Pegloticase Resolved Tophi in Chronic Refractory Gout

Pegloticase, a unique, recently approved urate-lowering therapy, was superior to placebo for lowering uric acid levels and resolved some tophi in patients with refractory chronic gout in two replicate randomized, placebo-controlled trials.

Patients in both trials, including 109 patients in Trial C0405 and 116 in Trial C0406, were randomized to receive either biweekly infusions of pegloticase (biweekly treatment), biweekly infusions with alternating pegloticase and placebo (monthly treatment), or biweekly placebo. The primary end point of plasma uric acid levels less than 6 mg/dL in months 3 and 6 of treatment was achieved in 47% and 38% of those in the two trials, respectively, who were randomized to receive biweekly treatment, and in 20% and 39% of patients in the two trials, respectively, who were randomized to receive monthly treatment. None of the patients in the placebo group in either trial achieved the primary end point, Dr. John S. Sundy of Duke University, Durham, N.C., and his colleagues report in the Aug. 17 issue of JAMA.

When data from the two trials were pooled, 42% of patients receiving active treatment biweekly and 35% of patients receiving active treatment monthly achieved the primary end point, the investigators found (JAMA 2011;306:711-20).

Pegloticase is a mammalian recombinant uricase conjugated to monomethoxypoly. It serves as an enzymatic alternative to conventional urate-lowering therapy, which fails in about 3% of gout patients as a result of refractoriness, contraindications, or intolerance. Treatment in these 6-month, multicenter trials was given starting at week 1 as a 2-hour intravenous infusion of 250 ml 0.9% sodium chloride containing 8 mg pegloticase or placebo, depending on randomization.

In addition to the significantly greater effectiveness of active treatment versus placebo in regard to the primary end point, 40% and 21% of patients in the biweekly and monthly treatment groups, respectively, also experienced a complete response for one or more tophus by the final follow-up visit, compared with only 7% of those in the placebo groups, the investigators said.

Also, the treatment groups experienced reductions in tender joint count and swollen joint count, compared with placebo, although the differences were significant only for tender joint count.

Significant improvements in physical function and quality of life were also noted in the treatment groups, compared with the placebo groups, and biweekly treatment was associated with significant changes from baseline in the Health Assessment Questionnaire-Disability Index scores and Short Form-36 Physical Component Summary scores that met or exceeded the minimum clinically important differences established for the respective instrument in inflammatory arthritides, the investigators noted.

During the first 3 months of the studies, both the incidence of gout flares and the number of flares per patient were higher in the treatment versus placebo groups, but during months 4-6, continued biweekly treatment was associated with a significant reduction in the proportion of patients with gout flare, compared with placebo, and flares per patient also were reduced, although this difference was not statistically significant, they said.

Adverse events were common in the treatment groups, with one or more occurring in more than 90% of patients receiving active treatment. Serious adverse events occurred more often in the biweekly treatment groups and the monthly groups, compared with the placebo groups (24% and 23% vs. 12%). Gout flare and infusion-related reactions were the most common adverse events.

Serious infusion reactions occurred in 5% and 8% of the biweekly and monthly patient groups, respectively, and resolution of all infusion reactions begin within minutes of slowing or discontinuing the infusion or initiating supportive treatment; all resolved completely. The investigators stressed the importance of minimizing the risk of infusion reactions by using prophylaxis in clinical practice, as was done in these studies.

They also emphasized the importance of stabilizing cardiovascular comorbidities prior to initiating treatment, given the "relatively small number of mechanistically diverse albeit serious cardiovascular adverse events" that occurred during these studies (two deaths were attributed to cardiovascular adverse events in the biweekly treatment group, and one nonfatal myocardial infarction occurred in a patient receiving monthly treatment). All of the cardiovascular events occurred in patients with four or more cardiovascular risk factors at baseline, they noted.

"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, the observed numerical imbalance in these events underlines the need for care in selecting patients for pegloticase treatment," they added.

These parallel trials "have documented sustained [uric acid] reductions and significant clinical improvement in a substantial proportion of patients with chronic gout and refractoriness to, or intolerance of, conventional urate-lowering therapy," the investigators wrote.

The significant disease-modifying benefits of biweekly treatment with pegloticase were evident within 6 months and, of note, the improvements in physical function and quality of life scores exceeding the minimal clinically important difference in pegloticase-treated patients, when considered in light of the deterioration in pain and quality of life seen in placebo patients in these studies, provide evidence that "chronic elevations in uric acid are associated with significant functional impairment as measured by several criteria," they said, explaining that this relationship has previously been difficult to distinguish from functional impairment associated with the serious comorbidities common in gout patients.

These studies were funded by Savient Pharmaceuticals, the maker of pegloticase. Dr. Sundy reported receiving fees for consulting and grants from Ardea Bioscience, Novartis, Nuon Therapeutics, Regeneron, and Savient Pharmaceuticals as well as payment for lectures, including service on the speakers bureau for Takeda Pharmaceuticals North America. Other authors also disclosed relationships with Savient Pharmaceuticals and other companies. Complete disclosures are included in the JAMA article.

Pegloticase, a unique, recently approved urate-lowering therapy, was superior to placebo for lowering uric acid levels and resolved some tophi in patients with refractory chronic gout in two replicate randomized, placebo-controlled trials.

Patients in both trials, including 109 patients in Trial C0405 and 116 in Trial C0406, were randomized to receive either biweekly infusions of pegloticase (biweekly treatment), biweekly infusions with alternating pegloticase and placebo (monthly treatment), or biweekly placebo. The primary end point of plasma uric acid levels less than 6 mg/dL in months 3 and 6 of treatment was achieved in 47% and 38% of those in the two trials, respectively, who were randomized to receive biweekly treatment, and in 20% and 39% of patients in the two trials, respectively, who were randomized to receive monthly treatment. None of the patients in the placebo group in either trial achieved the primary end point, Dr. John S. Sundy of Duke University, Durham, N.C., and his colleagues report in the Aug. 17 issue of JAMA.

When data from the two trials were pooled, 42% of patients receiving active treatment biweekly and 35% of patients receiving active treatment monthly achieved the primary end point, the investigators found (JAMA 2011;306:711-20).

Pegloticase is a mammalian recombinant uricase conjugated to monomethoxypoly. It serves as an enzymatic alternative to conventional urate-lowering therapy, which fails in about 3% of gout patients as a result of refractoriness, contraindications, or intolerance. Treatment in these 6-month, multicenter trials was given starting at week 1 as a 2-hour intravenous infusion of 250 ml 0.9% sodium chloride containing 8 mg pegloticase or placebo, depending on randomization.

In addition to the significantly greater effectiveness of active treatment versus placebo in regard to the primary end point, 40% and 21% of patients in the biweekly and monthly treatment groups, respectively, also experienced a complete response for one or more tophus by the final follow-up visit, compared with only 7% of those in the placebo groups, the investigators said.

Also, the treatment groups experienced reductions in tender joint count and swollen joint count, compared with placebo, although the differences were significant only for tender joint count.

Significant improvements in physical function and quality of life were also noted in the treatment groups, compared with the placebo groups, and biweekly treatment was associated with significant changes from baseline in the Health Assessment Questionnaire-Disability Index scores and Short Form-36 Physical Component Summary scores that met or exceeded the minimum clinically important differences established for the respective instrument in inflammatory arthritides, the investigators noted.

During the first 3 months of the studies, both the incidence of gout flares and the number of flares per patient were higher in the treatment versus placebo groups, but during months 4-6, continued biweekly treatment was associated with a significant reduction in the proportion of patients with gout flare, compared with placebo, and flares per patient also were reduced, although this difference was not statistically significant, they said.

Adverse events were common in the treatment groups, with one or more occurring in more than 90% of patients receiving active treatment. Serious adverse events occurred more often in the biweekly treatment groups and the monthly groups, compared with the placebo groups (24% and 23% vs. 12%). Gout flare and infusion-related reactions were the most common adverse events.

Serious infusion reactions occurred in 5% and 8% of the biweekly and monthly patient groups, respectively, and resolution of all infusion reactions begin within minutes of slowing or discontinuing the infusion or initiating supportive treatment; all resolved completely. The investigators stressed the importance of minimizing the risk of infusion reactions by using prophylaxis in clinical practice, as was done in these studies.

They also emphasized the importance of stabilizing cardiovascular comorbidities prior to initiating treatment, given the "relatively small number of mechanistically diverse albeit serious cardiovascular adverse events" that occurred during these studies (two deaths were attributed to cardiovascular adverse events in the biweekly treatment group, and one nonfatal myocardial infarction occurred in a patient receiving monthly treatment). All of the cardiovascular events occurred in patients with four or more cardiovascular risk factors at baseline, they noted.

"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, the observed numerical imbalance in these events underlines the need for care in selecting patients for pegloticase treatment," they added.

These parallel trials "have documented sustained [uric acid] reductions and significant clinical improvement in a substantial proportion of patients with chronic gout and refractoriness to, or intolerance of, conventional urate-lowering therapy," the investigators wrote.

The significant disease-modifying benefits of biweekly treatment with pegloticase were evident within 6 months and, of note, the improvements in physical function and quality of life scores exceeding the minimal clinically important difference in pegloticase-treated patients, when considered in light of the deterioration in pain and quality of life seen in placebo patients in these studies, provide evidence that "chronic elevations in uric acid are associated with significant functional impairment as measured by several criteria," they said, explaining that this relationship has previously been difficult to distinguish from functional impairment associated with the serious comorbidities common in gout patients.

These studies were funded by Savient Pharmaceuticals, the maker of pegloticase. Dr. Sundy reported receiving fees for consulting and grants from Ardea Bioscience, Novartis, Nuon Therapeutics, Regeneron, and Savient Pharmaceuticals as well as payment for lectures, including service on the speakers bureau for Takeda Pharmaceuticals North America. Other authors also disclosed relationships with Savient Pharmaceuticals and other companies. Complete disclosures are included in the JAMA article.

Pegloticase, a unique, recently approved urate-lowering therapy, was superior to placebo for lowering uric acid levels and resolved some tophi in patients with refractory chronic gout in two replicate randomized, placebo-controlled trials.

Patients in both trials, including 109 patients in Trial C0405 and 116 in Trial C0406, were randomized to receive either biweekly infusions of pegloticase (biweekly treatment), biweekly infusions with alternating pegloticase and placebo (monthly treatment), or biweekly placebo. The primary end point of plasma uric acid levels less than 6 mg/dL in months 3 and 6 of treatment was achieved in 47% and 38% of those in the two trials, respectively, who were randomized to receive biweekly treatment, and in 20% and 39% of patients in the two trials, respectively, who were randomized to receive monthly treatment. None of the patients in the placebo group in either trial achieved the primary end point, Dr. John S. Sundy of Duke University, Durham, N.C., and his colleagues report in the Aug. 17 issue of JAMA.

When data from the two trials were pooled, 42% of patients receiving active treatment biweekly and 35% of patients receiving active treatment monthly achieved the primary end point, the investigators found (JAMA 2011;306:711-20).

Pegloticase is a mammalian recombinant uricase conjugated to monomethoxypoly. It serves as an enzymatic alternative to conventional urate-lowering therapy, which fails in about 3% of gout patients as a result of refractoriness, contraindications, or intolerance. Treatment in these 6-month, multicenter trials was given starting at week 1 as a 2-hour intravenous infusion of 250 ml 0.9% sodium chloride containing 8 mg pegloticase or placebo, depending on randomization.

In addition to the significantly greater effectiveness of active treatment versus placebo in regard to the primary end point, 40% and 21% of patients in the biweekly and monthly treatment groups, respectively, also experienced a complete response for one or more tophus by the final follow-up visit, compared with only 7% of those in the placebo groups, the investigators said.

Also, the treatment groups experienced reductions in tender joint count and swollen joint count, compared with placebo, although the differences were significant only for tender joint count.

Significant improvements in physical function and quality of life were also noted in the treatment groups, compared with the placebo groups, and biweekly treatment was associated with significant changes from baseline in the Health Assessment Questionnaire-Disability Index scores and Short Form-36 Physical Component Summary scores that met or exceeded the minimum clinically important differences established for the respective instrument in inflammatory arthritides, the investigators noted.

During the first 3 months of the studies, both the incidence of gout flares and the number of flares per patient were higher in the treatment versus placebo groups, but during months 4-6, continued biweekly treatment was associated with a significant reduction in the proportion of patients with gout flare, compared with placebo, and flares per patient also were reduced, although this difference was not statistically significant, they said.

Adverse events were common in the treatment groups, with one or more occurring in more than 90% of patients receiving active treatment. Serious adverse events occurred more often in the biweekly treatment groups and the monthly groups, compared with the placebo groups (24% and 23% vs. 12%). Gout flare and infusion-related reactions were the most common adverse events.

Serious infusion reactions occurred in 5% and 8% of the biweekly and monthly patient groups, respectively, and resolution of all infusion reactions begin within minutes of slowing or discontinuing the infusion or initiating supportive treatment; all resolved completely. The investigators stressed the importance of minimizing the risk of infusion reactions by using prophylaxis in clinical practice, as was done in these studies.

They also emphasized the importance of stabilizing cardiovascular comorbidities prior to initiating treatment, given the "relatively small number of mechanistically diverse albeit serious cardiovascular adverse events" that occurred during these studies (two deaths were attributed to cardiovascular adverse events in the biweekly treatment group, and one nonfatal myocardial infarction occurred in a patient receiving monthly treatment). All of the cardiovascular events occurred in patients with four or more cardiovascular risk factors at baseline, they noted.

"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, the observed numerical imbalance in these events underlines the need for care in selecting patients for pegloticase treatment," they added.

These parallel trials "have documented sustained [uric acid] reductions and significant clinical improvement in a substantial proportion of patients with chronic gout and refractoriness to, or intolerance of, conventional urate-lowering therapy," the investigators wrote.

The significant disease-modifying benefits of biweekly treatment with pegloticase were evident within 6 months and, of note, the improvements in physical function and quality of life scores exceeding the minimal clinically important difference in pegloticase-treated patients, when considered in light of the deterioration in pain and quality of life seen in placebo patients in these studies, provide evidence that "chronic elevations in uric acid are associated with significant functional impairment as measured by several criteria," they said, explaining that this relationship has previously been difficult to distinguish from functional impairment associated with the serious comorbidities common in gout patients.

These studies were funded by Savient Pharmaceuticals, the maker of pegloticase. Dr. Sundy reported receiving fees for consulting and grants from Ardea Bioscience, Novartis, Nuon Therapeutics, Regeneron, and Savient Pharmaceuticals as well as payment for lectures, including service on the speakers bureau for Takeda Pharmaceuticals North America. Other authors also disclosed relationships with Savient Pharmaceuticals and other companies. Complete disclosures are included in the JAMA article.