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Steven P Weinstein - One of the best experts on this subject based on the ideXlab platform.
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Rilonacept for gout flare prevention during initiation of uric acid-lowering therapy: results from the PRESURGE-2 international, phase 3, randomized, placebo-controlled trial
Rheumatology (Oxford England), 2013Co-Authors: Essack Mitha, Steven P Weinstein, George D Yancopoulos, Jian Wang, H. Ralph Schumacher, Shirletta King-davis, Leon Fouche, Shue-fen Luo, Robert EvansAbstract: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 (87.892.9%). 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 70% of patients having no flares, and demonstrated an acceptable safety and tolerability profile.
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Rilonacept in the treatment of acute gouty arthritis: a randomized, controlled clinical trial using indomethacin as the active comparator.
Arthritis research & therapy, 2013Co-Authors: Robert Terkeltaub, Robert Evans, Jian Wang, H. Ralph Schumacher, John D. Carter, Herbert S. B. Baraf, Shirletta King-davis, Steven P WeinsteinAbstract: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 (patientreported 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.
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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
Arthritis Care and Research, 2012Co-Authors: Ralph H Schumacher, Robert Evans, Kenneth G Saag, James Clower, William C Jennings, Steven P Weinstein, George D Yancopoulos, Jian Wang, Robert TerkeltaubAbstract: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.
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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.
Clinical therapeutics, 2012Co-Authors: Hal M Hoffman, Martin L Throne, N J Amar, Alan J Kivitz, Yuhwen Soo, Robert C. Cartwright, Steven P WeinsteinAbstract:Abstract 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 .
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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.
Arthritis care & research, 2012Co-Authors: H. Ralph Schumacher, Robert Evans, Kenneth G Saag, James Clower, William C Jennings, Steven P Weinstein, George D Yancopoulos, Jian Wang, Robert TerkeltaubAbstract: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
Michael F. Mcdermott - One of the best experts on this subject based on the ideXlab platform.
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© 2008 Dove Medical Press Limited. All rights reserved Biologics: Targets & Therapy 2008:2(4) 733–742 733
2016Co-Authors: Leigh D Church, Michael F. Mcdermott, Sinisa Savic, Correspondence Michael, F McdermottAbstract:Long term management of patients with cryopyrin-associated periodic syndromes (CAPS): focus on Rilonacept (IL-1 Trap
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Rilonacept in the management of cryopyrin-associated periodic syndromes (CAPS).
Journal of Inflammation Research, 2010Co-Authors: Justin Gillespie, Rebeccah J. Mathews, Michael F. McdermottAbstract:Cryopyrin-associated periodic syndromes (CAPS) are a subgroup of the hereditary periodic fever syndromes, which are rare autoinflammatory and inherited disorders, characterized by recurrent inflammation and varying degrees of severity. CAPS are thought to be driven by excessive production of interleukin-1β (IL-1β), through over-activation of the inflammasome by gain of function mutations in the gene encoding cryopyrin (NLRP3). This conclusion is supported by the remarkable efficacy of IL-1β blockade in these conditions. Rilonacept (Arcalyst(TM); Regeneron) is the first us Food and Drug Administration-approved treatment for familial cold autoinflammatory syndrome and Muckle-Wells syndrome and the first in a new line of drugs designed for longer-acting IL-1 blockade. Rilonacept has been associated with a decrease in disease activity, high-sensitivity C-reactive protein (hsCRP) and serum amyloid A (SAA) in the treatment of CAPS. The clinical safety and efficacy of Rilonacept in CAPS and non-CAPS populations will be summarized in this review. Rilonacept is also beneficial for patients who tolerate injections poorly, due to an extended half-life over the unapproved CAPS treatment, anakinra, requiring weekly rather than daily self-administration. Other autoinflammatory disorders may also benefit from Rilonacept treatment, with clinical trials in progress for systemic onset juvenile idiopathic arthritis, gout and familial mediterranean fever.
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Rilonacept in the management of cryopyrin-associated periodic syndromes (CAPS)
Dove Medical Press, 2010Co-Authors: Justin Gillespie, Rebeccah Mathews, Michael F. McdermottAbstract:Justin Gillespie, Rebeccah Mathews, Michael F McDermottNIHR-Leeds Musculoskeletal Biomedical Research Unit (NIHR-LMBRU), Leeds Institute of Molecular Medicine (LIMM), St. James’s University Hospital, Leeds, UKAbstract: Cryopyrin-associated periodic syndromes (CAPS) are a subgroup of the hereditary periodic fever syndromes, which are rare autoinflammatory and inherited disorders, characterized by recurrent inflammation and varying degrees of severity. CAPS are thought to be driven by excessive production of interleukin-1β (IL-1β), through over-activation of the inflammasome by gain of function mutations in the gene encoding cryopyrin (NLRP3). This conclusion is supported by the remarkable efficacy of IL-1β blockade in these conditions. Rilonacept (ArcalystTM; Regeneron) is the first us Food and Drug Administration-approved treatment for familial cold autoinflammatory syndrome and Muckle–Wells syndrome and the first in a new line of drugs designed for longer-acting IL-1 blockade. Rilonacept has been associated with a decrease in disease activity, high-sensitivity C-reactive protein (hsCRP) and serum amyloid A (SAA) in the treatment of CAPS. The clinical safety and efficacy of Rilonacept in CAPS and non-CAPS populations will be summarized in this review. Rilonacept is also beneficial for patients who tolerate injections poorly, due to an extended half-life over the unapproved CAPS treatment, anakinra, requiring weekly rather than daily self-administration. Other autoinflammatory disorders may also benefit from Rilonacept treatment, with clinical trials in progress for systemic onset juvenile idiopathic arthritis, gout and familial mediterranean fever.Keywords: cryopyrin-associated periodic syndromes, Rilonacept, interleukin-1, IL-1 TRAP, inflammasome, autoinflammator
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Rilonacept IN THE TREATMENT OF CHRONIC INFLAMMATORY DISORDERS
Drugs of today (Barcelona Spain : 1998), 2009Co-Authors: Michael F. McdermottAbstract:Rilonacept (IL-1 Trap/Arcalyst) is a long-acting interleukin-1 (IL-1) blocker developed by Regeneron Pharmaceuticals. Initially, Regeneron entered into a joint development effort with Novartis to develop Rilonacept for the treatment of rheumatoid arthritis (RA) but this was discontinued following the review of phase II clinical data showing that IL-1 blockade appeared to have limited benefit in RA. In February 2008, Regeneron received Orphan Drug approval from the Food and Drug Administration for Rilonacept in the treatment of two cryopyrin-associated periodic syndromes (CAPS) disorders, namely, familial cold-induced autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS), for children and adults 12 years and older. CAPS is a group of inherited inflammatory disorders consisting of FCAS, MWS, neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic, cutaneous and articular (CINCA) syndrome, all associated with heterozygous mutations in the NLRP3 (CIAS1) gene, which encodes the protein NLRP3 or cryopyrin. Prior to the discovery of the NLRP3 (CIAS1) mutations and the advent of IL-1-targeted therapy, treatment was aimed at suppressing inflammation but with limited success. The dramatic success of selective blockade of IL-1beta, initially with the IL-1 receptor antagonist (IL-1Ra; Kineret(R) or anakinra/ Amgen, Inc.), not only provided supportive evidence for the role of IL-1beta in CAPS but also demonstrated the efficacy of targeting IL-1beta for treatment of these conditions. A high-affinity protein called Rilonacept has been produced by cytokine Trap technology and was developed by Regeneron. The desirable longer half-life of Rilonacept offers potential alternatives to patients who do not tolerate daily injections very well or have difficulty with drug compliance. The initial evidence for the beneficial effects of Rilonacept for MWS and FCAS suggests that it would also be a suitable treatment for CNICA/NOMID. It is yet to be determined whether Rilonacept would be an effective treatment for other chronic inflammatory conditions such as gout, familial Mediterranean fever and systemic juvenile idiopathic arthritis.
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Rilonacept in cryopyrin-associated periodic syndromes: the beginning of longer-acting interleukin-1 antagonism.
Nature Clinical Practice Rheumatology, 2008Co-Authors: Leigh D Church, Michael F. McdermottAbstract:The remarkable effectiveness of interleukin (IL)-1β blockade in treating the cryopyrin-associated periodic syndromes (CAPS), which present with unexplained fevers and severe localized inflammation, has provided strong evidence for a direct role of IL-1β in the pathogenesis of these diseases. Since 2003, patients with CAPS have been treated with anakinra, a recombinant nonglycosylated human IL-1 receptor antagonist. The short half-life of anakinra, however, necessitates daily injections; therefore, new IL-1β antagonists with longer half-lives, such as the fusion protein Rilonacept (IL-1 Trap), have been developed. In an open-label pilot study of Rilonacept, five patients with CAPS showed sustained responses and the agent was well tolerated, whilst a phase III clinical study in a large number of patients demonstrated the drug's safety and clinical efficacy. Rilonacept is the first therapy approved by the FDA for the treatment of CAPS and offers a new alternative to anakinra. Further trials are necessary to assess the long-term safety and efficacy of Rilonacept.
Robert Terkeltaub - One of the best experts on this subject based on the ideXlab platform.
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fri0368 gout flare prevention with Rilonacept in patients with tophi and or polyarticular disease who initiate uric acid lowering therapy
Annals of the Rheumatic Diseases, 2013Co-Authors: Robert Evans, H R Schumacher, C. Barton, Robert TerkeltaubAbstract:Background Patients (pts) with visible tophi and/or polyarticular disease (T/PD) may be at greater risk of gout flares (GFs) when initiating uric acid-lowering therapy (ULT). Objectives To determine the risk presented by T/PD for occurrence of GFs during initiation of ULT and to evaluate the efficacy of the IL-1 antagonist Rilonacept for GF prevention in these pts using data from three Phase 3 clinical trials. Methods PRE-SURGE 1, PRE-SURGE 2, and RE-SURGE were randomized, double-blind, placebo (PBO)-controlled trials evaluating safety and efficacy of weekly SC doses of Rilonacept 80mg (R80) and 160mg (R160) for prevention of GFs during initiation of ULT. Treatment duration was 16 wks. GF rate ratios were calculated in the PBO group for each study by comparing pts with T/PD vs pts without T/PD. GFs per pt and proportion of pts with ≥1 GF were estimated for pts with baseline serum urate ≥445 μmol/L (7.5 mg/dL), >2 GFs in the past year, and initiating allopurinol in each of the treatment groups within each study and pooled from the 3 studies. GFs were defined as pt-reported acute articular pain typical of a gout attack that required anti-inflammatory treatment. Results Pts with T/PD had significantly higher rates of GFs than those with monoarticular, non-tophaceous disease: GF rate ratios (95% confidence intervals) in PBO groups were 1.97 (1.02, 3.79), 3.69 (1.51, 9.02), and 1.93 (1.30, 2.86), in PRE-SURGE 1, PRE-SURGE 2, and RE-SURGE, respectively. Pooled data showed that for pts with T/PD, R80 resulted in a 69.5% reduction in mean number of GFs per pt vs PBO (from 1.81±2.52 [PB0] to 0.55±1.20 [R80]; P≤0.0001); the reduction with R160 was 67.7% (to 0.59±1.19; P≤0.0001). Reductions were generally similar to that observed in the total population. The proportions of pts with ≥1GF in the pooled T/PD population were 59.4%, 29.8%, and 30.7% for PBO, R80, and R160, respectively, almost a 50% reduction with Rilonacept. For the total study population, the most commonly reported adverse event (AE), infections, was balanced among treatment groups; the most frequently reported treatment-related AE was injection site reaction. Conclusions The presence of T/PD represents a risk factor for GFs in pts initiating ULT. Among patients with these risk factors, Rilonacept demonstrated efficacy for GF prevention that was generally similar to that of the overall population. Disclosure of Interest R. Evans Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., H. Schumacher Grant/Research support from: Regeneron Pharmaceuticals, Inc., Consultant for: Regeneron Pharmaceuticals, Inc., R. Wu Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., C. Barton Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., R. Terkeltaub Grant/Research support from: Regeneron Pharmaceuticals, Inc., Consultant for: Regeneron Pharmaceuticals, Inc.
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Rilonacept in the treatment of acute gouty arthritis: a randomized, controlled clinical trial using indomethacin as the active comparator.
Arthritis research & therapy, 2013Co-Authors: Robert Terkeltaub, Robert Evans, Jian Wang, H. Ralph Schumacher, John D. Carter, Herbert S. B. Baraf, Shirletta King-davis, Steven P WeinsteinAbstract: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 (patientreported 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.
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FRI0399 Rilonacept for GOUT flare prevention in patients initiating uric acid-lowering therapy: Efficacy in patient subpopulations
Annals of the Rheumatic Diseases, 2013Co-Authors: Robert Evans, Robert Terkeltaub, Essack Mitha, J. Wang, C. BartonAbstract:Background The IL-1 antagonist Rilonacept demonstrated efficacy for gout flare (GF) prevention in patients (pts) initiating uric acid-lowering therapy (ULT) in two phase 3 trials of similar design (PRE-SURGE 1 and PRE-SURGE 2). Objectives To evaluate the efficacy and safety of subcutaneous Rilonacept for GF prevention in various patient subpopulations using pooled data from these trials. Methods In both trials, pts with serum urate ≥7.5 mg/dL and ≥2 GFs within the past year who were initiating allopurinol were randomized to weekly treatment with Rilonacept 80mg (R80), Rilonacept 160mg (R160), or placebo (PBO). 16-week efficacy endpoints of GFs per pt and proportion of pts with ≥1 and ≥2 GFs were determined. Risk or rate ratios were estimated as treatment value divided by placebo value using generalized linear models and weighted for subgroup size; 1-risk ratio in percentage indicates relative risk reduction. Results Baseline characteristics were similar across treatment groups. The population was mainly male (93%), white (67%), and mean age was 51.7±12.3 yrs. By week 16, the R80 (n=162) and R160 (n=165) pts experienced GF rate reductions of 72%>76% relative to PBO (1.15 GFs per pt) (n=161) (both P Conclusions Pooled efficacy and safety data are consistent with those from the individual trials in demonstrating efficacy and tolerability of Rilonacept for GF prevention in pts initiating ULT. Reductions in GFs were broadly observed regardless of demographic or clinical characteristics. Disclosure of Interest R. Evans Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., R. Terkeltaub Grant/Research support from: Regeneron Pharmaceuticals, Inc., Consultant for: Regeneron Pharmaceuticals, Inc., E. Mitha Grant/Research support from: Regeneron Pharmaceuticals, Inc., J. Wang Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., C. Barton Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., H. Schumacher Grant/Research support from: Regeneron Pharmaceuticals, Inc., Consultant for: Regeneron Pharmaceuticals, Inc.
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FRI0368 GOUT flare prevention with Rilonacept in patients with TOPHI and/or polyarticular disease who initiate uric acid-lowering therapy
Annals of the Rheumatic Diseases, 2013Co-Authors: Robert Evans, C. Barton, Robert TerkeltaubAbstract:Background Patients (pts) with visible tophi and/or polyarticular disease (T/PD) may be at greater risk of gout flares (GFs) when initiating uric acid-lowering therapy (ULT). Objectives To determine the risk presented by T/PD for occurrence of GFs during initiation of ULT and to evaluate the efficacy of the IL-1 antagonist Rilonacept for GF prevention in these pts using data from three Phase 3 clinical trials. Methods PRE-SURGE 1, PRE-SURGE 2, and RE-SURGE were randomized, double-blind, placebo (PBO)-controlled trials evaluating safety and efficacy of weekly SC doses of Rilonacept 80mg (R80) and 160mg (R160) for prevention of GFs during initiation of ULT. Treatment duration was 16 wks. GF rate ratios were calculated in the PBO group for each study by comparing pts with T/PD vs pts without T/PD. GFs per pt and proportion of pts with ≥1 GF were estimated for pts with baseline serum urate ≥445 μmol/L (7.5 mg/dL), >2 GFs in the past year, and initiating allopurinol in each of the treatment groups within each study and pooled from the 3 studies. GFs were defined as pt-reported acute articular pain typical of a gout attack that required anti-inflammatory treatment. Results Pts with T/PD had significantly higher rates of GFs than those with monoarticular, non-tophaceous disease: GF rate ratios (95% confidence intervals) in PBO groups were 1.97 (1.02, 3.79), 3.69 (1.51, 9.02), and 1.93 (1.30, 2.86), in PRE-SURGE 1, PRE-SURGE 2, and RE-SURGE, respectively. Pooled data showed that for pts with T/PD, R80 resulted in a 69.5% reduction in mean number of GFs per pt vs PBO (from 1.81±2.52 [PB0] to 0.55±1.20 [R80]; P≤0.0001); the reduction with R160 was 67.7% (to 0.59±1.19; P≤0.0001). Reductions were generally similar to that observed in the total population. The proportions of pts with ≥1GF in the pooled T/PD population were 59.4%, 29.8%, and 30.7% for PBO, R80, and R160, respectively, almost a 50% reduction with Rilonacept. For the total study population, the most commonly reported adverse event (AE), infections, was balanced among treatment groups; the most frequently reported treatment-related AE was injection site reaction. Conclusions The presence of T/PD represents a risk factor for GFs in pts initiating ULT. Among patients with these risk factors, Rilonacept demonstrated efficacy for GF prevention that was generally similar to that of the overall population. Disclosure of Interest R. Evans Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., H. Schumacher Grant/Research support from: Regeneron Pharmaceuticals, Inc., Consultant for: Regeneron Pharmaceuticals, Inc., R. Wu Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., C. Barton Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., R. Terkeltaub Grant/Research support from: Regeneron Pharmaceuticals, Inc., Consultant for: Regeneron Pharmaceuticals, Inc.
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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
Arthritis Care and Research, 2012Co-Authors: Ralph H Schumacher, Robert Evans, Kenneth G Saag, James Clower, William C Jennings, Steven P Weinstein, George D Yancopoulos, Jian Wang, Robert TerkeltaubAbstract: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.
Neil Stahl - One of the best experts on this subject based on the ideXlab platform.
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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
Arthritis & Rheumatism, 2012Co-Authors: Ralph H Schumacher, George D Yancopoulos, Robert Terkeltaub, Neil Stahl, John S Sundy, Howard R Knapp, Scott Mellis, Yuhwen Soo, Shirletta Kingdavis, Steven P WeinsteinAbstract: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.
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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.
Arthritis and rheumatism, 2012Co-Authors: H. Ralph Schumacher, George D Yancopoulos, Robert Terkeltaub, Shirletta King-davis, Neil Stahl, John S Sundy, Howard R Knapp, Scott Mellis, Yuhwen Soo, Steven P WeinsteinAbstract: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
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Rilonacept--CAPS and beyond.
Annals of the New York Academy of Sciences, 2009Co-Authors: Neil Stahl, Allen Radin, Scott MellisAbstract:Rilonacept is a dimeric fusion protein consisting of the extracellular domains of interleukin (IL)-1 type 1 receptor and IL-1 receptor accessory protein joined to the constant region (Fc) of human immunoglobulin G1. By incorporating both components of the IL-1 binding complex, Rilonacept is able to tightly bind IL-1 with picomolar affinity. Although early clinical results in rheumatoid arthritis (RA) suggested that RA is not primarily an IL-1-driven disease, the discovery that the rare genetic conditions called cryopyrin-associated periodic syndromes (CAPS) were caused by overproduction of IL-1 led to clinical development and approval for these conditions. An assay that detects Rilonacept:IL-1 complexes in plasma is helping to identify new indications, such as gout, in which IL-1 overproduction plays a key pathogenic role. The development of Rilonacept for CAPS was achieved through collaboration between the pharmaceutical industry, academia, and government agencies, and demonstrates that knowledge gleaned in orphan indications can inform drug development for more common and heterogeneous diseases.
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efficacy and safety of Rilonacept interleukin 1 trap in patients with cryopyrin associated periodic syndromes results from two sequential placebo controlled studies
Arthritis & Rheumatism, 2008Co-Authors: Hal M Hoffman, Steven P Weinstein, George D Yancopoulos, Martin L Throne, N J Amar, Mohamed Sebai, Alan J Kivitz, Arthur Kavanaugh, Pavel Belomestnov, Neil StahlAbstract: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, physician's and patient's 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.
Hal M Hoffman - One of the best experts on this subject based on the ideXlab platform.
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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.
Clinical therapeutics, 2012Co-Authors: Hal M Hoffman, Martin L Throne, N J Amar, Alan J Kivitz, Yuhwen Soo, Robert C. Cartwright, Steven P WeinsteinAbstract:Abstract 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 .
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Rilonacept for the treatment of cryopyrin-associated periodic syndromes (CAPS).
Expert Opinion on Biological Therapy, 2009Co-Authors: Hal M HoffmanAbstract:Background: Cryopyrin-associated periodic syndromes (CAPS) encompass a group of rare inherited, autoinflammatory disorders that represent a spectrum of one disease with varying degrees of severity. Until recently, there was no effective treatment for CAPS, but identification of the genetic basis of CAPS highlighted the pathogenic role of IL-1β. Objectives: Rilonacept is a recently FDA approved biologic therapy for CAPS with high affinity for IL-1β. Limited pharmacological data has been reported to date. Methods: A review of the phamacokinetics and pharmacodynamics data as well as the results of a pilot study and Phase III placebo-controlled trials of Rilonacept in CAPS. Unpublished data on an open-label extension study in adult and pediatric subjects is also reviewed. Results: Rilonacept produced rapid and profound improvements in symptoms and also reduced high-sesitivity C-reactive protein levels and normalized elevated serum amyloid A concentrations, an important risk factor for amyloidosis. The primary...
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efficacy and safety of Rilonacept interleukin 1 trap in patients with cryopyrin associated periodic syndromes results from two sequential placebo controlled studies
Arthritis & Rheumatism, 2008Co-Authors: Hal M Hoffman, Steven P Weinstein, George D Yancopoulos, Martin L Throne, N J Amar, Mohamed Sebai, Alan J Kivitz, Arthur Kavanaugh, Pavel Belomestnov, Neil StahlAbstract: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, physician's and patient's 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.
