Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting ß2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial.

BACKGROUND: Dupilumab, a fully human anti-interleukin-4 receptor α monoclonal antibody, inhibits interleukin-4 and interleukin-13 signalling, key drivers of type-2-mediated inflammation. Adults with uncontrolled persistent asthma who are receiving medium-to-high-dose inhaled corticosteroids plus a long-acting ß2 agonist require additional treatment options as add-on therapy. We aimed to assess the efficacy and safety of dupilumab as add-on therapy in patients with uncontrolled persistent asthma on medium-to-high-dose inhaled corticosteroids plus a long-acting ß2 agonist, irrespective of baseline eosinophil count. METHODS: We did this randomised, double-blind, placebo-controlled, parallel-group, pivotal phase 2b clinical trial at 174 study sites across 16 countries or regions. Adults (aged ≥18 years) with an asthma diagnosis for 12 months or more based on the Global Initiative for Asthma 2009 Guidelines receiving treatment with medium-to-high-dose inhaled corticosteroids plus a long-acting ß2 agonist were eligible for participation. Patients were randomly assigned (1:1:1:1:1) to receive subcutaneous dupilumab 200 mg or 300 mg every 2 weeks or every 4 weeks, or placebo, over a 24-week period. The primary endpoint was change from baseline at week 12 in forced expiratory volume in 1 s (FEV1 in L) in patients with baseline blood eosinophil counts of at least 300 eosinophils per µL assessed in the intention-to-treat population. Safety outcomes were assessed in all patients that received at least one dose or part of a dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT01854047, and with the EU Clinical Trials Register, EudraCT number 2013-000856-16. FINDINGS: 769 patients (158 in the placebo group and 611 in the dupilumab groups) received at least one dose of study drug. In the subgroup with at least 300 eosinophils per µL, the greatest increases (200 mg every 2 weeks, p=0·0008; 300 mg every 2 weeks, p=0·0063) in FEV1 compared with placebo were observed at week 12 with doses every 2 weeks in the 300 mg group (mean change 0·39 L [SE 0·05]; mean difference 0·21 [95% CI 0·06-0·36; p=0·0063]) and in the 200 mg group (mean change 0·43 L [SE 0·05]; mean difference 0·26 [0·11-0·40; p=0·0008]) compared with placebo (0·18 L [SE 0·05]). Similar significant increases were observed in the overall population and in the fewer than 300 eosinophils per µL subgroup (overall population: 200 mg every 2 weeks, p<0·0001; 300 mg every 2 weeks, p<0·0001; <300 eosinophils per µL: 200 mg every 2 weeks, p=0·0034; 300 mg every 2 weeks, p=0·0086), and were maintained to week 24. Likewise, dupilumab every 2 weeks produced the greatest reductions in annualised rates of exacerbation in the overall population (70-70·5%), the subgroup with at least 300 eosinophils per µL (71·2-80·7%), and the subgroup with fewer than 300 eosinophils per µL (59·9-67·6%). The most common adverse events with dupilumab compared with placebo were upper respiratory tract infections (33-41% vs 35%) and injection-site reactions (13-26% vs 13%). INTERPRETATION: Dupilumab increased lung function and reduced severe exacerbations in patients with uncontrolled persistent asthma irrespective of baseline eosinophil count and had a favourable safety profile, and hence in addition to inhaled corticosteroids plus long-acting ß2-agonist therapy could improve the lives of patients with uncontrolled persistent asthma compared with standard therapy alone. FUNDING: Sanofi-Genzyme and Regeneron Pharmaceuticals.

Effect of Subcutaneous Dupilumab on Nasal Polyp Burden in Patients With Chronic Sinusitis and Nasal Polyposis: A Randomized Clinical Trial.

IMPORTANCE: Dupilumab has demonstrated efficacy in patients with asthma and atopic dermatitis, which are both type 2 helper T-cell-mediated diseases. OBJECTIVE: To assess inhibition of interleukins 4 and 13 with dupilumab in patients with chronic sinusitis and nasal polyposis. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled parallel-group study conducted at 13 sites in the United States and Europe between August 2013 and August 2014 in 60 adults with chronic sinusitis and nasal polyposis refractory to intranasal corticosteroids with 16 weeks of follow-up. INTERVENTIONS: Subcutaneous dupilumab (a 600 mg loading dose followed by 300 mg weekly; n = 30) or placebo (n = 30) plus mometasone furoate nasal spray for 16 weeks. MAIN OUTCOMES AND MEASURES: Change in endoscopic nasal polyp score (range, 0-8; higher scores indicate worse status) at 16 weeks (primary end point). Secondary end points included Lund-Mackay computed tomography (CT) score (range, 0-24; higher scores indicate worse status), 22-item SinoNasal Outcome Test score (range, 0-110; higher scores indicating worse quality of life; minimal clinically important difference ≥8.90), sense of smell assessed using the University of Pennsylvania Smell Identification Test (UPSIT) score (range, 0-40; higher scores indicate better status), symptoms, and safety. RESULTS: Among the 60 patients who were randomized (mean [SD] age, 48.4 years [9.4 years]; 34 men [56.7%]; 35 with comorbid asthma), 51 completed the study. The least squares (LS) mean change in nasal polyp score was -0.3 (95% CI, -1.0 to 0.4) with placebo and -1.9 (95% CI, -2.5 to -1.2) with dupilumab (LS mean difference, -1.6 [95% CI, -2.4 to -0.7]; P < .001). The LS mean difference between the 2 groups for the Lund-Mackay CT total score was -8.8 (95% CI, -11.1 to -6.6; P < .001). Significant improvements with dupilumab were also observed for the 22-item SinoNasal Outcome Test (LS mean difference between groups, -18.1 [95% CI, -25.6 to -10.6]; P < .001) and sense of smell assessed by UPSIT (LS mean difference, 14.8 [95% CI, 10.9 to 18.7]; P < .001). The most common adverse events were nasopharyngitis (33% in the placebo group vs 47% in the dupilumab group), injection site reactions (7% vs 40%, respectively), and headache (17% vs 20%). CONCLUSIONS AND RELEVANCE: Among adults with symptomatic chronic sinusitis and nasal polyposis refractory to intranasal corticosteroids, the addition of subcutaneous dupilumab to mometasone furoate nasal spray compared with mometasone alone reduced endoscopic nasal polyp burden after 16 weeks. Further studies are needed to assess longer treatment duration, larger samples, and direct comparison with other medications. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01920893.

Rilonacept for gout flare prevention during initiation of uric acid-lowering therapy: results from the PRESURGE-2 international, phase 3, randomized, placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of IL-1 inhibitor rilonacept (IL-1 Trap) for gout flare (GF) prevention during initiation of uric acid-lowering therapy (ULT) with allopurinol in a multiregional phase 3 clinical trial. METHODS: Hyperuricaemic adults (n = 248) from South Africa, Germany and Asia with gout and two or more GFs within the past year were initiated on allopurinol and randomized 1:1:1 to once-weekly s.c. treatment with placebo (PBO), rilonacept 80 mg (R80) or rilonacept 160 mg (R160) for 16 weeks. The primary endpoint was the number of GFs per patient through week 16. RESULTS: The population was predominantly male and racially diverse (white, 53.2%; Asian, 33.1%; black, 13.7%). Across treatments, most patients completed the study (87.8-92.9%). At 16 weeks the mean number of GFs per patient was reduced by 71.3% with R80 (0.35) and by 72.6% with R160 (0.34) relative to PBO (1.23; both P < 0.0001). The proportion of patients without GFs was higher with R80 (74.4%) and R160 (79.5%) than with PBO (43.9%; both P ≤ 0.0001), and the proportions of patients on rilonacept with multiple GFs were significantly lower (P < 0.001). Overall, the incidence of adverse events (AEs) was similar between PBO (61.0%) and rilonacept (65.1%). Injection site reactions, generally mild, were the most frequent AE with rilonacept (1.2% PBO, 12.2% R80 and 17.9% R160); none of these injection site reactions led to withdrawal. There were no study drug-related serious AEs or deaths. CONCLUSION: Rilonacept significantly reduced the occurrence of GFs associated with initiation of ULT, with >70% of patients having no flares, and demonstrated an acceptable safety and tolerability profile. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov/, NCT00958438.

Rilonacept for gout flare prevention in patients receiving uric acid-lowering therapy: results of RESURGE, a phase III, international safety study.

OBJECTIVE: To evaluate the safety and efficacy of once-weekly subcutaneous rilonacept 160 mg for prevention of gout flares in patients initiating or continuing urate-lowering therapy (ULT). METHODS: This phase III study was conducted in the United States, South Africa, Europe, and Asia. Adults (n = 1315, 18-80 yrs) with gout, who were initiating or continuing ULT, were randomized to treatment with weekly subcutaneous injections of rilonacept 160 mg or placebo for 16 weeks followed by a 4-week safety followup. The primary endpoint was safety, assessed by adverse events (AE) and laboratory values. Efficacy was a secondary endpoint. RESULTS: Demographic and clinical characteristics were similar between treatments; predominantly male (87.8%), mean age 52.7 ± 11.3 years. Patients with ≥ 1 AE were 66.6% with rilonacept versus 59.1% placebo, with slightly more AE-related withdrawals with rilonacept (4.7% vs 3.0%) because of the greater incidence of injection site reactions (15.2% rilonacept, 3.3% placebo). Serious AE were similar in both groups, as were serious infections (0.9% placebo, 0.5% rilonacept); no tuberculosis or opportunistic infections occurred. Most common AE were headache, arthralgia, injection site erythema, accidental overdose, and pain in extremity. Of the 6 deaths, only 1 in the placebo group was considered treatment-related. At Week 16, rilonacept resulted in 70.3% fewer gout flares per patient (p < 0.0001), fewer patients with ≥ 1 and ≥ 2 gout flares (p < 0.0001), and 64.9% fewer gout flare days (p < 0.0001) relative to placebo. CONCLUSION: Weekly subcutaneous administration of rilonacept 160 mg showed no new safety signals. The safety profile was consistent with previous studies. Rilonacept also significantly reduced the risk of gout flares. Clinicaltrials.gov identifier NCT00856206; EudraCT No. 2008-007784-16.

Rilonacept in the treatment of acute gouty arthritis: a randomized, controlled clinical trial using indomethacin as the active comparator.

INTRODUCTION: In phase-3 clinical trials, the interleukin (IL-1) blocker, rilonacept (IL-1 Trap), demonstrated efficacy for gout flare prevention during initiation of urate-lowering therapy. This trial evaluated rilonacept added to a standard-of-care, indomethacin, for treatment of acute gout flares. METHODS: Adults, aged 18-70 years, with gout presenting within 48 hours of flare onset and having at least moderate pain as well as swelling and tenderness in the index joint were randomized to subcutaneous (SC) rilonacept 320 mg at baseline plus oral indomethacin 50 mg TID for 3 days followed by 25 mg TID for up to 9 days (n = 74); SC placebo at baseline plus oral indomethacin as above (n=76); or SC rilonacept 320 mg at baseline plus oral placebo (n=75). The primary efficacy endpoint was change in pain in the index joint (patient-reported using a Likert scale (0=none; 4=extreme)) from baseline to the average of values at 24, 48 and 72 hours (composite time point) for rilonacept plus indomethacin versus indomethacin alone. Comparison of rilonacept monotherapy with indomethacin monotherapy was dependent on demonstration of significance for the primary endpoint. Safety evaluation included clinical laboratory and adverse event (AE) assessments. RESULTS: Patient characteristics were comparable among the groups; the population was predominantly male (94.1%), white (75.7%), with mean±SD age of 50.3±10.6 years. All treatment groups reported within-group pain reductions from baseline (P<0.0001). Although primary endpoint pain reduction was greater with rilonacept plus indomethacin (-1.55±0.92) relative to indomethacin alone (-1.40±0.96), the difference was not statistically significant (P=0.33), so formal comparison between monotherapy groups was not performed. Pain reduction over the 72-hour period with rilonacept alone (-0.69±0.97) was less than that in the other groups, but pain reduction was similar among groups at 72 hours. Treatment with rilonacept was well-tolerated with no reported serious AEs related to rilonacept. Across all groups, the most frequent AEs were headache and dizziness. CONCLUSIONS: Although generally well-tolerated, rilonacept in combination with indomethacin and rilonacept alone did not provide additional pain relief over 72 hours relative to indomethacin alone in patients with acute gout flare. TRIAL REGISTRATION: ClinicalTrials.gov registration number NCT00855920.

Rilonacept (interleukin-1 trap) for prevention of gout flares during initiation of uric acid-lowering therapy: results from a phase III randomized, double-blind, placebo-controlled, confirmatory efficacy study.

OBJECTIVE: To evaluate the efficacy and safety of the interleukin-1 inhibitor rilonacept (interleukin-1 Trap) for gout flare prevention during initiation of uric acid-lowering therapy (ULT). METHODS: In total, 241 adult patients with gout, ≥2 gout flares within the past year, and a serum urate level ≥7.5 mg/dl were initiated on allopurinol 300 mg daily and randomly allocated in a 1:1:1 ratio to receive 16 once-weekly subcutaneous injections of placebo, rilonacept 80 mg, or rilonacept 160 mg, with a double (loading) dose on day 1. Allopurinol was titrated to achieve a serum urate level of <6.0 mg/dl. The study was powered for the primary efficacy end point, the number of gout flares per patient through week 16. RESULTS: More patients in the rilonacept groups (80.0% in the rilonacept 80 mg group, 86.4% in the rilonacept 160 mg group) completed the study than in the placebo group (72.5%; P < 0.05 for the rilonacept 160 mg group versus the placebo group). Over 16 weeks, the mean number of gout flares per patient was significantly reduced by rilonacept treatment (placebo: 1.06, rilonacept 80 mg: 0.29 [P < 0.001], rilonacept 160 mg: 0.21 [P < 0.001]). Significantly lower proportions of patients reported ≥1 gout flares with rilonacept 80 mg (18.8%) and rilonacept 160 mg (16.3%) relative to placebo (46.8%; P < 0.001 for both). Except for injection site reactions (1.3% in the placebo group versus 8.8% in the rilonacept 80 mg group [P = 0.0635, post hoc analysis] and 19.8% in the rilonacept 160 mg group [P = 0.0001, post hoc analysis]), the incidence of adverse events was generally balanced among the treatment groups. CONCLUSION: Rilonacept markedly reduced the occurrence of gout flares associated with the initiation of ULT. The efficacy and safety profile suggests that rilonacept may have the potential to improve long-term disease control for some patients by improving adherence to ULT by reducing flares during the first months after ULT initiation.