken to assess the safety secondary analysis of patients with stage 4 and efficacy of this drug in patients with mild- COPD, moderate/severe exacerbations, were to-moderate COPD. In a randomized, double- significantly lower with roflumilast 18% blind, placebo-controlled study, COPD (p = 0.0147). This suggests roflumilast may be patients (n = 516, postbronchodilator FEV1 of greatest use in patients with more severe 35–75%) were all given placebo for 2 weeks, COPD [101]. followed by a further 26 weeks of either pla- To further examine whether roflumilast was cebo, 250 or 500 µg once daily. The efficacy of having an anti-inflammatory effect in patients roflumilast in this study was assessed with post- with COPD, 38 patients (mean post bronchodi- bronchodilator FEV1, FVC, FEF25–75, morning lator FEV1 61% expected) were treated with rof- PEF and exacerbation rate. Roflumilast dose lumilast 500 µg once daily for 4 weeks. Sputum dependently improved FEV1, FEF25–75, FVC samples were collected before and after 2 and and morning PEF. There was also a 48% reduc- 4 weeks of treatment and assessed for cell tion in exacerbations, relative to placebo, in the counts, interleukin (IL)-8 and neutrophil elastase group taking 500 µg [34]. In a wider study of levels. Roflumilast significantly reduced the 1411 patients with mild-to-moderate COPD number of neutrophils (38%) and eosinophils (post-bronchodilator FEV1 30–80%) receiving (50%) present in the sputum. Furthermore, a futurefuture sciencescience groupgroup www.futuremedicine.com 157 DRUG EVALUATION – Boswell-Smith & Page

concomitant reduction in NE (30.6%) and IL-8 were reportedly mild-to-moderate in intensity levels was observed [36]. These data provide fur- and transient in nature. In this study, 6% of ther evidence that roflumilast has an anti- patients discontinued the trial owing to adverse inflammatory effect, which may contribute to effects, but less than 3% were due to roflumilast. its efficacy in patients with COPD. A total of 16 patients in the study reported seri- ous adverse events, but none of these were Allergic rhinitis deemed to be drug related. Other laboratory A small-scale study has also investigated the parameters assessed included vital signs and elec- potential of roflumilast in patients with allergic trocardiogram (ECG). However, no clinically rhinitis. In a randomized, double-blind, pla- relevant changes occurred with these [33]. In cebo-controlled trial undertaken during the addition, a long-term safety study has been con- allergen-free season, 25 patients received either ducted in patients with COPD. Patients received roflumilast for 9 days, undertook a 14-day placebo, or roflumilast 250 or 500 µg in a pla- washout period and then took placebo for cebo-controlled, double-blind trial for 26 weeks. 9 days, or vice versa. During treatment intrana- Following this, 397 patients continued on an sal, allergen provocation was undertaken daily, open-label extension, taking roflumilast for a 2 h after drug administration, rhinal airflow was further 26 weeks of the study. There was no sig- assessed by anterior rhinomanometry and sub- nificant difference in the incidence of adverse jective symptoms (including itching and rhinor- effects between the placebo control and drug- rhea) were also measured. Roflumilast 500 µg treatment group (49% during the first 26 weeks, consistently improved rhinal airflow throughout 41% thereafter). More than 90% of these the 9 days of treatment and, on day 9, their was adverse drug events were deemed to be unrelated significant improvement over placebo [37]. These to drug treatment, although this still suggests data demonstrate the potential of roflumilast in that nearly 10% of adverse events were a result of treating allergic rhinitis and may provide an roflumilast treatment. However, the majority of alternative oral treatment for this disease. these events were mild to moderate in intensity and transient in nature. During the open-label Safety & tolerability extension, ten patients (2.5%) experienced The adverse side effects (mainly gastrointestinal adverse side effects that were definitely related to [GI] intolerance) of first-generation PDE4 roflumilast and three of these patients dropped inhibitors, such as rolipram, prevented further out of the study. Nevertheless, this represents a clinical development of these drugs. There is lit- small fraction of the total patients on roflumilast tle doubt that drugs of this class have the poten- and demonstrates that, although there are still tial to be highly effective, yet their use has been incidences of class-associated side effects, in gen- constrained by the class-limiting side effects of eral, administration of roflumilast for up to GI disturbances, nausea and sometimes vomit- 52 weeks is safe and well tolerated. ing. Thus, the predominant aim when develop- ing novel PDE4 inhibitors is to generate Long-term safety studies efficacious compounds while reducing the side The clinical effects of the long-term administra- effects associated with these drugs. tion of roflumilast have yet to be determined, Roflumilast 500 µg once daily is associated given that it has only been administered in with a low frequency of drug-related GI adverse humans for up to 52 weeks. However, in both events. Examination of the data from the major rats and cynomolgus monkeys, long-term clinical trials in asthmatic and COPD patients administration of high doses of other PDE4 reported the frequency of these drug-related inhibitors has elicited arteriopathy in the adverse effects to be approximately 6%, with the mesenteric bed. Arteriopathy is a condition most commonly reported events being headache associated with arterial necrosis and recruit- (3%), diarrhea (1%) and nausea (1%). In a study ment of inflammatory cells and has been of 456 asthmatic patients receiving roflumilast observed in rats after treatment with large doses 500 µg once daily for 40 weeks, the most com- of many vasodilators, including PDE3 and mon adverse events reported were associated PDE4 inhibitors, adenosine agonists, endothe- with the respiratory system and were deemed lin receptor antagonists and potassium channel unrelated to drug treatment. Nonetheless, 6% of openers [38]. This suggests that the hemody- patients exhibited side effects that were likely to namic properties of vasodilators rather than any relate to roflumilast treatment. These side effects cytotoxic effects of these drugs per se are causing

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this condition. Nevertheless, the mechanisms inhibitors examined in clinical studies, appears by which these agents induce arteriopathy in to be both efficacious and well tolerated, with a rats remain to be established, as does whether relatively low incidence of mild-to-moderate, rats are more susceptible to this condition that transient side effects. Nevertheless, these adverse other species. However, 3 months treatment of effects are dose limiting and, thus, the full rising, high doses of the PDE4 inhibitor potential of roflumilast in humans may not be SCH351591 (12, 24 and 48 mg/kg) to realized. Interpreting the data from these trials cynomolgus monkeys also induced inflamma- has also not been without its difficulties as, until tion of the arterioles in many organs and tis- recently, very few studies concerning this drug sues, including the mesentery, gall bladder, had been published as full articles in peer- esophagus, heart kidneys and stomach. Three reviewed journals. The long-term beneficial animals were also sacrificed due to inflamma- treatment effects associated with roflumilast are tion of the colon [39]. These data suggest that probably linked to the pharmacokinetic and arteriopathy resulting from PDE4 inhibitors is pharmacodynamic properties of roflumilast. not peculiar to the rat and can also be observed Roflumilast is converted to its primary active in nonhuman primates, previously thought metabolite roflumilast N-oxide, which is only resistant to such toxicity. However, no such twofold less potent than the parent compound changes have been reported with roflumilast. itself, thereby producing a prolonged half-life of These effects observed in preclinical studies 15 h. As a result, roflumilast has the added are not anticipated to be observed in clinical advantage over other PDE4 inhibitors, such as trials as the dose used in humans is likely to be cilomilast, in development as it only has to be a fraction of that used in human studies. Fur- administered once daily, thus reducing compli- thermore, theophylline, which has been used to ance problems encountered with repetitious treat asthma and COPD for over half a century, dosing. For the first time, roflumilast appears to can also induce arteriopathy in rats, with no be an orally active anti-inflammatory agent effi- evidence of this occurring in humans. None- cacious in both patients with asthma and theless, there remains the concern that PDE4 COPD. In both conditions, roflumilast signifi- inhibitors may induce mesenteric inflamma- cantly improves FEV1 peak flow and encourag- tion in patients with asthma and COPD, par- ingly appears equally as effective as low doses of ticularly as GI disturbances are the beclomethasone diproprionate in a limited trial predominant adverse effect observed with these in asthmatics [31]. In addition, in COPD drugs. Thus, the US FDA have highlighted patients, exacerbations of the disease appear to arteriopathy as a significant safety issue with be reduced [35]. Nevertheless, there remain key the use of PDE4 inhibitors and markers of this questions to be answered concerning the poten- condition must be rigorously monitored in tial prescribing of roflumilast. For example, it is clinical trials and postmarketing surveillance. yet to be determined whether roflumilast will be However, patients administered another PDE4, prescribed alone or in combination with gluco- cilomilast, were monitored closely for corticosteroids, perhaps to enable the dose of mesenteric vasculopathy and a number of both these drugs to be reduced. In addition, it patients who experienced GI disturbances and needs to clearly established which asthma positive fecal occult blood test underwent patient groups would derive most benefit from colonoscopy and no evidence of arteriopathy in treatment with roflumilast and to facilitate fur- any patient was observed [102]. Another poten- ther studies directly comparing roflumilast with tial consequence of chronic treatment with glucocorticosteroids and combination therapies. PDE4 inhibitors is immunosuppression, given Furthermore, to persuade clinicians to prescribe the data demonstrating an anti-inflammatory roflumilast, the differences between theophyl- mechanism of action of these drugs. This has line and PDE4 inhibitors need to be high- yet to be observed in patients treated with rof- lighted and indeed comparator trials with lumilast, although it is clearly something to be theophylline are required. However, it is evi- monitored in postmarketing surveillance. dent from studies conducted already that, in contrast to theophylline, roflumilast is not a Conclusion significant bronchodilator and is predomi- The clinical data arising from studies with roflu- nantly modulating inflammation. Any bron- milast should be interpreted with cautious opti- chodilator effects seen with PDE4 inhibitors in mism. Roflumilast, unlike other PDE4 COPD may be attributed to the attenuation in futurefuture sciencescience groupgroup www.futuremedicine.com 159 DRUG EVALUATION – Boswell-Smith & Page

airways inflammation, as has been observed with patients, thus allowing the investigation of cilomilast [40]. Additionally, the narrow thera- whether PDE4 inhibitors can achieve long-term peutic index and troublesome drug interactions disease control as well as improve the quality of that restrict the prescribing of theophylline are life in both asthmatics and COPD patients. not seen with roflumilast. Over 5 years, a more conclusive comparison between oral PDE4 inhibitors and inhaled glu- Future perspective cocorticosteroids can also be drawn, alongside There are many clinical trials being undertaken distinguishing the actions of PDE4 inhibitors with new classes of drugs for airways disease, from those of older nonselective PDE inhibi- including novel leukotriene antagonists, chem- tors, such as theophylline. Furthermore, some okine inhibitors, signal transduction pathway notion on the benefits of any possible synergis- inhibitors, antioxidants and proteinase inhibi- tic effects of PDE4 inhibitors and other respira- tors [41]. With this, and the promise that PDE4 tory drugs can begin to be investigated. It will inhibitors present, the next 5 years will be an also become apparent whether side effects asso- exciting time in this field. Within this time, it is ciated with roflumilast will constrain use and hoped that roflumilast will be licensed for the compliance of the drug. In addition, it is also treatment of asthma and COPD by both the highly probable that other drugs of the same FDA and European Medicines Agency (EMEA) class will begin to appear on the market. If this and start to have a significant therapeutic role. If is the case, there is likely to be real competition this is the case, it can be anticipated that pre- for market share, especially if any newer drugs scriptions will be given to a large number of appear to be better tolerated.

Executive summary

• Inhaled glucocorticosteroids are the recommended first therapy for treating the underlying inflammation in both asthma and chronic obstructive pulmonary disease (COPD). Nevertheless, the place of inhaled corticosteroids in the treatment of patients with COPD is controversial and, since they are administered via inhalation, problems with delivery and compliance occur with many patient groups.

• Roflumilast is a phosphodiesterase 4 inhibitor with potent anti-inflammatory properties currently under development for the treatment of asthma and COPD.

• Roflumilast is formulated as an oral, once-daily medication, which is converted to its primary metabolite roflumilast N-oxide, which contributes to its long duration of action.

• Roflumilast has demonstrated efficacy in patients with both COPD and asthma with minimal side effects and has the potential to be the first disease-modifying agent for COPD.

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