Steven P. Weinstein

Efficacy and safety of rilonacept (interleukin-1 trap) in patients with cryopyrin-associated periodic syndromes: Results from two sequential placebo-controlled studies†

OBJECTIVE To assess the efficacy and safety of rilonacept (Interleukin-1 [IL-1] Trap), a long-acting and potent inhibitor of IL-1, in patients with cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS). METHODS Forty-seven adult patients with CAPS, as defined by mutations in the causative NLRP3 (CIAS1) gene and pathognomonic symptoms, were enrolled in 2 consecutive phase III studies. Study 1 involved a 6-week randomized double-blind comparison of weekly subcutaneous injections of rilonacept (160 mg) versus placebo. Study 2 consisted of 9 weeks of single-blind treatment with rilonacept (part A), followed by a 9-week, randomized, double-blind, placebo-controlled withdrawal procedure (part B). Primary efficacy was evaluated using a validated composite key symptom score. RESULTS Forty-four patients completed both studies. In study 1, rilonacept therapy reduced the group mean composite symptom score by 84%, compared with 13% with placebo therapy (primary end point; P < 0.0001 versus placebo). Rilonacept also significantly improved all other efficacy end points in study 1 (numbers of multisymptom and single-symptom disease flare days, single-symptom scores, physicians and patients global assessments of disease activity, limitations in daily activities, and C-reactive protein and serum amyloid A [SAA] levels). In study 2 part B, rilonacept was superior to placebo for maintaining the improvements seen with rilonacept therapy, as shown by all efficacy parameters (primary end point; P < 0.0001 versus placebo). Rilonacept was generally well tolerated; the most common adverse events were injection site reactions. CONCLUSION Treatment with weekly rilonacept provided marked and lasting improvement in the clinical signs and symptoms of CAPS, and normalized the levels of SAA from those associated with risk of developing amyloidosis. Rilonacept exhibited a generally favorable safety and tolerability profile.

Dupilumab Treatment in Adults with Moderate-to-Severe Atopic Dermatitis

BACKGROUND Dupilumab, a fully human monoclonal antibody that blocks interleukin-4 and interleukin-13, has shown efficacy in patients with asthma and elevated eosinophil levels. The blockade by dupilumab of these key drivers of type 2 helper T-cell (Th2)-mediated inflammation could help in the treatment of related diseases, including atopic dermatitis. METHODS We performed randomized, double-blind, placebo-controlled trials involving adults who had moderate-to-severe atopic dermatitis despite treatment with topical glucocorticoids and calcineurin inhibitors. Dupilumab was evaluated as monotherapy in two 4-week trials and in one 12-week trial and in combination with topical glucocorticoids in another 4-week study. End points included the Eczema Area and Severity Index (EASI) score, the investigators global assessment score, pruritus, safety assessments, serum biomarker levels, and disease transcriptome. RESULTS In the 4-week monotherapy studies, dupilumab resulted in rapid and dose-dependent improvements in clinical indexes, biomarker levels, and the transcriptome. The results of the 12-week study of dupilumab monotherapy reproduced and extended the 4-week findings: 85% of patients in the dupilumab group, as compared with 35% of those in the placebo group, had a 50% reduction in the EASI score (EASI-50, with higher scores in the EASI indicating greater severity of eczema) (P<0.001); 40% of patients in the dupilumab group, as compared with 7% in the placebo group, had a score of 0 to 1 (indicating clearing or near-clearing of skin lesions) on the investigators global assessment (P<0.001); and pruritus scores decreased (indicating a reduction in itch) by 55.7% in the dupilumab group versus 15.1% in the placebo group (P<0.001). In the combination study, 100% of the patients in the dupilumab group, as compared with 50% of those who received topical glucocorticoids with placebo injection, met the criterion for EASI-50 (P=0.002), despite the fact that patients who received dupilumab plus glucocorticoids used less than half the amount of topical glucocorticoids used by those who received placebo plus the topical medication (P=0.16). Adverse events, such as skin infection, occurred more frequently with placebo; nasopharyngitis and headache were the most frequent adverse events with dupilumab. CONCLUSIONS Patients treated with dupilumab had marked and rapid improvement in all the evaluated measures of atopic dermatitis disease activity. Side-effect profiles were not dose-limiting. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT01259323, NCT01385657, NCT01639040, and NCT01548404.).

A pilot study to evaluate the safety and efficacy of the long‐acting interleukin‐1 inhibitor rilonacept (interleukin‐1 trap) in patients with familial cold autoinflammatory syndrome

OBJECTIVE Familial cold autoinflammatory syndrome (FCAS) is caused by mutations in the CIAS1 gene, leading to excessive secretion of interleukin-1beta (IL-1beta), which is associated with cold-induced fevers, joint pain, and systemic inflammation. This pilot study was conducted to assess the safety and efficacy of rilonacept (IL-1 Trap), a long-acting IL-1 receptor fusion protein, in patients with FCAS. METHODS Five patients with FCAS were studied in an open-label trial. All patients received an initial loading dose of 300 mg of rilonacept by subcutaneous injection, were evaluated 6 and 10 days later for clinical efficacy, and remained off treatment until a clinical flare occurred. At the time of flare, patients were again treated with 300 mg of rilonacept and then given maintenance doses of 100 mg/week. Patients whose FCAS was not completely controlled were allowed a dosage increase to 160 mg/week and then further to 320 mg/week during an intrapatient dosage-escalation phase. Safety, disease activity measures (daily diary reports of rash, joint pain and/or swelling, and fevers), health quality measures (Short Form 36 health survey questionnaire), and serum markers of inflammation (erythrocyte sedimentation rate [ESR], high-sensitivity C-reactive protein [hsCRP], serum amyloid A [SAA], and IL-6) were determined at 3, 6, 9, 12, and 24 months after initiation of rilonacept and were compared with baseline values. RESULTS In all patients, clinical symptoms typically induced by cold (rash, fever, and joint pain/swelling) improved within days of rilonacept administration. Markers of inflammation (ESR, hsCRP, and SAA) showed statistically significant reductions (P < 0.01, P < 0.001, and P < 0.001, respectively) at doses of 100 mg. Dosage escalation to 160 mg and 320 mg resulted in subjectively better control of the rash and joint pain. Furthermore, levels of the acute-phase reactants ESR, hsCRP, and SAA were lower at the higher doses; the difference was statistically significant only for the ESR. All patients continued taking the study drug. The drug was well-tolerated. Weight gain in 2 patients was noted. No study drug-related serious adverse events were seen. CONCLUSION In this study, we present 2-year safety and efficacy data on rilonacept treatment in 5 patients with FCAS. The dramatic improvement in clinical and laboratory measures of inflammation, the sustained response, and the good tolerability suggest that this drug may be a promising therapeutic option in patients with FCAS, and the data led to the design of a phase III study in this patient population.

Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial

BACKGROUND Data from early-stage studies suggested that interleukin (IL)-4 and IL-13 are requisite drivers of atopic dermatitis, evidenced by marked improvement after treatment with dupilumab, a fully-human monoclonal antibody that blocks both pathways. We aimed to assess the efficacy and safety of several dose regimens of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments. METHODS In this randomised, placebo-controlled, double-blind study, we enrolled patients aged 18 years or older who had an Eczema Area and Severity Index (EASI) score of 12 or higher at screening (≥16 at baseline) and inadequate response to topical treatments from 91 study centres, including hospitals, clinics, and academic institutions, in Canada, Czech Republic, Germany, Hungary, Japan, Poland, and the USA. Patients were randomly assigned (1:1:1:1:1:1), stratified by severity (moderate or severe, as assessed by Investigators Global Assessment) and region (Japan vs rest of world) to receive subcutaneous dupilumab: 300 mg once a week, 300 mg every 2 weeks, 200 mg every 2 weeks, 300 mg every 4 weeks, 100 mg every 4 weeks, or placebo once a week for 16 weeks. We used a central randomisation scheme, provided by an interactive voice response system. Drug kits were coded, providing masking to treatment assignment, and allocation was concealed. Patients on treatment every 2 weeks and every 4 weeks received volume-matched placebo every week when dupilumab was not given to ensure double blinding. The primary outcome was efficacy of dupilumab dose regimens based on EASI score least-squares mean percentage change (SE) from baseline to week 16. Analyses included all randomly assigned patients who received one or more doses of study drug. This trial is registered with ClinicalTrials.gov, number NCT01859988. FINDINGS Between May 15, 2013, and Jan 27, 2014, 452 patients were assessed for eligibility, and 380 patients were randomly assigned. 379 patients received one or more doses of study drug (300 mg once a week [n=63], 300 mg every 2 weeks [n=64], 200 mg every 2 weeks [n=61], 300 mg every 4 weeks [n=65], 100 mg every 4 weeks [n=65]; placebo [n=61]). EASI score improvements favoured all dupilumab regimens versus placebo (p<0·0001): 300 mg once a week (-74% [SE 5·16]), 300 mg every 2 weeks (-68% [5·12]), 200 mg every 2 weeks (-65% [5·19]), 300 mg every 4 weeks (-64% [4·94]), 100 mg every 4 weeks (-45% [4·99]); placebo (-18% [5·20]). 258 (81%) of 318 patients given dupilumab and 49 (80%) of 61 patients given placebo reported treatment-emergent adverse events; nasopharyngitis was the most frequent (28% and 26%, respectively). INTERPRETATION Dupilumab improved clinical responses in adults with moderate-to-severe atopic dermatitis in a dose-dependent manner, without significant safety concerns. Our findings show that IL-4 and IL-13 are key drivers of atopic dermatitis. FUNDING Sanofi and Regeneron Pharmaceuticals.

Sarilumab Plus Methotrexate in Patients With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate: Results of a Phase III Study

To evaluate the efficacy and safety of sarilumab in combination with methotrexate (MTX) for the treatment of rheumatoid arthritis (RA).

Rilonacept (interleukin-1 trap) in the prevention of acute gout flares during initiation of urate-lowering therapy: results of a phase II randomized, double-blind, placebo-controlled trial.

OBJECTIVE To evaluate the interleukin-1 inhibitor rilonacept (Interleukin-1 Trap) for prevention of gout flares occurring in the first few months following initiation of urate-lowering therapy. METHODS In this double-blind study, adult patients with hyperuricemia and gout were randomized to receive rilonacept administered subcutaneously once per week (loading dose 320 mg followed by 160 mg weekly) or placebo, and started on allopurinol (300 mg/day, titrated to serum urate <6 mg/dl). At study visits, physical and laboratory assessments were performed and information on any adverse events was ascertained. RESULTS Baseline characteristics were similar between the rilonacept and placebo groups (n = 41 and n = 42, respectively). The mean number of gout flares per patient through week 12 (primary efficacy end point) was markedly lower in the rilonacept group than in the placebo group (0.15 [6 flares] versus 0.79 [33 flares]; P = 0.0011). Fewer flares were observed with rilonacept as early as 4 weeks after initiation of treatment (P = 0.007). The proportion of patients experiencing a flare during the 12 weeks was lower in the rilonacept group than in the placebo group (14.6% versus 45.2%; P = 0.0037). No rebound in the flare rate was observed for 6 weeks after discontinuation of rilonacept or placebo at week 16. Adverse events were similar between groups, and no deaths or serious infectious adverse events were reported; the most common adverse events were infections (14.6% and 26.2% of rilonacept- and placebo-treated patients, respectively) and musculoskeletal disorders (14.6% and 21.4%, respectively). A higher percentage of rilonacept-treated patients (98%) compared with placebo-treated patients (79%) completed the primary 12-week evaluation period (P = 0.015). CONCLUSION The current findings indicate that rilonacept significantly reduces the frequency of gout flares during the initial period of treatment with urate-lowering therapy, with a favorable safety profile.

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†

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).

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

IntroductionIn 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.MethodsAdults, 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.ResultsPatient 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.ConclusionsAlthough 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 registrationClinicalTrials.gov registration number NCT00855920.

Long-Term Efficacy and Safety Profile of Rilonacept in the Treatment of Cryopryin-Associated Periodic Syndromes: Results of a 72-Week Open-Label Extension Study

BACKGROUND Cryopyrin-associated periodic syndromes (CAPS) are rare, inherited autoinflammatory disorders associated with considerable hardship to patients. The interleukin-1 inhibitor rilonacept has been shown to be well-tolerated and effective in preventing CAPS symptoms in 2 pivotal studies. OBJECTIVE In this study, the long-term effects of rilonacept for improvement in CAPS symptoms and its safety and tolerability were evaluated during extended treatment. METHODS Patients with CAPS entered a 72-week open-label extension (OLE) following 2 sequential placebo-controlled Phase III studies (n = 44), or entered directly into the OLE (n = 57). Adults received weekly subcutaneous rilonacept 160 mg, and pediatric patients received subcutaneous rilonacept 2.2 mg/kg, up to 160 mg/week. Safety was evaluated in all patients, and efficacy was evaluated using a validated composite key symptom score in 56 patients. RESULTS After rilonacept treatment for 72 to 96 weeks mean key symptom score at OLE Week 72 was reduced from 2.6 to 0, and the mean number of multisymptom flare days was reduced from 7.3 (34.8% of days) at baseline to 0.6 (2.9% of days) at end point. Elevated levels of inflammatory markers (eg, high sensitivity-C reactive protein and serum amyloid A, were normalized. Adverse events were generally mild to moderate, the most common being injection site reactions and upper respiratory tract infections. The incidence of these events was similar to or lower than the rate reported in the pivotal studies. CONCLUSIONS Long-term treatment with rilonacept of up to 96 weeks resulted in improvements in clinical signs and symptoms of CAPS and normalized biomarkers of inflammation. Rilonacept exhibited a generally favorable safety and tolerability profile in adult and pediatric patients with CAPS throughout the extended treatment period. ClinicalTrials.gov identifier: NCT 00288704.

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.