Roflumilast in severe COPD

Chronic obstructive pulmonary disease (COPD) is characterised by progressive non-fully reversible airflow obstruction, which does not change markedly over several months.(1) It is a chronic condition associated with increasing frequency of exacerbations and reliance on symptomatic treatments, and at present there are no treatment options that alter disease pathology, thereby slowing disease progression.

Consequently, the aim of treatment is to improve symptoms and functional status, which is based mainly on the use of various inhaled agents including short- and long-acting bronchodilators such as b2-agonists and muscarinic antagonists. Inhaled corticosteroids (ICS) are reserved for patients with severe COPD where they may reduce exacerbation frequency, and improve symptoms and quality of life.(2)

Roflumilast is the first selective phosphodiesterase-4 (PDE4) inhibitor to be released onto the market, although theophylline (a non-selective PDE inhibitor) is recommended as an alternative oral bronchodilator, but its use is limited due to the fact that it is less effective and less well tolerated than inhaled long-acting bronchodilators.(3)

Roflumilast is licensed for maintenance treatment of severe COPD (defined as a post-bronchodilator FEV1 <50% predicted) associated with chronic bronchitis in adult patients with a history of frequent exacerbations as add on to bronchodilator treatment.(4) This offers clinicians the option of a different therapeutic class and an oral preparation in addition to standard treatment for COPD.

PDE4 is a key enzyme responsible for the upregulation of immune and inflammatory cells such as neutrophils, lymphocytes and macrophages, which are often involved in the pathogenesis of COPD.(2,5) Through inhibition of PDE4, roflimulast exerts an anti-inflammatory effect on both systemic and pulmonary inflammation4 and offers an attractive new target for COPD. It may also provide positive effects such as relaxation of airway smooth muscle and modulation of pulmonary nerves.(5)

Roflumilast has an oral bioavailability of approximately 80%. It is readily distributed to organs and tissues but there is no evidence of accumulation or retention in organs or fatty tissues and its penetration of the blood–brain barrier is low. Roflumilast is primarily metabolised via phase I (cytochrome P450) and phase II (conjugation) reactions in the liver, with the formation of a major pharmacodynamically active metabolite, roflumilast N-oxide metabolite. Both roflumilast and roflumilast N-oxide contribute to PDE4 inhibitory activity. Elimination is primarily via the kidneys (70%).

Peak concentrations of roflumilast and roflumilast N-oxide metabolite are reached after one hour and eight hours, respectively. Roflumilast N-oxide has a tenfold greater AUC than roflumilast and is considered to be the main PDE4 inhibitor. If taken with food, the time to peak concentration is delayed by one hour but there is no effect on PDE4 inhibition. Steady state is achieved between four and six days with once-daily dosing. However, the manufacturer states it may take several weeks for roflumilast to achieve its effect.(6)

Roflumilast is only available for oral administration at a recommended dose of one tablet of roflumilast 500 micrograms once daily.

Smoking has been shown to decrease the total PDE4 inhibition of roflumilast but this is not considered significant and doses should not be adjusted dependent on smoking status. Dosage adjustments are not necessary for the elderly or in renal impairment.(6) For patients with moderate or severe hepatic impairment (classified as Child-Pugh B or C) roflumilast should not be used because of accumulation.

In the elderly, females and non-Caucasians, total PDE4 inhibitory activity is increased, which may result in higher exposure to roflumilast and persistent adverse effects. If these persist, continued treatment should be reassessed.(6)

There are four published double-blind, randomised studies comparing the effect of roflumilast to placebo in patients with COPD. A phase III study (running between 2002 and 2003) compared six months’ treatment with either roflumilast 250microgram or 500 micrograms once daily to placebo in 1411 patients with moderate to severe COPD.(7) Roflumilast improved lung function significantly compared to placebo (post-bronchodilator FEV1 increase of 74ml and 97ml, respectively), as well as reducing exacerbations (particularly mild exacerbations).

Two subsequent 12-month studies were conducted in patients with severe-to-very severe COPD (M2-112 and M2-111).(8,9) In the former study, 1513 patients were randomised to treatment with either roflumilast or 500 micrograms daily or placebo, of which 62–63% were prescribed concomitant ICS, but no long-acting bronchodilators or theophylline were allowed. A modest but statistically significant improvement in lung function was reported (post-bronchodilator FEV1 increase of 39ml), but no significant improvement in exacerbations was found.(8) Similar findings have been described for the M2-111 study,(10) although a trend towards overall lower exacerbation rates with roflumilast was seen in each study. A subsequent pooled analysis of these two studies found that roflumilast significantly decreased exacerbations compared to placebo in the presence of chronic bronchitis with or without emphysema, presence of cough, presence of sputum, and concurrent use of ICS.(10)

These findings were used to aid the design of four subsequent placebo-controlled studies. HERMES (M2-124) and AURA (M2-125), published as a single pooled analysis, were identical 12-month studies in 1568 and 1523 patients respectively, with severe-to-very severe COPD, bronchitic symptoms and a history of exacerbations.(11) Patients were allowed concomitant treatment with short- (SABA) and long-acting b2-agonists (LABA) (which were used by approximately 50% of patients in each study arm), but not with ICS or long-acting muscarinic antagonists (LAMA). In the pooled analysis, the pre-bronchodilator FEV1 increased significantly compared to placebo (mean 48ml (95% confidence intervals 35–62); p<0.0001), and there was a 17% reduction in the rate of moderate and severe exacerbations (RR 0.83 (95% CI 0.75–0.92); p=0.0003). Roflumilast was also found to produce a small but significant improvement on dyspnoea as measured by the Transition Dyspnoea Index (TDI), but had no effect on quality of life as measured using the Euroquol 5-dimension (EQ-5D) questionnaire.

EOS (M2-127) and HELIOS (M2-128) were two 24-week studies in 933 and 743 patients with moderate-to-severe COPD reported as a pooled analysis, although only HERMES recruited patients specifically with symptoms of chronic cough and sputum production.(12) Patients were randomised to roflumilast 500 micrograms daily plus salmeterol or placebo plus salmeterol (EOS), or roflumilast 500 micrograms daily plus tiotropium or placebo plus tiotropium (HELIOS). No other long-acting bronchodilators, short-acting muscarinic antagonists, theophylline or other respiratory drugs were allowed. The pre-bronchodilator FEV1 increased significantly compared with placebo in the roflumilast plus salmeterol group (49ml (95% CI 25–71); p<0.0001) and the roflumilast plus tiotropium group (80ml (95% CI 51–110); p<0.0001). However there was no significant effect on exacerbations in either group (RR 0.79 (95% CI 0.58–1.08); p=0.1408; and RR 0.84 (95% CI 0.57–1.23); p=0.3573 respectively).

Roflumilast also produced a small but significant improvement on dyspnoea (measured using TDI and Shortness of Breath Questionnaire) and use of rescue medication when used in combination with tiotropium, but not when used in combination with salmeterol.

In summary, the effect of roflumilast on lung function is modest and may not be clinically significant, and may produce a reduction in COPD exacerbation rate. In the last two publications specifically recruiting the chronic bronchitic subgroup of COPD patients thought likely to benefit from roflumilast treatment, exacerbations were reduced by a similar extent (17%(11) and 16–21%(12)), although this was only significant in the former study. This report quantified exacerbations as moderate (requiring oral/parenteral corticosteroids) or severe (associated with hospital admission or death), and found that the number needed to treat was small (approximately five patients).

It is important to note, however, that there are currently no data assessing the effect of roflumilast when used in combination with LABA plus LAMA, or with ICS/LABA plus LAMA.

Patients who are treated with CYP1A2 inhibitors (fluvoxamine) or dual CYP3A4/1A2 inhibitors (enoxacin and cimetidine) may suffer from persistent adverse effects because they are exposed to increased PDE4 inhibition, in which case continued treatment should be reassessed.(6) There is a low probability of relevant interactions with inhibitors of P450 enzymes such as erythromycin and ketoconazole.(6)

Strong enzyme inducers such as rifampicin, phenobarbital, carbamazepine and phenytoin are likely to reduce the therapeutic effect of roflumilast, although no dose adjustments are recommended.(6)

Roflumilast is not recommended for patients with a history of depression associated with suicidal ideation or behaviour, because it has been associated with an increased risk of suicide ideation and behaviour, particularly in the first few weeks of treatment.(13)

In the HERMES/AURA11 and EOS/HELIOS(12) studies, the most commonly reported adverse drug reactions were weight loss, diarrhoea and nausea. In the HERMES/AURA study, adverse events were reported by 67% of patients treated with roflumilast and 62% of those treated with placebo, of which approximately a third were classed as serious in both groups.(11)

Patients treated with roflumilast were more likely to discontinue treatment that those treated with placebo (14% versus 11%; number needed to harm: 35), and stopping roflumilast was more likely in the first 12 weeks of treatment. In EOS, adverse events were reported by 63% of patients treated with roflumilast plus salmeterol compared with 59% treated with placebo plus salmeterol.(12) In HELIOS, adverse events were reported by 46% of patients treated with roflumilast plus tiotropium compared to 41% treated with placebo plus tiotropium.(12)

Weight loss of approximately 2kg, irrespective of the initial body mass index, was reported in both the HERMES/AURA11 and EOS/HELIOS12 studies. Consequently the patients’ weight should be monitored and treatment should be stopped in the event of unexplained weight loss.(6)

Atrial fibrillation has been reported with roflumilast but it is not considered cardio-toxic, unlike non-specific PDE inhibitors, such as theophylline.(8) Co-administration of theophylline and roflumilast is not recommended because of the lack of long-term combination therapy data and their shared PDE4 inhibition.(6,14) Theophylline mildly inhibits roflumilast metabolism and therefore may affect tolerability.(13)

The current position of roflumilast is unclear. In the UK, it is licensed for the maintenance treatment of severe COPD associated with chronic bronchitis in adult patients with a history of frequent exacerbations as add on to bronchodilator treatment.(6) However, according to UK National Institute for Health and Clinical Excellence (NICE) guidelines, which predate the launch of roflumilast, these patients should be managed with either ICS/LABA plus LAMA, or LABA plus LAMA if the patient is intolerant of ICS.(3) In practice, it is unlikely that roflumilast would replace either of these regimens, but is more likely to be used as an additional therapy despite the absence of data to recommend this.

NICE has published a technology appraisal for roflumilast that was not favourable, advising that roflumilast be recommended only in the context of research as part of a clinical trial within the licensed indication.(15) This recommendation was made owing to the lack of clinical data to demonstrate whether roflumilast is effective in combination with ICS/LABA plus LAMA as well as in combination with either LABA or LAMA alone. Consequently, it was difficult to demonstrate whether roflumilast is likely to be cost effective.

The 2013 update to the Global Initiative for Chronic Obstructive Lung Disease guideline, which included recommendations on when a trial of roflumilast is likely to be appropriate.(16) They recommended that the first-line therapy for patients with severe COPD, few symptoms but at high risk of exacerbations is a combination ICS/LABA inhaler or a LAMA, but that roflumilast could be considered as a third choice treatment for patients with chronic bronchitis. The first-line treatment for patients with severe COPD, many symptoms and a high risk of exacerbations is again ICS/LABA or a LAMA, second choice is triple therapy (that is, ICS/LABA plus LAMA), with consideration made for adding roflumilast to either regimen for patients with chronic bronchitis.

The drug costs of roflumilast are significantly higher than standard therapy because of roflumilast’s place in treatment as an add-on therapy. Cost–utility analysis demonstrated that roflumilast is likely to produce an incremental cost-effectiveness ratio (ICER) of £16,600 per quality-adjusted life year (QALY) gained in the ICS-tolerant population and £13,800 in the ICS-intolerant population. However, owing to the lack of data, there was significant uncertainty around these ICERs. For example, when the reported risk ratio for exacerbations were considered (varying from 0.73 to 0.84), the ICER ranged from £10,000 to £48,000 per QALY gained. Consequently, NICE have concluded that further data are required to determine the cost effectiveness of roflumilast.

Roflumilast’s inhibition of airway inflammation has the potential for use in allergen-induced late asthmatic response and airway hyperresponsiveness.(17) PDE4 inhibition can down-regulate eosinophils, neutrophils and lymphocytes. Corticosteroids are currently effective at inhibiting eosinophillic inflammation but not neutrophillic inflammation, which is present in atopic asthma and not well controlled by corticosteroids.(17)

Roflumilast represents a novel therapeutic option for COPD patients who are unstable with frequent exacerbations and require a not inconsiderable amount of healthcare resource. It may also be useful for patients who are otherwise unable to receive maximal therapy according to previous published guidelines because they either fail to tolerate or decline the use of an inhaled corticosteroid inhaler. However, the lack of data for its use in combination with currently available maximal COPD treatments cast a degree of uncertainty as to its additive efficacy and overall cost effectiveness.

• Daxas® (Roflumilast) is a first-in-class, oral phosphodiesterase type-4 (PDE4) inhibitor.
• It is indicated for maintenance treatment of severe COPD associated with chronic bronchitis with a history of frequent exacerbations as add-on to bronchodilator treatment.
• Roflumilast has been demonstrated in clinical trials to produce a small improvement in lung function when used in addition to b2-agonists, or tiotropium. Additionally, it has been shown to reduce the number of moderate to severe exacerbations compared with placebo in patients treated with b2-agonists.
• The most commonly reported adverse reactions were diarrhoea, weight loss, nausea, abdominal pain and headache.
• There is a lack of data to determine the effect of roflumilast in patients on standard triple therapy in severe COPD (ICS + LABA + LAMA).  However, in patients who are still experiencing exacerbations of COPD requiring repeated hospital admissions, roflumilast may represent a potential additional therapy in attempt to prevent exacerbations.

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