Update on Gout Management: What Is Old and What Is New

Drugs in the Pipeline

There are numerous drugs that are currently in the pipeline for gout management, some of which are summarized in Table 2. The general categories of drug mechanisms being explored are related to renal urate excretion, minimizing immunogenicity of uricase-based therapy, additional targets on the purine metabolism pathway and leveraging the gastrointestinal system for urate excretion. In addition, IL-1 inhibition and inflammasome targets are among the programmes in development for gout flare management.

Table 1. Approved urate-lowering therapies currently available on the market in the USA
Drug (FDA approval date)	Dosing and considerations in CKD	Select side effects	Select drug interactions/considerations
Allopurinol (1966)	Start at dose ≤100 mg/day and titrate by ≤100 mg every 2–4 weeks to goal serum urate; max FDA recommended dose 800 mg/day GFR<30: start at 50 mg/day and titrate by 50 mg every 2–4 weeks to goal serum urate. Okay to use in patients with ESRD on dialysis	• Mobilization gout flares when initiating ULT • Rash • Haematologic abnormalities • Hepatotoxicity • AHS/DRESS syndrome especially if HLA-B58 : 01 positive	• Potentiation of immunosuppressive effects of azathioprine and 6-mercapropurine • Increased likelihood of ampicillin induced rash
Febuxostat (2009)	Start at 40 mg/day and titrate to 80 mg/day if serum urate not at goal GFR 15–29 ml/min: doses above 40 mg/day not recommended per FDA label, but studies indicate that doses up to 80 mg/day may be safe Limited data on febuxostat use in patients with ESRD on dialysis	• Mobilization gout flares when initiating ULT • Nausea • Arthralgias • Rash • Unclear potential cardiovascular risk • Hepatic abnormalities • Hypersensitivity reactions/DRESS	• Potentiation of immunosuppressive effects of azathioprine and 6-mercapropurine
Probenecid (1979)	Start at 250 mg twice daily with dose titration to maximal effective dose of 2000 mg/day GFR<30 ml/min: probenecid not recommended due to lack of efficacy in setting of inadequate renal function	• Mobilization gout flares when initiating ULT • Rash, flushing • GI intolerance • Urolithiasis	• Prolonged half-life of penicillin and ampicillin • High dose aspirin may reduce probenecid's uricosuric effect
Pegloticase (2010)	8 mg i.v. every 2 weeks Check serum urate prior to each infusion after first dose, and stop if serum urate > 6 mg/dl No dose adjustment needed in patents with CKD or ESRD on dialysis *Discontinue all ULT prior to initiation of pegloticase to avoid masking loss of urate response	• Contraindicated in G6PD deficiency (haemolysis, methemoglobulinemia) • Mobilization gout flares • Nausea, vomiting • Anaphylaxis and serious infusion reactions related to antidrug antibodies • Caution in patients with CHF

Table 1. Approved urate-lowering therapies currently available on the market in the USA

Drug (FDA approval date)

Dosing and considerations in CKD

Select side effects

Select drug interactions/considerations

Allopurinol (1966)

Start at dose ≤100 mg/day and titrate by ≤100 mg every 2–4 weeks to goal serum urate; max FDA recommended dose 800 mg/day
GFR<30: start at 50 mg/day and titrate by 50 mg every 2–4 weeks to goal serum urate. Okay to use in patients with ESRD on dialysis

• Mobilization gout flares when initiating ULT
• Rash
• Haematologic abnormalities
• Hepatotoxicity
• AHS/DRESS syndrome especially if HLA-B58 : 01 positive

• Potentiation of immunosuppressive effects of azathioprine and 6-mercapropurine
• Increased likelihood of ampicillin induced rash

Febuxostat (2009)

Start at 40 mg/day and titrate to 80 mg/day if serum urate not at goal
GFR 15–29 ml/min: doses above 40 mg/day not recommended per FDA label, but studies indicate that doses up to 80 mg/day may be safe
Limited data on febuxostat use in patients with ESRD on dialysis

• Mobilization gout flares when initiating ULT
• Nausea
• Arthralgias
• Rash
• Unclear potential cardiovascular risk
• Hepatic abnormalities
• Hypersensitivity reactions/DRESS

• Potentiation of immunosuppressive effects of azathioprine and 6-mercapropurine

Probenecid (1979)

Start at 250 mg twice daily with dose titration to maximal effective dose of 2000 mg/day
GFR<30 ml/min: probenecid not recommended due to lack of efficacy in setting of inadequate renal function

• Mobilization gout flares when initiating ULT
• Rash, flushing
• GI intolerance
• Urolithiasis

• Prolonged half-life of penicillin and ampicillin
• High dose aspirin may reduce probenecid's uricosuric effect

Pegloticase (2010)

8 mg i.v. every 2 weeks
Check serum urate prior to each infusion after first dose, and stop if serum urate > 6 mg/dl
No dose adjustment needed in patents with CKD or ESRD on dialysis
*Discontinue all ULT prior to initiation of pegloticase to avoid masking loss of urate response

• Contraindicated in G6PD deficiency (haemolysis, methemoglobulinemia)
• Mobilization gout flares
• Nausea, vomiting
• Anaphylaxis and serious infusion reactions related to antidrug antibodies
• Caution in patients with CHF

Table 2. Ongoing clinical trials in gout ^a
Drug	Mechanism of action	Study phase
Urate-lowering therapy
Inhibition of urate reabsorption in the kidney
Dotinurad	Inhibitor of urate transporter 1 (URAT1)	Phase 3
SHR4640	Inhibitor of URAT1	Phase 3
SAP-001	Inhibitor of URAT1	Phase 2
D-0120	Inhibitor of URAT1	Phase 1/2
XNW3009	Small molecule hURAT1 inhibitor	Phase 1
AC-201^b	Inhibitor of production and activity of caspase-1 and Il-1b and selective inhibitor of re-absorption transporters in kidney	Phase 2
Xanthine oxidase inhibitors
ABP-671	Novel xanthine oxidase inhibitor	Phase 2
LC350189	Novel xanthine oxidase inhibitor	Phase 1
Metabolizers of serum urate
SEL-212	Combination product of pegadricase, proprietary pegylated uricase, coadministered with ImmTOR, designed to mitigate formation of antidrug antibodies	Phase 3
ALLN-346	Engineered urate oxidase that acts in the gastrointestinal tract	Phase 2
SSS11	PEGylated recombinant candida urate oxidase	Phase 1
Gout flare management
RPH-104	Novel heterodimeric fusion protein that inhibits IL-1	Phase 2
AC-201^b	Inhibitor of production and activity of caspase-1 and Il-1b and selective inhibitor of re-absorption transporters in kidney	Phase 2
Anakinra in CKD or renal transplant	IL-1 receptor antagonist	Phase 2/3
Adrenocorticotropic hormone (ACTH)	Activation of melanocortin type 3 receptor; adrenal corticosteroid release	n/a

Table 2. Ongoing clinical trials in gout ^a

Drug

Mechanism of action

Study phase

Urate-lowering therapy

Inhibition of urate reabsorption in the kidney

Dotinurad

Inhibitor of urate transporter 1 (URAT1)

Phase 3

SHR4640

Inhibitor of URAT1

Phase 3

SAP-001

Inhibitor of URAT1

Phase 2

D-0120

Inhibitor of URAT1

Phase 1/2

XNW3009

Small molecule hURAT1 inhibitor

Phase 1

AC-201^b

Inhibitor of production and activity of caspase-1 and Il-1b and selective inhibitor of re-absorption transporters in kidney

Phase 2

Xanthine oxidase inhibitors

ABP-671

Novel xanthine oxidase inhibitor

Phase 2

LC350189

Novel xanthine oxidase inhibitor

Phase 1

Metabolizers of serum urate

SEL-212

Combination product of pegadricase, proprietary pegylated uricase, coadministered with ImmTOR, designed to mitigate formation of antidrug antibodies

Phase 3

ALLN-346

Engineered urate oxidase that acts in the gastrointestinal tract

Phase 2

SSS11

PEGylated recombinant candida urate oxidase

Phase 1

Gout flare management

RPH-104

Novel heterodimeric fusion protein that inhibits IL-1

Phase 2

AC-201^b

Inhibitor of production and activity of caspase-1 and Il-1b and selective inhibitor of re-absorption transporters in kidney

Phase 2

Anakinra in CKD or renal transplant

IL-1 receptor antagonist

Phase 2/3

Adrenocorticotropic hormone (ACTH)

Activation of melanocortin type 3 receptor; adrenal corticosteroid release

n/a

Update on Gout Management: What Is Old and What Is New

Drugs in the Pipeline

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

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