Efficacy and Tolerability of Pegloticase for the Treatment of Chronic Gout in Patients Refractory to Conventional Treatment: Title and subTitle BreakTwo Randomized Controlled Trials FREE

Long-term urate-lowering therapy in gout aims to prevent or reverse tissue urate crystal deposits and associated symptoms and signs by maintaining concentrations of uric acid (UA) below the limit of solubility (6.8 mg/dL).^{1 - 2} However, it is common for UA levels to exceed the recommended goal urate range of less than 6.0 mg/dL² during oral urate-lowering therapy among the 5 to 6 million US patients with gout,^{3 - 4} a finding documented in a majority of individuals treated with the most frequently prescribed doses of allopurinol (≤300 mg/d).^{5 - 8} Although dose titration of available oral urate-lowering agents can achieve target UA in most patients, urate-lowering therapy fails for perhaps 3% of patients⁹ because of refractoriness, contraindication, or intolerance. Without effective urate lowering, many such patients progress to severe chronic gout characterized by frequent arthritic flares, chronic arthropathy, and enlarging tophi, often accompanied by deformity, chronic pain, functional disability, and impaired health-related quality of life (QOL).^{10 - 12} High rates of cardiovascular (CV),^{13 - 14} metabolic, and renal comorbidities¹⁵ further complicate QOL and management of individuals with chronic gout.

In contrast to nonprimate mammals, humans excrete UA rather than the soluble metabolite allantoin as the end product of purine metabolism because of mutational inactivation of the urate oxidase (uricase) gene.¹⁶ Pegloticase, a recently approved⁹ mammalian recombinant uricase conjugated to monomethoxypoly(ethylene glycol),^{17 - 19} is an enzymatic alternative to conventional urate-lowering agents. Intravenously administered (IV) pegloticase remains in the circulation where it rapidly degrades urate.^{17 - 18} We hypothesize that the resulting urate concentration gradient draws extravascular urate into the circulation for degradation and that persistent reduction of extracellular fluid urate concentration favors urate crystal dissolution, with eventual normalization of the body urate pool and resolution of gout symptoms and signs.

Single- and multiple-dose studies of pegloticase in patients with refractory gout^{17 - 18 ,20} have established dose-related UA reduction lasting several weeks after each IV infusion. In a 3-month randomized open-label efficacy and safety trial,²⁰ profound and sustained urate lowering occurred most often when 8-mg pegloticase was infused every 2 weeks. Here, we report results of replicate, randomized, placebo-controlled, 6-month trials of the urate-lowering and clinical efficacy and tolerability of pegloticase in patients with refractory gout.

Patients were 18 years or older and met the following criteria for refractory gout: a baseline serum UA of 8.0 mg/dL or greater (to convert to μmol/L, multiply by 59.485) and at least 1 of the following: 3 or more self-reported gout flares during the previous 18 months; 1 or more tophi; and gouty arthropathy, defined clinically or radiographically as joint damage due to gout. Patients also had contraindication to treatment with allopurinol or history of failure to normalize UA despite 3 or more months of treatment with the maximum medically appropriate allopurinol dose (determined by the treating physician). Exclusion criteria were glucose-6-phosphate dehydrogenase deficiency (because of hemolysis/methemoglobinemia associated with administration of unmodified recombinant uricase), prior treatment with a uricase-containing agent, pregnancy, unstable angina, uncontrolled hypertension (>150/95 mm Hg) or cardiac arrhythmia, uncompensated congestive heart failure, renal dialysis, or solid organ transplant.

This study received institutional review board approval at each site. Written informed consent and Health Insurance Portability and Accountability Act assurances were completed for each participant before enrollment.

Two replicate, randomized, 6-month, double-blind, placebo-controlled trials (C0405 and C0406) were conducted at 56 rheumatology practices in the United States, Canada, and Mexico between June 2006 and October 2007. Starting at week 1, patients received 2-hour IV infusions of 250-mL 0.9% sodium chloride containing either pegloticase 8 mg at each infusion (biweekly treatment group), pegloticase 8 mg alternating with placebo (every-4-week or monthly treatment group), or placebo (placebo group). As prespecified, the primary end point was analyzed separately for each trial, and safety and secondary end points were analyzed using data pooled from both trials. Randomization used an automated interactive voice response system and was stratified to ensure comparable numbers of patients with tophi in each group.

Participants receiving urate-lowering medication at screening underwent a 1-week washout. Gout flare prophylaxis (colchicine, 0.6 mg once or twice daily, or a nonsteroidal anti-inflammatory drug) was initiated 1 week before first infusion and continued throughout the study. Prophylaxis against infusion-related reactions (IRs) was given to all patients before each infusion: oral fexofenadine, 60 mg the evening before and again before infusion; acetaminophen, 1000 mg; and IV hydrocortisone, 200 mg, immediately before infusion.

The primary efficacy end point was the proportion of plasma UA responders in each pegloticase treatment group vs the placebo group. A responder was defined as a patient with plasma UA less than 6.0 mg/dL for 80% of the time or longer during both months 3 and 6, the periods extending, respectively, from the week-9 infusion to just prior to the week-13 infusion and from the week-21 infusion to the week-25 final study visit. Plasma UA (measured in trichloroacetic acid–precipitated chilled plasma) was chosen to study this end point in order to avoid possible ex vivo serum UA degradation by circulating pegloticase. Plasma UA was determined at baseline, at 2 and 24 hours after initial infusion, preceding each biweekly infusion, and at 5 additional prespecified time points in both month 3 and month 6: 2 hours, 1 day, and 7 days after the week-9 and week-21 infusions and 2 hours and 7 days after the week-11 and week-23 infusions.

Secondary end points included tophus resolution; reductions in the proportion of patients with gout flare and in the number of flares per patient during months 1-3 and 4-6 of the trial; reductions in tender joint count (TJC) and swollen joint count (SJC); and patient-reported changes in pain, physical function, and QOL, measured, respectively, by the Health Assessment Questionnaire (HAQ) pain scale,²¹ HAQ–Disability Index (HAQ-DI),^{22 - 24} and 36-Item Short Form Health Survey (SF-36).^{25 - 26}

Secondary end points were assessed at baseline, at the week-13 and week-19 visits, and at the week-25 final visit. For tophus measurement, serial standardized digital photographs of hands and feet and up to 2 other sites with tophi were obtained and compared by a blinded central reader using computer-assisted quantitative measurement and key concepts of photographic assessment of skin tumors by Response Evaluation Criteria in Solid Tumors (RECIST) software (MedStudio version 4.4; Megasoft, Hyderabad, India).²⁷ This validated method for evaluating quantitative response of malignant skin lesions to cancer treatments was applied based on analogy of tophaceous mass lesions to malignant skin lesions. A tophus complete response (CR) was defined as 100% reduction in the measured area of at least 1 tophus (of baseline diameter ≥5 mm) without growth of any baseline tophus or appearance of any new tophus.

Gout flare (acute joint pain and swelling requiring treatment) occurrence, duration, and severity were reported by patients at time of occurrence and confirmed by investigator interview. Each investigator assessed SJC and TJC in 54 specified joints. Patients completed HAQ and SF-36 forms. Values for SJC, TJC, and patient-reported end points were imputed using last observation carried forward²⁸ for participants not completing all infusions and the week-25 final study visit.

Safety assessments included biweekly physical examination and medical history and adverse event (AE) updates and monthly complete blood counts, serum chemistry, and urinalysis. An AE occurring during infusion or within 2 hours after was declared an IR and prompted standardized assessment: physical examination, electrocardiogram, and measurement of serum tryptase (to detect significant mast cell degranulation).

All participant files were reviewed in a post hoc analysis by an independent, blinded CV event adjudication committee. Deaths and AEs considered possibly of CV type were assessed using the Anti-Platelet Trialists' Collaboration (APTC) composite of end points for the primary analysis.²⁹ Non-APTC serious CV events were identified from a modified list³⁰ of additional serious CV AEs.

Serum samples for pegloticase-antibody and pegloticase neutralization assays were obtained before infusions at weeks 1, 3, 5, 9, 13, 17, 21, and 25. Standard ELISA methodology was used to detect IgM, IgG, and total pegloticase antibody using pegloticase as capture antigen and horseradish peroxidase–conjugated secondary antibody.^{31 - 32} (See eMethods for assay details.)

A modified intent-to-treat population (randomized patients who received at least 1 infusion) was used for all efficacy and safety determinations except for deaths, which were tracked for all patients from randomization to study database closure and recorded as occurring before, during, or after completion of the 25-week treatment period. Each replicate trial was considered adequately powered (>80%) to demonstrate a difference in responder rates of 35% vs 5% between each active treatment group and the respective placebo treatment group (significance level of P = .05 for each comparison).

Comparisons of baseline demographics and disease characteristics across treatment groups were made using analysis of variance for continuous parameters and the χ² test for categorical parameters. The primary efficacy of pegloticase in each trial was evaluated in responder analyses, with patients who withdrew before the week-25 final visit designated nonresponders. The proportion of responders in each pegloticase treatment group was compared with that in the corresponding placebo group using the Fisher exact test.

Numbers of patients with a tophus CR were compared between each pegloticase group and the placebo group using the Fisher exact test. Flare frequencies during months 1-3 and 4-6 were analyzed separately using the 2-sample t test, comparing each pegloticase group with placebo. Numbers of patients reporting flares during these periods were compared using the Fisher exact test. Comparisons of change from baseline for TJC and SJC and in pain scores, HAQ-DI scores, and SF-36 domains between each pegloticase group and the placebo group used the 2-sample t -test.

Two-sided analyses were performed for all statistical tests. P values less than .05 were considered significant. All statistical analyses were performed using Stata/SE version 11.2 (StataCorp, College Station, Texas).

A total of 225 participants (109 in trial C0405 and 116 in trial C0406) were randomized to the 3 study groups (pegloticase biweekly or monthly or placebo) in a 2:2:1 ratio (Figure 1). All urate-lowering, clinical efficacy, and tolerability analyses (except deaths) were carried out on a modified intent-to-treat population (n = 212; 104 in trial C0405 and 108 in trial C0406) comprising all randomized patients who received at least 1 infusion. Baseline characteristics were similar across the trials and treatment groups; metabolic and renal disorders were common and CV comorbidities or risk factors were present in more than 80% of study participants (Table 1).

Plasma UA normalized within 24 hours of the first infusion in all patients receiving pegloticase, but afterward, some patients lost the urate-lowering response whereas others maintained UA less than 6.0 mg/dL throughout the trial. The proportion of UA responders (defined as a plasma UA <6.0 mg/dL for ≥80% of the time during months 3 and 6) in both pegloticase treatment groups was significantly greater than for the placebo group in the pooled analysis (P < .001 for both) (Table 2) and in the individual trials. When analyzed separately by dose, patients treated with biweekly pegloticase experienced response rates of 47% (20/43; 95% CI, 31%-62%) and 38% (16/42; 95% CI, 24%-54%) in the 2 trials. Patients treated with monthly pegloticase reported response rates of 20% (8/41; 95% CI, 9%-35%) and 49% (21/43; 95% CI, 33%-65%) in the 2 trials. Response rates were 0% in both placebo groups (95% CI, 0%-17% and 0%-15% in the 2 trials). Serum UA was also measured at most study time points, and the κ coefficient, which provides a measure of agreement between corresponding serum and plasma UA values, was 0.74 (P < .001), indicating near excellent agreement between the 2 methods.

Mean plasma UA for responders was substantially below 6.0 mg/dL for the entire 6-month treatment period (Figure 2). For nonresponders treated with biweekly pegloticase, mean plasma UA remained below 6.0 mg/dL through week 10 but was above target levels at all subsequent time points (Figure 2B). These findings suggest that a loss of urate-lowering efficacy manifested relatively early following treatment initiation. Among 74 patients treated with pegloticase (33 of 85 in the biweekly cohort and 41 of 84 in the monthly cohort) who lost urate-lowering efficacy prior to trial completion or withdrawal, 72 did so by month 4.

Forty percent of patients in the biweekly pegloticase group and 21% in the monthly group had a CR for 1 or more tophi by the final visit compared with 7% of patients receiving placebo (P = .002 and P = .20, respectively) (Table 2). Examples of tophus size reductions in patients receiving pegloticase therapy are shown in eFigure 1 and eFigure 2. During months 1-3, both the incidence of gout flares (proportion of patients suffering at least 1 flare) and the number of flares per patient were higher for pegloticase-treated patients compared with the placebo group (Table 2). However, with continued treatment during months 4-6, significant reductions were seen in the proportion of patients with gout flare in the biweekly treatment group vs the placebo group (Table 2). Flares per patient were also numerically fewer during this period with biweekly pegloticase treatment compared with placebo treatment, but the difference was not significant. There were also reductions in TJC and SJC in patients treated with pegloticase compared with the respective values in placebo recipients, but only differences in TJC were statistically significant (Table 2).

Both pegloticase dosing groups reported significant improvements in physical function and QOL compared with placebo. Patient-reported pain (visual analog scale) was significantly reduced (Table 2) with biweekly pegloticase vs placebo. Treatment with biweekly pegloticase was also associated with significant changes from baseline in HAQ-DI scores²¹ and SF-36 Physical Component Summary scores that met or exceeded the minimum clinically important differences established for the respective instrument in inflammatory arthritides (Table 2).^{12 ,34 - 37}

One or more AEs occurred in more than 90% of participants in each treatment group (Table 3). Serious AEs occurred more frequently in patients treated with biweekly (24%; 95% CI, 15%-34%) and monthly pegloticase (23%; 95% CI, 14%-33%) than in patients receiving placebo (12%; 95% CI, 4%-25%). Gout flare was the most common AE and was reported in approximately 80% of patients across the 3 pooled study groups.

Infusion-related reaction was the second most common AE (occurring in 26%, 42%, and 5% of patients receiving pegloticase biweekly, pegloticase monthly, and placebo, respectively) and was also the most common reason for study discontinuation among pegloticase-treated patients (10% for biweekly; 13% for monthly). Serious IRs occurred in 5% (pegloticase biweekly) and 8% (pegloticase monthly) of patients. Resolution of all IRs began within minutes of slowing or discontinuing the infusion or initiating supportive treatment (which included epinephrine in 1 patient). All IRs resolved completely. Serum tryptase levels were increased in 12 of 108 IRs (10.2%), including 3 instances of IR classified as serious. In a retrospective analysis of IRs, 5 patients experienced IRs with signs and symptoms that met the criteria for anaphylaxis from the National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network.³⁸ These included 2 patients each in the pegloticase biweekly and pegloticase monthly cohort and a fifth patient who experienced these clinical features during the first infusion of the biweekly regimen. All of these reactions were judged as mild to moderate in severity by the investigator; 2 patients were treated with antihistamines and 1 with glucocorticoids. Serum tryptase activity was elevated in 1 of 5 patients. All signs and symptoms resolved completely in these 5 patients, and 3 of 5 continued in the trial.

Seven deaths (4 among patients assigned pegloticase and 3 in the placebo group) occurred between randomization and closure of the study database (February 15, 2008). One patient randomized to placebo died before the first infusion; 3 patients, each assigned pegloticase, died during the 6-month treatment period; and 3 patients (1 assigned pegloticase and 2 placebo) died after completing the treatment period (Figure 1 and Table 3). Two deaths during the treatment period were attributed to CV AEs (cardiac arrest in a 61-year-old man and arrhythmia in a 69-year-old man) in the biweekly pegloticase group. The third treatment period death resulted from renal failure in a 64-year-old man (monthly pegloticase) who withdrew from dialysis initiated during a hospitalization. Other non-CV related deaths occurring outside the treatment period included methicillin-resistant Staphylococcus aureus sepsis in an 89-year-old man 12 weeks after completing biweekly pegloticase treatment; recurrent chronic lymphocytic leukemia in an 80-year-old man receiving placebo; and multiorgan failure in an 85-year-old woman who was randomized to placebo but died before infusion. One death (cause indeterminate because of insufficient information) occurred 4 months after study withdrawal in a 67-year-old placebo-treated man with a history of congestive heart failure and insulin-dependent diabetes mellitus.

Three APTC events were identified by the adjudication committee: 2 CV deaths in patients treated with biweekly pegloticase (described in preceding paragraph) and 1 nonfatal myocardial infarction in a pegloticase monthly patient. All APTC events occurred in patients with 4 or more CV risk factors at baseline. Serious non-APTC events occurred in 2 patients in the biweekly group (2.3%; 95% CI, 0.3%-8.2%), 6 patients in the monthly group (7.1%; 95% CI, 2.7%-14.9%), and 0 patients in the placebo group (95% CI, 0%-8.2%). All non-APTC events occurred in patients with prior histories of CV disease but were not clustered by event category or duration of pegloticase treatment.

Antibodies to pegloticase appeared early in treatment and were detected in 134 of 150 patients treated with pegloticase (89%; 95% CI, 83%-94%). Pegloticase antibody was of IgM and IgG isotypes and, with the exception of antibody from 1 patient, did not neutralize pegloticase activity in vitro.

Only 1 of 52 (2%; 95% CI, 0.0%-10%) pegloticase-treated patients with pegloticase antibody exceeding a titer of 1:2430 at any time maintained a urate-lowering response to therapy. In contrast, 52 of 82 (63%; 95% CI, 52%-74%) pegloticase-treated patients who remained in the study for 2 months or longer and never had pegloticase-antibody titer greater than 1:2430 maintained their urate-lowering responses. A post hoc analysis comparing response rates in patients with and without antibody titers exceeding 1:2430 revealed a significant difference (P < .001).

Antibody titers against pegloticase may also have been associated with the incidence of IRs in the 2 trials. Infusion-related reactions were reported in 31 of 52 patients (60%; 95% CI, 45%-72%) with pegloticase-antibody titers greater than 1:2430 at any time during the trial, compared with 16 of 84 patients (19%; 95% CI, 11%-29%) in whom pegloticase-antibody titer never exceeded 1:2430 (P < .001). Although IRs were more common in patients with high titers of pegloticase antibody at some point during treatment, antibody titers at the time of occurrence of the first IR did not reliably predict IR. In contrast and importantly, a post hoc analysis found that loss of urate-lowering efficacy (plasma UA >6.0 mg/dL) preceded the first IR in 91% (20/22 receiving biweekly pegloticase; 95% CI, 71%-99%) and 71% (24/34 receiving monthly pegloticase; 95% CI, 53%-85%) of patients with IRs.

These parallel, 6-month, placebo-controlled trials of pegloticase treatment have documented sustained UA reductions and significant clinical improvements in a substantial proportion of patients with chronic gout and refractoriness to, or intolerance of, conventional urate-lowering therapy. The significant disease-modifying benefits of pegloticase given every 2 weeks (tophus resolution, reduced flare frequency, reduction in TJC, and improved patient-reported outcomes in pain, physical function, and QOL) were demonstrable within 6 months, a time frame unique in randomized controlled trials of urate-lowering agents.^{7 - 8}

As documented here and previously reported,^{11 - 12} chronic gout is associated with decreased physical function and diminished QOL. Improvements in physical function and QOL scores exceeding the minimal clinically important difference in pegloticase-treated patients, coupled with deterioration in pain and QOL in placebo-treated patients, provide evidence that chronic elevations in UA are associated with significant functional impairment as measured by several criteria. This relationship has previously been difficult to distinguish from functional impairment imparted by serious comorbidities that typically characterize gout patients, and therefore, the ability of pegloticase to improve patient reported outcomes in this context is noteworthy.

Infusion-related reactions, including some cases fulfilling criteria for anaphylaxis, were the most common AEs causing withdrawal from these trials. Although all IRs resolved promptly and without sequelae, minimizing the risk for IRs is important for the safe administration of pegloticase in clinical practice.¹⁹ In our post hoc analysis, we observed that most (79%) pegloticase-treated patients experiencing IRs in the course of development of high titers of pegloticase antibody did so only after an associated loss of the urate-lowering response to pegloticase. Since all patients in this study received routine prophylaxis for IRs, including glucocorticoids, the extent to which this regimen may have mitigated the frequency and severity of IRs is uncertain. Nevertheless, it would seem prudent to maintain IR prophylaxis in all individuals receiving pegloticase therapy.

A relatively small number of mechanistically diverse albeit serious CV AEs occurred during this study. Despite the 4-fold greater number of patients receiving pegloticase vs placebo, the elevated CV risk profile of this population, and the absence of a compelling mechanism connecting pegloticase with CV AEs,³⁹ the observed numerical imbalance in these events underlines the need for care in selecting patients for pegloticase treatment. All patients who had serious CV events had baseline CV risk factors or previous events; thus, measures to stabilize CV comorbidities prior to and during pegloticase treatment would be appropriate.