New Agents for Gout Provide Alternatives to Allopurinol

For a related video with Dr. Wortmann, go to www.youtube.com/InternalMedicineNews

FORT LAUDERDALE, FLA. — The likely approval of febuxostat for the treatment of gout means that there soon will be an alternative for the underserved group of patients with severe disease who cannot tolerate allopurinol.

No new urate-lowering treatments have been approved for gout since 1964, but the advisory panel of the Food and Drug Administration voted 12-0, with 1 abstention, in favor of approval for this nonpurine selective xanthine oxidase inhibitor. Although the FDA is not required to follow the recommendations of its advisory panel, it usually does so.

Febuxostat is structurally distinct from allopurinol, another xanthine oxidase inhibitor that also exerts inhibitory activity on other enzymes involved in purine and pyrimidine metabolism, according to Dr. Robert L. Wortmann, professor of medicine, Dartmouth-Hitchcock Medical Center, Lebanon, N.H.

Experience to date with febuxostat in more than 4,000 patients has shown that, unlike with allopurinol, there appears to be no need for dose adjustment in patients with mild to moderate renal dysfunction. Dosage concerns exist for patients with renal insufficiency taking allopurinol, because of the possible occurrence of toxic epidermal necrolysis.

There also have been no reports of hypersensitivity reactions, even among patients who previously had such reactions to allopurinol, most likely because of the two drugs' differences in structure, Dr. Wortmann said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

In a phase III clinical trial, 81% of patients receiving 80 mg febuxostat per day had serum urate levels below 6 mg/dL after 52 weeks of therapy, compared with 39% of patients receiving 300 mg allopurinol per day (N. Engl. J. Med. 2005;353:2450–61).

“It seems to be a very effective drug,” said Dr. Wortmann, who is a consultant to Takeda Pharmaceutical Co., the manufacturer of febuxostat.

Although not all patients can tolerate allopurinol, that drug also is effective. However, it often is not prescribed in sufficiently high doses, with 97% of prescriptions in this country being for 300 mg/day or less, according to Dr. Wortmann. The drug is approved for doses up to 800 mg/day.

The goal of antihyperuricemic therapy is to lower the serum urate to 5–6 mg/dL. “If you lower the urate from 12 mg/dL to 7 or 7.5 mg/dL with allopurinol, it seems like you are helping but all you are doing is retarding the rate at which the crystals will deposit,” he said.

Regardless of what urate-lowering agent is chosen, the lowest dose that brings the serum urate below the target of 6 mg/dL should be used.

Another agent being investigated for gout is uricase, which converts urease to the more soluble allantoin. A commercially available formulation, rasburicase, is used for the treatment of tumor lysis syndrome. Although that drug is very effective for lowering serum urate levels, it carries a black box warning regarding anaphylaxis, Dr. Wortmann said.

Accordingly, two companies have been working on developing pegylated formulations, based on the principle that the polyethylene glycol would make uricase less antigenic and increase the half-life. Dr. Wortmann disclosed that he is also a consultant to Savient Pharmaceuticals Inc., the manufacturer of one of these formulations, Puricase.

“In trials this agent has knocked the devil out of urate levels very rapidly,” he said. However, the number of dropouts has been high in these trials, primarily because of allergic and infusion reactions.

“Whether that can be alleviated by giving a more dilute form of the drug or giving it over longer periods of time, I'm not sure,” he said.

There also have been a number of deaths during trials of uricase, although apparently none of these deaths could be attributed to the drug. For example, one patient who died was a 92-year-old man with severe tophaceous gout who had had three bypass surgeries and a stroke previously, and who succumbed to heart disease.

“I think the investigators were not as selective as they could have been in patient selection, which is unfortunate because this to me would be an exciting alternative for patients with severe tophaceous gout. Uricase could be given for a few doses to get the urate really low and mobilize the crystals as much as possible, and then the patient could be maintained on another agent once it's under control,” he said.

SDEF and this news organization are owned by Elsevier.

'In trials [uricase] has knocked the devil out of urate levels very rapidly.' DR. WORTMANN

A proton density image of the foot of a gout patient shows the low- to intermediate-signal tophus. ©American College of Rheumatology Clinical Slide Collection 1972–2004

For a related video with Dr. Wortmann, go to www.youtube.com/InternalMedicineNews

FORT LAUDERDALE, FLA. — The likely approval of febuxostat for the treatment of gout means that there soon will be an alternative for the underserved group of patients with severe disease who cannot tolerate allopurinol.

No new urate-lowering treatments have been approved for gout since 1964, but the advisory panel of the Food and Drug Administration voted 12-0, with 1 abstention, in favor of approval for this nonpurine selective xanthine oxidase inhibitor. Although the FDA is not required to follow the recommendations of its advisory panel, it usually does so.

Febuxostat is structurally distinct from allopurinol, another xanthine oxidase inhibitor that also exerts inhibitory activity on other enzymes involved in purine and pyrimidine metabolism, according to Dr. Robert L. Wortmann, professor of medicine, Dartmouth-Hitchcock Medical Center, Lebanon, N.H.

Experience to date with febuxostat in more than 4,000 patients has shown that, unlike with allopurinol, there appears to be no need for dose adjustment in patients with mild to moderate renal dysfunction. Dosage concerns exist for patients with renal insufficiency taking allopurinol, because of the possible occurrence of toxic epidermal necrolysis.

There also have been no reports of hypersensitivity reactions, even among patients who previously had such reactions to allopurinol, most likely because of the two drugs' differences in structure, Dr. Wortmann said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

In a phase III clinical trial, 81% of patients receiving 80 mg febuxostat per day had serum urate levels below 6 mg/dL after 52 weeks of therapy, compared with 39% of patients receiving 300 mg allopurinol per day (N. Engl. J. Med. 2005;353:2450–61).

“It seems to be a very effective drug,” said Dr. Wortmann, who is a consultant to Takeda Pharmaceutical Co., the manufacturer of febuxostat.

Although not all patients can tolerate allopurinol, that drug also is effective. However, it often is not prescribed in sufficiently high doses, with 97% of prescriptions in this country being for 300 mg/day or less, according to Dr. Wortmann. The drug is approved for doses up to 800 mg/day.

The goal of antihyperuricemic therapy is to lower the serum urate to 5–6 mg/dL. “If you lower the urate from 12 mg/dL to 7 or 7.5 mg/dL with allopurinol, it seems like you are helping but all you are doing is retarding the rate at which the crystals will deposit,” he said.

Regardless of what urate-lowering agent is chosen, the lowest dose that brings the serum urate below the target of 6 mg/dL should be used.

Another agent being investigated for gout is uricase, which converts urease to the more soluble allantoin. A commercially available formulation, rasburicase, is used for the treatment of tumor lysis syndrome. Although that drug is very effective for lowering serum urate levels, it carries a black box warning regarding anaphylaxis, Dr. Wortmann said.

Accordingly, two companies have been working on developing pegylated formulations, based on the principle that the polyethylene glycol would make uricase less antigenic and increase the half-life. Dr. Wortmann disclosed that he is also a consultant to Savient Pharmaceuticals Inc., the manufacturer of one of these formulations, Puricase.

“In trials this agent has knocked the devil out of urate levels very rapidly,” he said. However, the number of dropouts has been high in these trials, primarily because of allergic and infusion reactions.

“Whether that can be alleviated by giving a more dilute form of the drug or giving it over longer periods of time, I'm not sure,” he said.

There also have been a number of deaths during trials of uricase, although apparently none of these deaths could be attributed to the drug. For example, one patient who died was a 92-year-old man with severe tophaceous gout who had had three bypass surgeries and a stroke previously, and who succumbed to heart disease.

“I think the investigators were not as selective as they could have been in patient selection, which is unfortunate because this to me would be an exciting alternative for patients with severe tophaceous gout. Uricase could be given for a few doses to get the urate really low and mobilize the crystals as much as possible, and then the patient could be maintained on another agent once it's under control,” he said.

SDEF and this news organization are owned by Elsevier.

'In trials [uricase] has knocked the devil out of urate levels very rapidly.' DR. WORTMANN

A proton density image of the foot of a gout patient shows the low- to intermediate-signal tophus. ©American College of Rheumatology Clinical Slide Collection 1972–2004

For a related video with Dr. Wortmann, go to www.youtube.com/InternalMedicineNews

FORT LAUDERDALE, FLA. — The likely approval of febuxostat for the treatment of gout means that there soon will be an alternative for the underserved group of patients with severe disease who cannot tolerate allopurinol.

No new urate-lowering treatments have been approved for gout since 1964, but the advisory panel of the Food and Drug Administration voted 12-0, with 1 abstention, in favor of approval for this nonpurine selective xanthine oxidase inhibitor. Although the FDA is not required to follow the recommendations of its advisory panel, it usually does so.

Febuxostat is structurally distinct from allopurinol, another xanthine oxidase inhibitor that also exerts inhibitory activity on other enzymes involved in purine and pyrimidine metabolism, according to Dr. Robert L. Wortmann, professor of medicine, Dartmouth-Hitchcock Medical Center, Lebanon, N.H.

Experience to date with febuxostat in more than 4,000 patients has shown that, unlike with allopurinol, there appears to be no need for dose adjustment in patients with mild to moderate renal dysfunction. Dosage concerns exist for patients with renal insufficiency taking allopurinol, because of the possible occurrence of toxic epidermal necrolysis.

There also have been no reports of hypersensitivity reactions, even among patients who previously had such reactions to allopurinol, most likely because of the two drugs' differences in structure, Dr. Wortmann said at a meeting sponsored by RHEUMATOLOGY NEWS and Skin Disease Education Foundation.

In a phase III clinical trial, 81% of patients receiving 80 mg febuxostat per day had serum urate levels below 6 mg/dL after 52 weeks of therapy, compared with 39% of patients receiving 300 mg allopurinol per day (N. Engl. J. Med. 2005;353:2450–61).

“It seems to be a very effective drug,” said Dr. Wortmann, who is a consultant to Takeda Pharmaceutical Co., the manufacturer of febuxostat.

Although not all patients can tolerate allopurinol, that drug also is effective. However, it often is not prescribed in sufficiently high doses, with 97% of prescriptions in this country being for 300 mg/day or less, according to Dr. Wortmann. The drug is approved for doses up to 800 mg/day.

The goal of antihyperuricemic therapy is to lower the serum urate to 5–6 mg/dL. “If you lower the urate from 12 mg/dL to 7 or 7.5 mg/dL with allopurinol, it seems like you are helping but all you are doing is retarding the rate at which the crystals will deposit,” he said.

Regardless of what urate-lowering agent is chosen, the lowest dose that brings the serum urate below the target of 6 mg/dL should be used.

Another agent being investigated for gout is uricase, which converts urease to the more soluble allantoin. A commercially available formulation, rasburicase, is used for the treatment of tumor lysis syndrome. Although that drug is very effective for lowering serum urate levels, it carries a black box warning regarding anaphylaxis, Dr. Wortmann said.

Accordingly, two companies have been working on developing pegylated formulations, based on the principle that the polyethylene glycol would make uricase less antigenic and increase the half-life. Dr. Wortmann disclosed that he is also a consultant to Savient Pharmaceuticals Inc., the manufacturer of one of these formulations, Puricase.

“In trials this agent has knocked the devil out of urate levels very rapidly,” he said. However, the number of dropouts has been high in these trials, primarily because of allergic and infusion reactions.

“Whether that can be alleviated by giving a more dilute form of the drug or giving it over longer periods of time, I'm not sure,” he said.

There also have been a number of deaths during trials of uricase, although apparently none of these deaths could be attributed to the drug. For example, one patient who died was a 92-year-old man with severe tophaceous gout who had had three bypass surgeries and a stroke previously, and who succumbed to heart disease.

“I think the investigators were not as selective as they could have been in patient selection, which is unfortunate because this to me would be an exciting alternative for patients with severe tophaceous gout. Uricase could be given for a few doses to get the urate really low and mobilize the crystals as much as possible, and then the patient could be maintained on another agent once it's under control,” he said.

SDEF and this news organization are owned by Elsevier.

'In trials [uricase] has knocked the devil out of urate levels very rapidly.' DR. WORTMANN

A proton density image of the foot of a gout patient shows the low- to intermediate-signal tophus. ©American College of Rheumatology Clinical Slide Collection 1972–2004