A randomised, placebo-controlled trial of anti–interleukin-1 receptor 1 monoclonal antibody MEDI8968 in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory disease of the lower airways, characterised by persistent airflow limitation [1]. Acute exacerbations of COPD (AECOPD) cause a persistent deterioration of the patients’ quality of life [2]. Once hospitalisation occurs, patients often require repeated hospital admissions, with deterioration of COPD leading to eventual death [3].

Interleukin (IL)-1α and IL-1β are pro-inflammatory cytokines produced by a variety of immune and stromal cells [4] and are thought to play an important role in the pathophysiology of COPD. In patients with COPD, IL-1β is elevated in sputum, serum and bronchoalveolar lavage fluid [4] and, along with IL-1α, is elevated both in patients with stable disease and those experiencing exacerbations [5]. Furthermore, both cytokines are released in response to cigarette smoke [4, 6], the most common risk factor for COPD [1]. IL-1α and IL-1β bind to the IL-1 receptor 1 (IL-1R1) [4, 7]. This leads to stimulation of neutrophilic inflammation, which is associated with the narrowing of small airways [6, 8] and the release of other cytokines that sustain the inflammatory response. IL-1β concentrations in sputum from patients with COPD correlate with concentrations of sputum neutrophils and sputum IL-8, and are inversely correlated with forced expiratory volume in 1 s (FEV₁) [9, 10]. Sputum IL-1β concentrations are further increased in patients with AECOPD and show a strong correlation with bacterial infections [11]. Animal models of smoke exposure have shown that inflammation of the airways is dependent on IL-1R1 signalling [7]. In particular, IL-1α is a crucial mediator of neutrophilic inflammation [6], with inhibition of IL-1β reducing this inflammation [12]. Additionally, chronic inflammation may increase susceptibility to bacterial and viral infections that are the major cause of AECOPD [13, 14]. Inhibition of IL-1R1 using anakinra resulted in a reduction of airway neutrophilia in a human lipopolysaccharide challenge model of lung inflammation in a small number of healthy volunteers [15]. Inhibition of IL-1R1 represents a potential strategy for the treatment of patients with COPD by blocking the effects of both IL-1α and IL-1β.

MEDI8968, a fully human immunoglobulin G2 monoclonal antibody that binds selectively to IL-1R1 to inhibit its activation by IL-1α and IL-1β, has been investigated in subjects with rheumatoid arthritis [16] and osteoarthritis [17]. We hypothesised that inhibition of IL-1R1 would reduce neutrophilic airway inflammation in subjects with stable COPD, resulting in a reduced frequency and severity of AECOPD. To test this hypothesis, we undertook a phase II study to examine the efficacy and safety/tolerability of MEDI8968 in adults with moderate-to-very severe COPD, with the primary objective of examining whether the frequency of moderate/severe AECOPD was reduced. In addition, we evaluated the response to MEDI8968 in subject subgroups defined by C-reactive protein (CRP), fibrinogen and, in post-hoc analyses, blood neutrophil counts.

This is the first study to investigate the efficacy and safety/tolerability of MEDI8968, an anti–IL-1R1 monoclonal antibody, in subjects with COPD. Despite being well tolerated, MEDI8968 (600 mg IV loading dose; 300 mg SC Q4W) did not produce statistically significant improvements in the rate of moderate/severe or severe-only AECOPD, time to first AECOPD, SGRQ-C total or symptom domain score or FEV₁ in the total study population.

In this study population, MEDI8968 treatment was associated with a similar incidence of TEAEs and TESAEs as the placebo treatment. MEDI8968 decreased the neutrophil concentration after the first dose, an effect that persisted throughout the treatment period, but which was reversible following washout. This is consistent with the mechanism of action of MEDI8968 and the effect previously observed with MEDI8968 in osteoarthritis [17]. An increase in bacterial infections is a concern associated with the use of biologic therapies, due to potential immunosuppression [23, 24]. However, in our study, the incidence of pneumonia in MEDI8968-treated subjects was similar to that in the placebo group (n = 10 [6.3%] vs. n = 8 [4.9%]); furthermore, the overall highest incidence of infections was reported with placebo. It is possible this was, in part, due to the exclusion of subjects with neutrophil counts <2.5 × 10³ cells/μL at baseline.

MEDI8968 has previously been evaluated in subjects with rheumatoid arthritis [16] and osteoarthritis of the knee [17]; however, only modest improvements were observed in these studies. Specifically, MEDI8968 demonstrated statistically significant higher scores in ACR20/50 (20/50% improvement in American College of Rheumatology criteria) and Disease Activity Score 28–CRP protein compared with placebo in subjects with rheumatoid arthritis, but responses were weak or absent in swollen joints count and physician and patient global assessments [16]. In subjects with osteoarthritis of the knee, MEDI8968 did not demonstrate statistically significant improvements in pain [17].

PK analysis showed that MEDI8968 exposure concentrations were as expected for the dosing regimen used; the mean MEDI8968 trough concentration at week 4 (after loading dose) was approximately double that at week 53 (28.6 ng/μL), which was similar to the trough concentration previously observed with MEDI8968 300 mg SC Q4W in subjects with osteoarthritis of the knee (31.1 ng/μL) [17]. Moreover, MEDI8968 exposure was higher than in subjects with rheumatoid arthritis receiving 250 mg SC Q4W, in whom a statistically significant improvement was seen [16], and more than 10 times higher than the MEDI8968 concentration of 2.03 ng/μL that resulted in a 90% inhibition of IL-1R1 signalling in vitro. Suppression of neutrophil counts in the MEDI8968-treated group compared with placebo was consistent with achievement of pharmacologically active exposure concentrations.

In addition, it was considered that MEDI8968 exposure was affected by the presence of ADA in only nine (5.6%) MEDI8968-treated subjects. Consequently, inadequate exposure was not considered to be a significant factor affecting the outcome of the study. Nevertheless, a lack of sufficient pulmonary exposure cannot be ruled out since concentrations of MEDI8968 reaching the lung were not measured directly. If this were the case, it would be difficult to rectify, as subject exposure in this study was as high as practically possible.

For the primary analysis, the study was designed with sufficient power to detect a 40% reduction in the rate of moderate/severe AECOPD at a 26 week-interim analysis. The annual rate of moderate/severe AECOPD observed in the placebo group was lower than expected (0.78), and lower than that assumed in the power calculation of this study (1.27). Despite this, the study did have sufficient power to detect a 40% difference after all subjects had completed 52 weeks of treatment and ruled out a reduction in exacerbation rate of more than 32%. A smaller effect of MEDI8968 on AECOPD cannot be excluded and could be investigated further in another larger study, powered to detect a smaller effect size. A number of current therapies for COPD that are indicated to reduce exacerbations have small effect sizes, demonstrating a 14% reduction in exacerbations [25, 26].

Pre-specified subgroup analyses were based on common covariates, such as age, gender, severity of disease and smoking status, as well as subgroups relevant to the mechanism of action of MEDI8968, such as baseline CRP and fibrinogen concentrations. Serum CRP and fibrinogen concentrations have both been used as surrogate markers of inflammation in COPD, and plasma fibrinogen concentration is now an approved biomarker in COPD, although not at the time this study was conducted [27, 28]. However, none of these analyses identified a subgroup in which treatment with MEDI8968 had a significant effect on AECOPD rate, despite a clear, statistically significant impact of treatment on serum CRP and fibrinogen concentrations. As pharmacodynamic markers may also serve as predictive biomarkers of response [29], and IL-1 pathway activation has been clearly linked to neutrophilia pre-clinically in multiple animal models, we sought to evaluate efficacy of MEDI8968 in the subjects with COPD in this study by their baseline blood neutrophil counts. Neutrophils are thought to be a marker of future exacerbation risk [30]. This analysis suggests potential for a greater treatment effect with MEDI8968 at higher neutrophil baseline counts, but the numbers of subjects with higher baseline neutrophils were low and therefore no significant effect could be demonstrated when the analysis was performed using a tertile approach. It has been demonstrated that the simultaneous elevation of all three markers (neutrophils, CRP and fibrinogen) increases the risk of COPD exacerbations [31]. It could be expected that the inverse, the simultaneous reduction in all three markers, would reduce exacerbations. While we did not specifically evaluate this, it is likely that the majority of subjects who received MEDI8968 within this study experienced this combined reduction in neutrophil count and serum CRP and fibrinogen concentration, but with no subsequent impact on AECOPD rate.

The population of this study included subjects with symptomatic moderate-to-very severe COPD receiving standard maintenance therapy; it was hypothesised that targeting a more specific patient population may result in greater clinical benefits. COPD exacerbations are heterogeneous in their aetiology and different phenotypes respond differently to therapy [11]. Bacterial infections, together with viral infections, are responsible for the majority of exacerbations of COPD [5, 32]. The lower respiratory tract of 25–50% of patients with stable COPD is colonised by bacteria [14], which has been linked to disease progression [13].

An elevated concentration of sputum IL-1β is a marker for bacterial colonisation of the lower respiratory tract during stable disease [33] and for bacteria-associated exacerbations [11]. Furthermore, an elevated CRP concentration, a marker of systemic inflammation, can act as a potential biomarker for identifying patients with bacteria-associated AECOPD [34, 35]. This suggests that sputum IL-1β or serum CRP concentrations could be used as biomarkers for identifying patients with COPD whose exacerbations are associated with bacterial infection and who may benefit from anti–IL-1 treatment approaches. However, our data suggest that baseline CRP concentration is not sufficient to identify these individuals. Recognizing that a biomarker approach would be desirable for this type of treatment, we did attempt to identify novel serum biomarkers in this study. However, we did not reliably detect IL-1 in serum, nor identify any serum biomarkers that could be clearly linked to clinical response or even PD effects. This perhaps reflects a lack of down-stream biomarkers that are exclusively dependent on IL-1 within those that were measurable in the serum by the methods used, and possibly lack of sufficient power in the study to detect a biomarker-driven subgroup.

Several studies have suggested that IL-1α and IL-1β play an important role in COPD by initiating an inflammatory response, and that blocking their signalling through IL-R1 could lead to clinical benefits [4, 6, 7, 15]. However, when tested in COPD studies, anti-cytokine treatments (tumour necrosis factor-α inhibitors, anti–IL-8 therapies, the anti–IL-1β antibody canakinumab) have had little clinical efficacy, despite showing potential in pre-clinical models [4, 36‐42]. This inability of anti-cytokine therapies, including MEDI8968, to produce clinical benefits in patients with COPD could be due to the functional redundancy in inflammatory signalling pathways involved in the disease [43].

A limitation of anti-cytokine studies in COPD, including the current study, is that clinical surrogate biomarkers are used for increased concentrations of IL-1 during subject selection. Given the clinical and pathophysiological heterogeneity of COPD, it may be more appropriate for future studies to select subjects using direct measurements of the concentrations of the target cytokines. However, analysis of target cytokine concentrations in the blood alone may not accurately represent inflammation occurring in the lungs [44] and can be difficult to detect, while sputum sampling can be variable and challenging in large multicentre studies. Improvements in non-invasive lung sampling would be desirable. These sampling challenges also limited our ability to determine whether IL-1R1 and its downstream pathways were inhibited in the lung by MEDI8968 treatment.

In conclusion, although MEDI8968 demonstrated an acceptable safety profile, it did not produce statistically significant results for efficacy endpoints and ruled out a reduction in exacerbation rate of more than 32%, despite strong pre-clinical data and efforts to identify a target patient population by segmentation of subjects with COPD into subgroups defined by clinical characteristics or biomarkers. This clinical study raises the possibility that patients with COPD and high neutrophil counts may benefit from inhibition of IL-1R1; however, baseline serum CRP or fibrinogen concentrations may not be suitable biomarkers to identify this population.