A number of studies in gout presented updates on the two agents that can be helpful in patients who cannot tolerate allopurinol.
Febuxostat, a non-purine xanthine oxidase inhibitor, is the most promising drug to be FDA approved in the near future for allopurinol-intolerant patients. Prior work on febuxostat have found it to have hepatic metabolism and to have no increase in half-life in patients with renal insufficiency. Only 5% of the drug is excreted in the urine as unchange drug. Earlier studies have not suggested any cross-allergenicity with allopurinol. If studies continue to find this drug efficacious and well-tolerated, patients with both renal insufficiency and those with allopurinol intolerance will have a new and important option.
PEGylated uricase has made the use of uricase closer to a potential reality by prolonging the half-life sufficiently that chronic treatment is possible, although still likely burdensome. Uricase studies have not gotten past Phase 2 but Phase 3 studies of febuxostat were presented.
A Phase 2 study of febuxostat was presented as a poster[1](see full abstract below), and included 116 patients. 91% were male, 22% had tophi and 12% had history of kidney stones. 22% had cardiovascular disease and 67% were overweight, with BMI > 30. The subjects began the trial at 80mg daily febuxostat, and after 4 weeks a dosage adjustment was permitted. Colchicine prophylaxis, 0.6mg bid, was provided for the first month. At each visit 74-81% of subjects had serum urate < 6.0. The drug was well-tolerated. 9% of subjects had diarrhea, five of whom were receiving colchicine. Headaches (4%) and liver function tests (4%) were also noted. The drug was found to be effective in lowering uric acid and to be well tolerated.
Another study with febuxostat confirmed that tophi shrink when the serum urate is kept < 6.0[2] (see full abstract below). Looked at with MRI, a small study looking at 9 patients, showed that tophus volume decreased in patients where the urate was <6.0 and increased when it was >6.0.
Gout flares were evaluated in 153 patients on febuxostat in a 24 month study[3] (see full abstract below). Gouty flares decreased in a step-wise manner over the two years, so long as serum urate was kept < 6.0. Colchicine was given for the first month of febuxostat treatment, and flares increased when it was stopped. Early flares peaked at 3 months, with 58% flare at that time, which decreased after that. The authors suggested that using colchicine for at least 3 months after starting a urate-lowering agent was supported by their study.
Since febuxostat has hepatic metabolism, the effect of mild to moderate hepatic insufficiency was investigated[4] (see full abstract below). Giving 80mg daily for 7 days, the pharmacokinetics and metabolites were not affected in a clinically meaningful way, nor was the degree of lowering of serum urate. Patients with even moderate hepatic dysfunction tolerated the drug well.
A phase 3 study from Japan[5] (see full abstract below) compared febuxostat to allopurinol in 256 patients in a 44 day treatment study. Febuxostat 40mg lowered uric acid better than 200mg of allopurinol, and febuxostat was well-tolerated.
Febuxostat is thus the new agent for gout which is the closest to potential clinical availability, and so far appears effective, to have a low incidence of serious side-effects, and to offer some significant advantages over allopurinol (e.g. minimal renal excretion and no apparent cross-allergenicity).
In an earlier stage of evaluation is PEGylated uricase (Puricase®). PEGylation appearing to have succeeded in significantly increasing its half-life over presently available uricase for infusion. A single intravenous dose, in a Phase 1 trial,[6] (see full abstract below) lowered urate to desired levels for 14 to 21 days. A phase 2 study is in progress, looking at repeated infusions. The single infusion was without side effects, other than some patients experiencing gout flares, and 3 of 24 complaining of transient dizziness.
Data from the 2004 ACR provided more hope for new agents for gout than rheumatologists have seen for years. Patients presently intolerant of allopurinol, or with renal insufficiency, may see significant improvements in their therapy in the near future.
Abstracts
1. Phase 2, Long Term Open-Label Safety and Efficacy Study of Febuxostat, A Novel Non-Purine, Selective Inhibitor of Xanthine Oxidase
Category: 13 Metabolic and crystal arthropathies
HR Schumacher1, R. Wortmann2, MA Becker3, P. MacDonald4, WA Palo4, D. Eustace4, J. Streit4, N. Joseph-Ridge4. 1University of Pennsylvania/VAMC, Philadelphia, PA; 2University of Oklahoma, Tulsa, OK; 3University of Chicago, Chicago, IL; 4TAP Pharmaceutical Products Inc., Lake Forest, IL
Presentation Number: 800
Poster Board Number: 180
Purpose: Febuxostat is a novel, non-purine, selective inhibitor of xanthine oxidase (NP-SIXO), which is being developed for the management of hyperuricemia in patients with gout. This on-going Phase 2 study is a long-term, open-label extension of a 4-week, double-blind, placebo-controlled study evaluating the safety and efficacy of febuxostat.
Subjects and Methods: Subjects with gout and serum uric acid levels (sUA) > 8.0 mg/dL, who completed the initial Phase 2, 4-week, double-blind, placebo-controlled, dose-response study, were eligible to participate. Subjects initially received febuxostat 80 mg/day. At Week 4 and at subsequent visits, dose titration to either 40 mg or 120 mg/day was permitted, based on sUA and adverse event (AE) reporting. Subjects were to achieve a stable febuxostat dose by Week 28. Colchicine 0.6 mg twice daily was provided as gout flare prophylaxis during the first 4 weeks of treatment.
Results: Subjects [116 (76% of the placebo-controlled cohort)] enrolled in the open-label extension study, with 69 (59%) subjects participating for at least 24 months. The majority of subjects were male (91%), Caucasian (85%), and > 45 years of age (73%). In this group, 22% had palpable tophi and 12% a history of kidney stones. Comorbidities included a history of hypertension (52%), hyperlipidemia (46%), cardiovascular disease (22%), and BMI > 30 kg/m2 (67%). The majority of subjects (63%) did not require a change in dose from febuxostat 80 mg/day. For 72% of subjects, the stable dose was 80mg/day; for 20%, 120-mg/day; and for 9%, 40 mg/day. At each visit, most subjects (74% to 81%) had sUA < 6.0 mg/dL. The mean percent reduction from baseline in sUA at each visit ranged from 45% to 48%. The most common treatment-related AEs were diarrhea [10 subjects, (9%), five of whom were also receiving colchicine], and headaches [5 (4%)]. Five subjects (4%) had increases in liver function tests, reported as treatment-related adverse events, that were also associated with concomitant colchicine use. The majority of the adverse events were mild or moderate in severity. Twelve subjects reported serious adverse events; all were considered unrelated or unlikely related to febuxostat use.
Conclusions: In the great majority of subjects with gout and hyperuricemia, long term (2 years) treatment with febuxostat resulted in significant reduction in and maintenance of sUA < 6.0 mg/dL. Febuxostat doses of 40, 80, and 120 mg daily were safe and well tolerated in long-term use.
2. Magnetic Resonance Imaging of Gouty Tophi During Treatment with Febuxostat, a Non-Purine Selective Inhibitor of Xanthine Oxidase
Category: 13 Metabolic and crystal arthropathies
HR Schumacher1, MA Becker2, R. Wortmann3, P. MacDonald4, WA Palo4, J. Streit4, C. Lademacher4, N. Joseph-Ridge4. 1University of Pennsylvania/VAMC, Philadelphia, PA; 2University of Chicago, Chicago, IL; 3University of Oklahoma, Tulsa, OK; 4TAP Pharmaceutical Products Inc., Lake Forest, IL
Presentation Number: 802
Poster Board Number: 182
Purpose: Gouty tophi are crystalline aggregates of monosodium urate located primarily in connective tissue and bone of a subset (20-25%) of gout patients. No accepted standardized tool is available for monitoring tophaceous gout, limiting the ability to track tophus progression or regression. MRI has been suggested as a sensitive modality to detect small tophi, determine extent of involvement, and measure tophus volume. MRI was utilized to determine the change in tophus volume in subjects treated with febuxostat, a non-purine selective inhibitor of xanthine oxidase (NP-SIXO).
Subjects and Methods: Nine subjects with gouty tophi, who were among those participating in a Phase 2, open-label study with febuxostat, underwent pre- and post-contrast MRI on 2 occasions 2 to 6 months apart. Subjects initially received treatment with febuxostat 80 mg/day and the dose was titrated to 40 mg or 120 mg/day based on serum uric acid levels (sUA) or adverse events. Anatomic sites imaged included the hand, wrist, elbow, knee and foot. The quantitative variable was the volume (cm3) of pre-selected tophi, measured by a radiologist from MR scans performed using a specified MRI protocol.
Results: Two MRI scans were performed on 9 subjects during the course of treatment with febuxostat. Eight tophi could be visualized and measured in MRIs from 6 subjects. Tophus volumes decreased in subjects with sUA <6.0 mg/dL and increased in subjects with sUA >6.0 mg/dl. In one subject, one of 2 tophi was reduced in volume despite sUA of 6.2 and 6.5 mg/dL.
3. Gout Flare Prophylaxis During Management of Chronic Gout with Febuxostat, A Non-Purine Selective Inhibitor of Xanthine Oxidase
Category: 13 Metabolic and crystal arthropathies
R. Wortmann1, MA Becker2, HR Schumacher3, P. MacDonald4, WA Palo4, N. Joseph-Ridge4. 1University of Oklahoma, Tulsa, OK; 2University of Chicago, Chicago, IL; 3University of Pennsylvania/VAMC, Philadelphia, PA; 4TAP Pharmaceutical Products Inc., Lake Forest, IL
Presentation Number: 801
Poster Board Number: 181
Purpose: Prophylactic treatment with colchicine is often prescribed to prevent acute flares of gout when antihyperuricemic therapy is initiated. Because initiation of treatment with febuxostat, a non-purine selective inhibitor of xanthine oxidase (NP-SIXO), could precipitate acute gout flares, prophylactic colchicine was prescribed for subjects in Phase 2 trials.
Subjects and Methods: Subjects with gout and serum uric acid (sUA) >8.0 mg/dL were enrolled in a 4-wk double-blind study (febuxostat 40 mg, 80 mg, 120 mg/day or placebo). Prophylactic colchicine 0.6 mg twice daily was given during a 2-wk antihyperuricemic drug washout period preceding and for 2 wk after the beginning of double-blind therapy. Subjects were then eligible to participate in an ongoing open-label extension, initially receiving febuxostat 80 mg/day and titrating to either 40 or 120 mg based on sUA and adverse event (AE) reporting. Colchicine prophylaxis was provided during initiation of each study.
Results: The majority of the 153 subjects enrolled in the double-blind study were male (89%), = 45 years of age (76%) and Caucasian (87%). In the double-blind study, gout flare incidence during co-administration of colchicine and febuxostat 40, 80, 120 mg or placebo was 8%, 8%, 13% and 11%, respectively, compared with 30%, 40%, 42% and 34%, respectively, during febuxostat 40, 80, 120 mg or placebo administration alone. Subjects (116) with similar demographics participated in the open-label study with the majority (74% - 81%) of subjects achieving a sUA <6.0 mg/dL at each visit. Gout flare incidence was lower during colchicine prophylaxis (10% at 1 mo) than in the preceding febuxostat-alone period, but, after cessation of colchicine prophylaxis, flare rates increased (58% at 3 mo) then gradually declined over time (35% at 6 mo, 26% at 1 yr, and 17% at 2 yr). The most common long-term treatment-related AEs were diarrhea [10 subjects (9%), 5 with alternate etiology of colchicine administration], and headaches [5 subjects (4%)]. Five subjects (4%) had abnormal liver function tests reported as treatment-related AEs that were also associated with concomitant colchicine. The majority of long-term AEs were mild or moderate in severity and all serious AEs (reported by 12 subjects) were considered not or unlikely to be related to febuxostat.
Conclusions: Prophylaxis with colchicine was associated with a decreased incidence of gout flares in hyperuricemic gout subjects given either febuxostat or placebo. Long term (2 years) treatment with febuxostat and maintenance of sUA <6.0 mg/dL was associated with a step-wise decrease in the incidence of acute gout flares. These observations suggest that in many gout patients colchicine prophylaxis be continued longer than 3 months after initiating a potent urate lowering agent.
4. Febuxostat, a Non-Purine Selective Inhibitor of Xanthine Oxidase - Effect of Mild and Moderate Hepatic Impairment on Pharmacokinetics, Pharmacodynamics, and Safety
Category: 13 Metabolic and crystal arthropathies
R. Khosravan, M. Mayer, B. Grabowski, L. Vernillet, JT Wu, N. Joseph-Ridge. TAP Pharmaceutical Products Inc., Lake Forest, IL
Presentation Number: 806
Poster Board Number: 186
Purpose: To evaluate the effect of mild and moderate hepatic impairment on pharmacokinetics (PK), pharmacodynamics (PD), and safety of febuxostat, a non-purine selective inhibitor of xanthine oxidase (NP-SIXO).
Methods: Male and female subjects (39-62 years) with normal hepatic function (n=11), and with mild (Child-Pugh Class A, n=8) and moderate (Child Pugh Class B, n=8) hepatic dysfunction received once daily 80 mg oral doses of febuxostat for 7 days. Blood and urine samples were collected up to 24 h post-dose on Day 7. Concentrations of febuxostat and its major active metabolites (67-M1, 67-M2 and 67-M4) in plasma and urine, and those of hypoxanthine, xanthine, and uric acid in serum and urine were determined by HPLC or LC/MS/MS. Plasma protein binding of febuxostat was also assessed using equilibrium dialysis.
Results: The mean (±SD) plasma PK and serum PD parameters are presented in the following table:
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The differences in the mean percent change in serum uric acid Cmean,24 between subjects with normal hepatic function and those with hepatic impairment were statistically significant (p-value of 0.005 and 0.003 for mild and moderate, respectively), but were not considered clinically significant. All adverse events were mild and self-limiting with the most frequently reported being diarrhea, abdominal pain, headache, and urinary frequency.
Conclusions: There was no clinically significant change in the PK and PD parameters of febuxostat with increasing hepatic impairment in this study. In addition, febuxostat 80 mg was safe and well tolerated regardless of the degree of hepatic dysfunction. Therefore, dose adjustments for febuxostat in subjects with mild or moderate hepatic impairment are not necessary.
5. Febuxostat, a Novel Non-Purine Selective Inhibitor of Xanthine Oxidase, in an Allopurinol-controlled Phase III Clinical Trial in Japanese Subjects with Gout or Hyperuricemia
Category: 13 Metabolic and crystal arthropathies
Naoyuki Kamatani1, Shin Fujimori2, Toshikazu Hada3, Tatsuo Hosoya4, Yuji Matsuzawa5, Takanori Ueda6, Hisashi Yamanaka1, Ryuichi Kato7. 1Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan; 2Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan; 3Hyogo College of Medicine, Nishinomiya Hyogo, Japan; 4Jikei University School of Medicine, Minato-ku, Tokyo, Japan; 5Sumitomo Hospital, Kita-ku, Osaka, Japan; 6University of Fukui, Matsuoka Fukui, Japan; 7Keio University, Shinjuku-ku, Tokyo, Japan
Presentation Number: 804
Poster Board Number: 184
Purpose: Febuxostat is a non-purine selective inhibitor of xanthine oxidase (NP-SIXO) which binds to the enzyme in a mode different from allopurinol and oxypurinol. We conducted a Phase III clinical trial to evaluate efficacy and safety of febuxostat compared to allopurinol in Japanese subjects with gout or hyperuricemia.
Methods: It was a multicenter, allopurinol-controlled, double-dummy, double-blind, parallel group comparative study conducted in 256 subjects with gout or hyperuricemia [sUA >= 8.0 mg/dL]. Subjects were randomized to either allopurinol or febuxostat group (128 each), and treated with allopurinol 100 mg QD or febuxostat 10 mg QD for 12 days-introductory phase, and then allopurinol 100 mg BID (200 mg/day) or febuxostat 40 mg QD for respective groups for 44 days-treatment phase.
Results: Percent decreases in sUA levels at the end of treatment compared to baseline were 40.5 and 33.9% for febuxostat and allopurinol groups, respectively. The sUA reduction by febuxostat was significantly greater than allopurinol (P<0.001). The proportions of subjects with sUA levels <= 6.0 mg/dL differed significantly between treatment groups [105/128 (82.0%) and 87/126 (69.0 %); P=0.019]. For febuxostat, percent decreases in sUA levels for subjects with under-excretors ( ( uUA×sCre ) / ( uCre×sUA )×100 <= 5.5; over producers, normal types ) were 41.3 and 41.4%, respectively. In contrast, they were 34.7 and 34.4%, respectively for allopurinol.
Among 255 subjects, at least one adverse event (AE) was observed in 91/128 (71.1%) of febuxostat-treated and 83/127 (65.4%) of allopurinol-treated subjects. The most frequently reported AEs for febuxostat included nasopharyngitis and gout flare. The majority of AEs were mild in severity and had subsided by the end of the study. Adverse drug reactions were reported in 11/128 (8.6%) of febuxostat-treated and 14/127 (11.0%) of allopurinol-treated subjects. No serious adverse drug reactions were observed in either of groups.
Conclusion: Febuxostat (40 mg QD) was significantly more potent in reducing sUA levels compared to allopurinol (100 mg BID (200 mg/day)). In addition febuxostat reduced the sUA levels to equivalent degrees in under-excretors and in non-under-excretors. Febuxostat 40 mg QD was safe and well tolerated. Present study suggested that febuxostat is a safe and effective drug for the treatment of gout or hyperuricemia.
6. A Phase I Study of Pegylated-Uricase (Puricase®) in Subjects with Gout
Category: 13 Metabolic and crystal arthropathies
John S. Sundy, Nancy Ganson, Susan J. Kelly, Edna L. Scarlett, Michael S. Hershfield. Duke University Medical Center, Durham, NC
Presentation Number: 807
Poster Board Number: 187
Purpose: To determine the pharmacokinetic profile and safety of a single intravenous dose of pegylated (PEG)-uricase (Puricase®) in subjects with gout.
Methods: 24 adult subjects (4 per group) with symptomatic gout received recombinant porcine PEG-uricase as a single dose of 0.5 mg, 1 mg, 2 mg, 4 mg, 8 mg, or 12 mg. Uric acid lowering therapy was discontinued for one week prior to dosing. Inclusion criteria included: a physician diagnosis of gout; baseline serum uric acid >7 mg/dL; and one of the following - acute gout flare within the previous 6 months, tophi, or chronic gout arthritis. Subjects were excluded if they had end-stage renal disease, ongoing immunosuppressive therapy, or prednisone dose >10 mg/d. Subjects were followed-up for 35 days after dosing. Plasma samples were assessed for uricase activity and uric acid concentration at various time points for 21 days. The urine uric acid/creatinine ratio was also determined. Safety and tolerability were assessed by clinical and laboratory evaluation.
Results: 24 subjects (20 male: 4 female) were enrolled and completed the study. Mean age was 56.7 years. Tophi were present in 75% of the subjects. The mean plasma uric acid concentration at baseline was 11.0 mg/dL. Dose proportional responses were observed for: Cmax of plasma uricase activity, maximum reduction in plasma uric acid, and area under the curve for both plasma uricase activity and uric acid concentration. The half-life of plasma uricase activity ranged from 153-332 hours.
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In the 4 mg, 8 mg, and 12 mg dose groups, plasma uric acid levels normalized within 24 hours in all subjects and remained normal in 9/12 subjects after 14 days. Importantly, the average daily uric acid concentration calculated over 21 days was less than 6 mg/dL in the 3 highest dose groups. A marked decline in the urine uric acid/creatinine ratio paralleled the fall in plasma uric acid concentration. There were no severe or serious adverse events. Common adverse events included gout flares (20 flares in 14 subjects), arthralgias (6 subjects), and transient dizziness (3 subjects). Low titer antibodies to PEG-uricase were detected in 9 subjects and were not associated with any adverse events (see abstract by N. Ganson et al).
Conclusions: A single dose of intravenous PEG-uricase was well tolerated and resulted in effective lowering of plasma and urine uric acid levels. Most subjects in the 3 highest dose groups had sustained reduction of plasma uric acid below 6 mg/dL for at least 14 days; and in many cases for 21 days. These results support the use of PEG-uricase in treating patients with severe gout. Phase II studies are underway to assess the efficacy and safety of repeated administration of PEG-uricase in subjects with refractory gout.
[1] Schumacher et al: A phase 2, Long-Term Open-Label Safety and Efficacy Study of Febuxostat, a Novel Non-Purine Selective Inhibitor of Xanthine Oxidase. Arthritis Rheum Suppl: , 2004.
[2] Schumacher et al: Magnetic Resonance Imaging of Gouty Tophi During Treatment with Febuxostat, a Non-Purine Selective Inhibitor of Xanthine Oxidase. Arthritis Rheum Suppl: , 2004.
[3] Wortmann et al: Gout Flare Prophylaxis During Management of Chronic Gout with Febuxostat, A Non-Purine Selective Inhibitor of Xanthine Oxidase. Arthritis Rheum Suppl: , 2004.
[4] Khosravan et al: Febuxostat, a Non-Purine Selective Inhibitor of Xanthine Oxidase - Effect of Mild and Moderate Hepatic Impairment on Pharmacokinetics, Pharmacodynamics, and Safety. Arthritis Rheum Suppl: , 2004.
[5] Kamatani et al: Febuxostat, a Novel Non-Purine Selective Inhibitor of Xanthine Oxidase, in an Allopurinol-controlled Phase III Clinical Trial in Japanese Subjects with Gout or Hyperuricemia. Arthritis Rheum Suppl: , 2004.
[6] Sundy et al: A Phase I Study of Pegylated-Uricase (Puricase®) in Subjects with Gout. Arthritis Rheum Suppl: , 2004.
