Rilonacept - Wiley Online Library

Arthritis Care & Research Vol. 64, No. 10, October 2012, pp 1462–1470 DOI 10.1002/acr.21690 © 2012, American College of Rheumatology

ORIGINAL ARTICLE

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 H. RALPH SCHUMACHER JR.,1 ROBERT R. EVANS,2 KENNETH G. SAAG,3 JAMES CLOWER,4 WILLIAM JENNINGS,5 STEVEN P. WEINSTEIN,2 GEORGE D. YANCOPOULOS,2 JIAN WANG,2 AND ROBERT TERKELTAUB6

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 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 ⴝ 0.0635, post hoc analysis] and 19.8% in the rilonacept 160 mg group [P ⴝ 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.

Gout is the most common inflammatory arthropathy in adults, and both the incidence and prevalence of gout are increasing (1). Recent estimates suggest that ⬃8 million adults in the US have gout (2). High health care resource

utilization and reduced work productivity contribute to the economic burden associated with this disease (3–5). Gout results from deposition of crystals of the monosodium salt of urate (MSU) in soft tissues of synovial joints and bursae, mediated by hyperuricemia and other factors (6,7). MSU crystal deposition can be clinically silent, or

ClinicalTrials.gov identifier: NCT00829829. Supported by Regeneron Pharmaceuticals. 1 H. Ralph Schumacher Jr., MD: VA Medical Center and University of Pennsylvania, Philadelphia; 2Robert R. Evans, PharmD, Steven P. Weinstein, MD, PhD, George D. Yancopoulos, MD, PhD, Jian Wang, MS: Regeneron Pharmaceuticals, Tarrytown, New York; 3Kenneth G. Saag, MD: University of Alabama, Birmingham; 4James Clower, MD: Westside Center for Clinical Research and Baptist Primary Care,

Jacksonville, Florida; 5William Jennings, MD: Radiant Research, San Antonio, Texas; 6Robert Terkeltaub, MD: VA Healthcare System San Diego and University of California, San Diego. Dr. Schumacher has received consultancy fees, speaking fees, and/or honoraria (less than $10,000 each) from Regeneron, Takeda, Novartis, Ardea, and Pfizer. Dr. Evans owns stock or stock options in Regeneron. Dr. Saag has received consultancy fees, speaking fees, and/or honoraria (less than

INTRODUCTION

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Rilonacept for Gout Flare Prevention

Significance & Innovations ●

The treatment of gout with uric acid–lowering therapy is complicated by the induction of gout flares with treatment initiation, which can also decrease long-term treatment compliance.

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Interleukin-1 inhibition with rilonacept reduced the occurrence of gout flares associated with initiation of allopurinol as uric acid–lowering therapy.

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Rilonacept demonstrated a favorable tolerability profile, with injection site reactions as the most common adverse event.

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Gout flare prevention with rilonacept has the potential to improve the low patient adherence associated with initiation of uric acid–lowering therapies.

can initiate acute and chronic inflammatory responses. Acute gouty arthritis attacks (acute gout flares) can be associated with substantial and disabling pain. Initial episodes typically resolve spontaneously within 1–2 weeks; however, crystal deposits, which are readily visualized by high-resolution ultrasound, may remain at the articular cartilage surface and in synovial tophaceous deposits in the joint space. These deposits may leave patients vulnerable to further flares and may contribute to sustained synovitis and associated joint destruction (7). In addition to joint disease, chronic hyperuricemia potentially contributes to other serious health problems, including nephrolithiasis and renal failure (8,9) and cardiovascular disease (10). The foundation of long-term gout management strategies remains prolonged uric acid–lowering therapy (ULT) to reduce and maintain serum uric acid concentrations well below the in vitro solubility limit of urate in physiologic buffers (6.8 mg/dl), with the therapeutic goal of promoting gradual MSU crystal dissolution to reduce flare risk and prevent long-term complications of hyperuricemia (11). However, ULT has the paradoxical potential to promote gout flares during the first months of therapy, which is thought to be due to remodeling of MSU crystal deposits in tophi and at the articular cartilage surface, with release of $10,000 each) from Takeda, Novartis, Ardea, and Savient. Dr. Weinstein owns stock or stock options in Regeneron and holds a patent licensed to Regeneron for Arcalyst (rilonacept). Dr. Yancopoulos owns stock or stock options in Regeneron and holds a patent licensed to Regeneron for Arcalyst (rilonacept). Dr. Wang owns stock or stock options in Regeneron. Dr. Terkeltaub has received consultancy fees, speaking fees, and/or honoraria (less than $10,000 each) from Regeneron, Novartis, URL, Takeda, Ardea, and Pfizer, and has served as a paid consultant to Leerink Swann Investment Banking Group. Address correspondence to H. Ralph Schumacher Jr., MD, Philadelphia VA Medical Center, 151K, University & Woodland Avenues, Philadelphia, PA 19104. E-mail: schumacr@ mail.med.upenn.edu. Submitted for publication July 28, 2011; accepted in revised form March 28, 2012.

1463 small inflammatory MSU crystals during dissolution of crystal macroaggregates (12). The occurrence of treatment-associated gout flares may contribute to low rates of adherence to ULT (13,14). To reduce the flare risk when initiating ULT, concomitant prophylaxis with colchicine or nonsteroidal antiinflammatory drugs (NSAIDs) is recommended (15,16). Gout flare prevention with low-dose NSAIDs is not yet evidence based, and only 1 small randomized controlled study has been conducted to evaluate the potential prophylactic effects of colchicine (17). Prophylactic use of colchicine and NSAIDs is further complicated by the well-recognized side effects and contraindications associated with these drugs, especially in older adults and those with polypharmacy and comorbidities, which are frequent characteristics of the gout population (7,18). These limitations suggest an unmet need in some patients for newer approaches to flare prevention that demonstrate efficacy and tolerability. Several lines of evidence have contributed to the recognition that the proinflammatory cytokine interleukin-1 (IL-1) is a major inflammatory factor in gout. This evidence includes findings that MSU crystals induce release of active IL-1␤ via activation of the NLRP3 inflammasome (19) and via proteolysis of pro–IL-1␤ by proteases, such as mast cell chymase, neutrophil proteinase 3, and elastase (20 – 22); that IL-1 blockade suppresses inflammation and reduces pain in a murine model of gout (23); and that case reports and clinical trials of IL-1 inhibition with rilonacept, anakinra, and canakinumab suggested a potential role for these agents as treatment options for manifestations of gouty arthritis (24 –29). IL-1 blockade has been suggested to be most effective in the earliest phase of crystal-induced inflammation when, as in use for prophylaxis, it can abort the downstream effects of IL-1 (30). A study in murine air pouches injected with urate crystals also showed that messenger RNA encoding IL-1 was an early response to crystals (21). Rilonacept is a soluble decoy receptor fusion protein that binds IL-1␣ and IL-1␤, thus preventing their activation of cell surface receptors. Rilonacept was generated using trap technology and is therefore known as IL-1 Trap (31). In the US and European Union, rilonacept has been approved for the treatment of cryopyrin-associated periodic syndromes (32), a group of rare diseases that share with gout an underlying NLRP3 inflammasome–mediated excess production of IL-1␤. The purpose of the current study was to confirm the efficacy and safety of rilonacept for the prevention of gout flares during ULT initiation with allopurinol that were previously observed (28).

PATIENTS AND METHODS Design overview. The Preventative Study Against Urate-Lowering Drug-Induced Gout Exacerbations was a phase III randomized, double-blind, placebo-controlled, confirmatory efficacy study that evaluated the efficacy and safety of 2 dose levels of rilonacept for gout flare prevention during initiation of ULT with allopurinol. The study

1464 was performed at 64 study centers in the US and Canada; the appropriate institutional review boards or independent ethics committees granted approval and all patients provided written informed consent. Participants. Eligible patients were 18 – 80 years of age with a documented presence of either at least 6 of the 13 American College of Rheumatology 1977 preliminary criteria for the classification of acute arthritis of primary gout (33) or MSU crystals in the joint fluid. A serum urate concentration ⱖ7.5 mg/dl and a self-reported history of ⱖ2 gout flares within the past year were also required. Patients were excluded if they had a gout flare within 2 weeks prior to screening, but they could be rescreened and enrolled at a later date. Other exclusion criteria were chronic or active infections or recent use of anti-infective agents; chronic active gouty arthritis; use of allopurinol, probenecid, or sulfinpyrazone (in the prior 3 months); use of colchicine or parenteral glucocorticoids (in the prior month) or NSAIDs (in the prior 2 weeks); dialysis or confirmed evidence of severe renal impairment (estimated glomerular filtration rate ⬍30 ml/minute/1.73 m2); or current use of immunosuppressive therapy. Randomization and interventions. Patients were randomly allocated in a 1:1:1 ratio to a placebo, rilonacept 80 mg, or rilonacept 160 mg group, with all treatments administered subcutaneously once weekly for 16 weeks, and with a 4-week safety followup subsequent to doubleblind dosing. Loading doses of placebo, rilonacept 160 mg (in the 80 mg group), and rilonacept 320 mg (in the 160 mg group) were administered on treatment day 1, at which time the patients were also initiated on daily allopurinol. Allopurinol was initiated at 300 mg and titrated in 100-mg increments every 2 weeks up to a maximum daily dose of 800 mg to achieve a serum urate level of ⬍6 mg/dl; dosing was continued through the safety followup (week 20). For patients with renal impairment, the initial daily dose of allopurinol was based on the proposed allopurinol dosing adjusted according to estimated creatinine clearance using the Cockcroft-Gault equation (34) as suggested by Hande et al (35). Subsequent dose increments (50 mg or 100 mg) were determined at the investigators’ discretion, with the objective of reaching the target serum urate level. No rilonacept dose adjustments were made in patients with renal impairment, since a clinically relevant alteration in drug exposure would not be expected (36). Other medications for preventing gout flares were not allowed; however, flares were treated at the investigators’ discretion for 5–10 days with an NSAID and/or an oral glucocorticoid. All patients stayed on the study drug during a flare even if receiving an NSAID and/or a glucocorticoid as flare treatment. A 7–10-day course of short-acting NSAIDs or oral glucocorticoids was permitted for non– gout-related inflammatory events; determination and treatment of these events were at the investigators’ discretion. Outcome assessments and followup. Patients completed a daily diary using a telephone interactive voice response

Schumacher et al system, in which the presence or absence of a flare was reported. On flare days, flare characteristics were queried, including the assessment of flare joint pain using a 0 –10 numerical rating scale (where 0 ⫽ no pain and 10 ⫽ severe pain, with a recall period of 24 hours), swelling, tenderness, redness, rapidity of pain onset, range of motion, warmth, and other gout flare symptoms. The primary efficacy end point was the mean number of gout flares per patient through week 16. For analysis purposes, a gout flare was defined in part based on the working definition proposed by Outcome Measures in Rheumatology (37). For the main analyses, the flare definition required all of the following: 1) the presence of patientreported acute articular pain typical of a gout attack deemed by the patient and/or the investigator to require treatment with an antiinflammatory therapeutic agent; 2) the presence of at least 2 additional key signs/symptoms of joint swelling, redness, and tenderness; and 3) the presence of at least one of the following additional clinical variables of rapid onset of pain, decreased range of motion, joint warmth, or other symptoms similar to a prior gout flare. Secondary efficacy end points, assessed from day 1 to week 16, included the proportion of patients with ⱖ1 flares, the proportion of patients with ⱖ2 flares, the mean number of gout flare days, and the mean number of days with a pain severity score ⱖ5. An additional end point was the number of flares using another gout flare definition that was implemented in a prior phase II trial of rilonacept (patient-reported articular pain typical of a gout attack deemed to require treatment with an antiinflammatory agent) (28). The patients’ adherence to study drugs (injected rilonacept and placebo, and allopurinol) was determined by diary review and study drug accounting. Safety and tolerability were evaluated in all patients receiving at least 1 dose of study treatment based on clinical laboratory assessments and incidence of adverse events (AEs). On-treatment scheduled study visits occurred at baseline and at weeks 2, 4, 8, 12, and 16; at these times, patient assessments occurred, including physical examination. All patients had postbaseline serum urate levels checked at weeks 2, 16, and 20; the levels were also initially assessed every 2 weeks for allopurinol titration until the goal of ⬍6.0 mg/dl was reached. Statistical analysis. The sample size was based on the power to detect differences in the primary efficacy end point; it was not specifically powered for safety end points. All analyses were performed using SAS, version 9. The full analysis set, used for all efficacy end points, included all randomized patients who received any study medication. The last observation carried forward method was used only for the sensitivity analysis to impute missing pain severity scores between onset and end dates of a reported flare. The safety analysis included all patients who received any study medication (rilonacept or placebo) and was based on the treatment received. For the primary efficacy end point, a 2-sided Wilcoxon’s rank sum test was used in a step-down sequential testing


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procedure that compared the rilonacept 80 mg group versus the placebo group only if the comparison of the rilonacept 160 mg group versus the placebo group was statistically significant. The number needed to treat (NNT) was estimated for the primary efficacy end point. For secondary end points, which were also tested sequentially, continuous variables were analyzed with a 2-sample t-test or Wilcoxon’s rank sum test with exact method, and variables that were proportions were analyzed using Fisher’s exact test.

RESULTS A total of 241 patients were randomized to receive treatment; 240 patients received at least 1 dose of a study drug, and data from all treated patients were available for analysis (Figure 1). The demographic and clinical characteristics were generally similar among the treatment groups (Table 1); the population was predominantly composed of male (92.9%) and white participants (80.4%), with a mean ⫾ SD age of 52.3 ⫾ 12.6 years. Across the treatment groups at baseline, the mean uric acid levels ranged from 9.03–9.42 mg/dl, the presence of visible tophi ranged from 9.9 –12.5%, polyarticular gout was present in 65.4 –79.7% of patients, and 58.2– 66.3% of patients were obese (body mass index ⱖ30 kg/m2). More patients in the rilonacept 80 mg group (80.0%) and 160 mg group (86.4%) completed the study than in the placebo group (72.5%; P ⬍ 0.05 for the rilonacept 160 mg group versus the placebo group). The proportions of

withdrawals prior to week 16 due to AEs were similar among the treatment groups (range 3.7–5.0%). While no patients in any treatment group reported withdrawal due to lack of efficacy, the proportion of patients using rescue medication (NSAIDs or oral glucocorticoids) for a gout flare from day 1 to week 16 was significantly higher for the placebo group (54.4% for the placebo group, 25.0% for the rilonacept 80 mg group, and 23.5% for the rilonacept 160 mg group; P ⬍ 0.001 for both rilonacept groups versus placebo). Medication adherence and serum urate levels. The mean ⫾ SD daily dose of allopurinol from day 1 through the end of the double-blind period (week 16) was similar among treatment groups (312.1 ⫾ 79.3 mg for the placebo group, 310.4 ⫾ 70.9 mg for the rilonacept 80 mg group, and 316.3 ⫾ 70.4 mg for the rilonacept 160 mg group). At week 16, the mean ⫾ SD uric acid levels were similarly reduced among treatment groups (5.5 ⫾ 1.1 mg/dl, 5.7 ⫾ 1.1 mg/dl, and 5.4 ⫾ 0.9 mg/dl for the placebo, rilonacept 80 mg, and rilonacept 160 mg groups, respectively). Although the proportions of patients achieving a uric acid concentration of ⬍6 mg/dl were similar among the treatment groups, the rilonacept 160 mg group (76.8%) numerically had the highest proportion, followed by the placebo group (69.0%) and the rilonacept 80 mg group (66.7%). There was similar high adherence to the study drug injections (93.7% for the placebo group, 87.5% for the rilonacept 80 mg group, and 96.3% for the rilonacept 160 mg group).

Figure 1. Study flow diagram.

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Table 1. Baseline demographic and clinical characteristics Variable Age, mean ⫾ SD years Male, no. (%) Race or ethnic group, no. (%) White African American Other Body mass index, mean ⫾ SD kg/m2 Duration of gout, mean ⫾ SD years Serum uric acid concentration, mean ⫾ SD mg/dl Polyarticular gout, no. (%) Patients with presence of visible tophi, no. (%) Gout flares per year, mean ⫾ SD Duration of a typical gout flare, mean ⫾ SD days

Primary outcome. The cumulative number of gout flares over the 16-week treatment period that met the definition of the main analyses was 84 with placebo, 23 with rilonacept 80 mg, and 17 with rilonacept 160 mg. The mean number of gout flares per patient with rilonacept 160 mg (primary end point) was 0.21 (95% confidence interval [95% CI] 0.09 – 0.33), a statistically significant 80.0% (95% CI 66.3– 88.1%) reduction compared with placebo (mean number of gout flares per patient 1.06 [95% CI 0.71–1.42]) (Figure 2). Sequential testing with rilonacept 80 mg showed that the mean number of gout flares per patient was 0.29 (95% CI 0.12– 0.46), a statistically significant 73.0% (95% CI 57.1– 83.0%) reduction compared with placebo (Figure 2). The NNT for a reduction of at least 1 gout flare was ⬃2.0 for both the rilonacept 80 mg and 160 mg groups. A significant reduction from placebo in the number of gout flares per patient was observed with both doses of rilonacept as early as the first tabulation time (4 weeks after initiating treatment [P ⬍ 0.002]), and these differences were maintained over the treatment duration (Figure 2). Secondary outcomes. By week 16, significantly lower proportions of patients in both rilonacept groups reported

Figure 2. Primary efficacy end point of the mean number of gout flares per patient to week 16. The cumulative number of flares at week 16 meeting the main analyses definition was 84 for placebo, 23 for rilonacept 80 mg, and 17 for rilonacept 160 mg. 95% CI ⫽ 95% confidence interval.

Placebo (n ⴝ 79)

Rilonacept 80 mg (n ⴝ 80)


52.2 ⫾ 13.6 76 (96.2)

52.9 ⫾ 12.5 71 (88.8)

51.9 ⫾ 11.6 76 (93.8)

64 (81.0) 11 (13.9) 4 (5.1) 33.1 ⫾ 7.6 11.2 ⫾ 9.4 9.42 ⫾ 1.35 63 (79.7) 8 (10.1) 4.6 ⫾ 3.6 6.7 ⫾ 4.6

60 (75.0) 15 (18.8) 5 (6.3) 33.3 ⫾ 6.3 9.1 ⫾ 8.3 9.03 ⫾ 1.24 55 (68.8) 10 (12.5) 4.6 ⫾ 2.9 6.1 ⫾ 4.1

69 (85.2) 10 (12.3) 2 (2.4) 33.3 ⫾ 6.7 10.0 ⫾ 8.3 9.07 ⫾ 1.23 53 (65.4) 8 (9.9) 4.5 ⫾ 3.6 7.7 ⫾ 8.4

ⱖ1 gout flares relative to placebo (P ⬍ 0.001) (Figure 3). The risk ratio for having ⱖ1 gout flares during the 16-week treatment period was 0.40 (95% CI 0.24 – 0.67) for the rilonacept 80 mg group and 0.35 (95% CI 0.20 – 0.60) for the rilonacept 160 mg group, representing risk reductions of 60.0% and 65.3%, respectively. Similarly, 31.6% of patients in the placebo group reported multiple gout flares compared with 5.0% in the rilonacept 80 mg group and 3.8% in the rilonacept 160 mg group (P ⬍ 0.001 for both), representing risk reductions of 84.2% and 88.2%, respectively, for having at least 2 gout flares. From day 1 to week 16, rilonacept 80 mg and 160 mg resulted in fewer gout flare days per patient relative to placebo (Table 2), with reductions of 57.2% (95% CI 49.2– 63.9%) and 82.3% (95% CI 77.5– 86.1%), respectively. Although rilonacept did not reduce the duration of individual flares, patients treated with rilonacept had reductions of 60.0% (95% CI 47.0 – 69.8%) and 83.5% (95% CI 75.4 – 89.0%) for the 80-mg and 160-mg doses, respectively (P ⬍ 0.0001 for both doses), in days per patient with a pain severity score ⱖ5 (Table 2). Using an alternative definition of gout flare that relied exclusively on patient-reported gouty articular pain and treatment with an antiinflammatory medication, the number of flares per patient during the 16-week treatment period was 1.19 (95% CI 0.80 –1.58) for the placebo group, 0.40 (95% CI 0.20 – 0.60) for the rilonacept 80 mg group, and 0.28 (95% CI 0.14 – 0.41) for the rilonacept 160 mg

Figure 3. Proportion of patients reporting gout flares at week 16.


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Table 2. Secondary outcomes at week 16* Placebo (n ⴝ 79)



5.52 (3.34–7.70) 5.19 ⫾ 5.54 2.13 (1.41–2.84)

2.36 (0.00–4.89)† 8.52 ⫾ 17.99 0.85 (0.00–1.72)†

0.98 (0.32–1.63)† 5.12 ⫾ 3.30 0.35 (0.06–0.64)†

Outcome Gout flare days per patient, mean (95% CI) Gout flare days per flare, mean ⫾ SD Days per patient with pain severity score ⱖ5, mean (95% CI)

* 95% CI ⫽ 95% confidence interval. † P ⬍ 0.0001 versus placebo using Wilcoxon’s rank sum test with exact method.

group. This definition therefore showed similar benefits of rilonacept versus placebo. During the 4-week safety followup (weeks 16 to 20), when allopurinol was continued but not the study drug injections, the rate of flares reported in the rilonacept groups increased, although this increase was not above that observed with the placebo group. The number of flares reported during this period was 14, 8, and 11 in the placebo, rilonacept 80 mg, and rilonacept 160 mg groups, respectively. Safety and tolerability. Except for injection site reactions, the incidence of treatment-emergent AEs, generally of mild to moderate severity, was similar among treatment

groups (Table 3). The most frequently reported AEs were injection site reactions (which were generally mild in severity and dose related), upper respiratory tract infection, and headache (Table 3). A post hoc statistical analysis showed that the incidence of injection site reactions relative to placebo (1.3%) was greater among patients treated with rilonacept 80 mg (8.8%; P ⫽ 0.0635) and rilonacept 160 mg (19.8%; P ⫽ 0.0001). AEs led to study discontinuation of 4 patients in the placebo group (decreased appetite, muscle atrophy, rash, and urticaria), 4 patients in the rilonacept 80 mg group (injection site reaction, liver abscess, dizziness, and rash), and 3 patients in the rilonacept 160 mg group (injection site reaction, gout exacerbation, and balanitis). No deaths

Table 3. Summary of AEs through week 20* Incidence AE by MedDRA Preferred Term Any AEs Serious AEs, no.† Musculoskeletal chest pain Drug overdose; depression Pneumonia Squamous cell carcinoma on leg Obstructing abdominal hernia Liver abscess Spontaneous abortion (patient’s wife) Gout exacerbation Coronary artery disease (nighttime angina) Treatment-related AEs‡ Treatment-related serious AEs, no. Withdrawals due to AEs Most common AEs§ Injection site reactions (HLT)¶ Upper respiratory tract infection Bronchitis Pain in extremity Headache Infections and infestations (SOC)#

Placebo (n ⴝ 79)



All rilonacept (n ⴝ 161)

48 (60.8) 3 (3.8) 1 1 1

49 (61.3) 3 (3.8)

53 (65.4) 3 (3.7)

102 (63.4) 6 (3.7)

1 1 1 1 1 1 40 (24.8) 0 7 (4.3) 23 (14.3) 9 (5.6) 4 (2.5) 5 (3.1) 7 (4.3) 29 (18.0)

1 1 1

6 (7.6) 0 4 (5.1)

14 (17.5) 0 4 (5.0)

1 1 1 26 (32.1) 0 3 (3.7)

1 (1.3) 2 (2.5) 1 (1.3) 4 (5.1) 1 (1.3) 18 (22.8)

7 (8.8) 4 (5.0) 4 (5.0) 2 (2.5) 5 (6.3) 15 (18.8)

16 (19.8) 5 (6.2) 0 3 (3.7) 2 (2.5) 14 (17.3)

* Values are the number (percentage) unless otherwise indicated. AEs ⫽ adverse events; MedDRA ⫽ Medical Dictionary for Regulatory Activities; MedDRA is the international medical terminology developed under the auspices of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use and is a registered trademark of the International Federation of Pharmaceutical Manufacturers and Associations. † A serious AE was life threatening or resulted in death, hospitalization or prolongation of hospitalization, persistent or significant disability or incapacity, or congenital anomaly or birth defect. ‡ A treatment-related AE was considered by the investigator to be possibly, probably, or definitely related to the study drug. § Occurring in ⱖ5% of patients in any treatment group; unless otherwise specified, common AEs are presented as MedDRA Preferred Terms. ¶ HLT ⫽ MedDRA High Level Term for injection site reaction grouping together multiple types of injection site reactions. # SOC ⫽ MedDRA System Organ Class; it is the highest level for grouping AEs of a certain type.

1468 occurred. In each treatment group, 3 patients reported serious AEs, which were not considered by the investigator to be treatment related. These AEs included musculoskeletal chest pain, drug overdose, depression (the latter 2 in the same patient), and pneumonia in the placebo group; squamous cell carcinoma of the leg, obstructing abdominal hernia, and liver abscess in the rilonacept 80 mg group; and initial presentation of coronary artery disease (nighttime angina), gout exacerbation, and spontaneous abortion (which the patient’s wife had) in the rilonacept 160 mg group. The one serious infection, a liver abscess, was reported in a 57-year-old white man in the rilonacept 80 mg group who had a history of hepatic abscess prior to study entry. There were no reports of tuberculosis or other opportunistic infections.

DISCUSSION These results are the first from a phase III study to show that IL-1 inhibition with rilonacept may be an effective approach to reducing the occurrence of gout flares associated with the initiation of ULT. The results confirm the potential benefits of rilonacept for the prevention of gout flares previously suggested in a smaller proof of principle phase II study (28). These data, the first from among 2 confirmatory efficacy studies and a large phase III safety study, suggest that for some patients, blockade of IL-1 by rilonacept may be an effective alternative to current approaches of gout flare management. Gout flare prevention during the initiation of ULT remains an important need in gout management, not least because of the limitations associated with currently available drugs (15,18,38). The current standards, NSAIDs and colchicine, are associated with AEs and contraindications that limit their use. As many as 90% of patients with gout may have a contraindication to NSAIDs (hypertension, cardiovascular disease, chronic kidney disease, and gastroesophageal disease), and up to 40% may have a relative contraindication to colchicine (chronic kidney disease and chronic hepatitis) (38). Of note, renal impairment does not appear to alter rilonacept exposure (36). Gout has one of the lowest rates of medication adherence relative to patients with hypertension, osteoporosis, or selected metabolic disorders; ⬃50 –75% of patients become nonadherent during the first year of therapy (39,40). It is likely that gout flares occurring during initiation with ULT may contribute to this poor adherence (13,41). Studies indicate that up to 50% of patients discontinue ULT within 3 months of initiation (13,41), resulting in continued hyperuricemia that contributes to poor disease control (13) and also possibly to increased cardiovascular risk (42). Since the therapeutic goal of gout management is maintaining low serum urate levels through long-term ULT adherence, reduction of initial ULT-associated flares may improve adherence. In the current study, after a double (loading) dose, onceweekly administration of either 80 mg or 160 mg of rilonacept markedly reduced the occurrence of gout flares, consistent with the results of a previous phase II study (28). The primary end point (80.0% reduction in mean flares for

Schumacher et al 160 mg versus 73.0% for 80 mg of rilonacept) and all secondary end points in this study favored the 160-mg dose compared with the 80-mg dose. Putting the efficacy results in a clinical perspective, an NNT of ⬃2.0 for both the 80- and 160-mg doses suggests that ⬃1 out of every 2 patients treated can be expected to have fewer flares relative to the placebo. While a consensus approach has been initiated to establish a definition of a gout flare that can be uniformly applied in clinical trials and clinical practice (37), such a definition has yet to be finalized. The definition used in the main analyses of the current study included items recommended in the consensus statement (37) and was based on the patient-reported clinical characteristics that have been suggested to increase specificity for a gout flare (43). When another definition of gout flare used in a prior study was applied, the relative changes were similar to those of the main analysis, representing significant reductions of gout flares with rilonacept. While the rate of gout flares from week 16 to week 20 increased in the rilonacept groups after injections were discontinued at week 16, this rate was not greater than that observed with the placebo during this period, indicating the absence of a rebound phenomenon after discontinuing prophylactic treatment. The need for extended flare prevention in some patients initiating ULT was recently suggested by an analysis of clinical trials of febuxostat (44); a 6-month preventative therapy regimen was observed to provide greater benefits than a 2-month preventative therapy regimen. While the increase in the number of flares after the discontinuation of rilonacept at week 16 suggests the potential need for continued therapy in some patients, this study did not evaluate the efficacy and safety of rilonacept treatment for ⬎16 weeks. Both rilonacept doses appeared to be generally well tolerated in these patients. The rates of withdrawals due to AEs were similar to the placebo, as were the rates of serious AEs. Consistent with a previous study (28), injection site reactions were the most common treatmentrelated event, and injection site reactions were more frequent among patients receiving the higher rilonacept dose. Although the study was not powered to detect significant differences in individual AEs, post hoc analysis suggested that the differences were significant; however, it should be noted that only 2 rilonacept-treated patients discontinued due to injection site reactions. There is concern that agents targeting proinflammatory cytokines have a demonstrated, or at least a theoretical, potential to interfere with response to infection (45), although the proportions of patients reporting an infection in this study were similar among treatment groups. The half-life of rilonacept (⬃8.6 days) is expected to allow for the reversal of its effect in the case of infection. It would nevertheless be prudent to assess patients for the presence of infection during rilonacept treatment (4,46,47). Additional data will be needed to further inform the safety and tolerability profile of rilonacept in patients with gout. A possible limitation of this study is that the starting dose of allopurinol, 300 mg daily (in patients with normal renal function), may have the potential to increase the flare risk relative to a lower starting dose. However, 300 mg of

Rilonacept for Gout Flare Prevention allopurinol is often initiated in clinical practice, and therefore this dose served to provide the setting for a robust and often real-world assessment of rilonacept for gout flare prevention (48). In conclusion, this phase III trial confirmed the results of a prior phase II study, supporting IL-1 inhibition with rilonacept as a potential new option for the prevention of gout flares in patients initiated on ULT. The combination of significant reductions in flare occurrence relative to placebo with an apparent favorable safety and tolerability profile suggests that this therapy has the potential to be of clinical benefit to many patients. The ability of rilonacept to reduce the risk of gout flares during the first months after initiation of ULT may translate into improved longterm ULT adherence and better disease control.

ACKNOWLEDGMENT Editorial support in the preparation of this manuscript was provided by E. Jay Bienen at Regeneron Pharmaceuticals. AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Schumacher had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design. Schumacher, Evans, Weinstein, Yancopoulos, Wang, Terkeltaub. Acquisition of data. Saag, Clower, Jennings, Wang. Analysis and interpretation of data. Schumacher, Evans, Weinstein, Yancopoulos, Wang, Terkeltaub.

ROLE OF THE STUDY SPONSOR Regeneron Pharmaceuticals was involved in the study design, analysis, and interpretation of data. Regeneron Pharmaceuticals was not involved in the acquisition of data. Regeneron Pharmaceuticals funded the technical editorial support for this manuscript. Review of this manuscript was required by Regeneron Pharmaceuticals prior to submission.

ADDITIONAL DISCLOSURE Dr. Jennings is an employee of Radiant Research.

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