Description:
Pegloticase (Krystexxa^™) has been indicated for the treatment of chronic gout in adult patients who remain refractory to conventional therapy. Pegloticase (Krystexxa^™) is a PEGylated uric acid specific enzyme that reduces serum uric acid levels by catalyzing the oxidation of uric acid to allantoin.

Pegloticase (Krystexxa^™) is a pegylated uric acid specific enzyme that consists of recombinant modified mammalian urate oxidase produced by a genetically modified strain of Escherichia coli (Krystexxa^™ prescribing information, 2010). It is approved for the treatment of chronic gout in adult patients refractory to conventional therapy.

Policy:
Krystexxa is MEDICALLY NECESSARY when the member meets four of the five criteria listed below:  

1. Patient has a diagnosis of symptomatic chronic gout (e.g.,at least 1 tophi or gouty arthropathy, radiographic changes of gout, multiple joint involvement, associated uric acid nephrolithiasis, symptomatic gout with at least 3 gout flares in the previous 18 months).  
2. The patient has a baseline serum uric acid level of at least 8 mg/dL.  
3. The patient is currently (within the last 30 days) receiving prophylaxis for gout flares with NSAIDS or colchicine or both.
4. Patient has tried but had a documented inadequate response (defined as uric acid  levels > 6 mg/dL) at least three months of xanthine oxidase (XO) inhibitor therapy (allopurinol and febuxostat) at the maximum medically appropriate dose and a uricosuric agent (probenecid) at the maximum medically appropriate does.
5. Patient was not able to complete a three-month trial of XO inhibitor therapy/uricosuric for one of the following documented clinical reasons:  

• • Patient experienced a severe allergic reaction to the XO inhibitor/uricosuric.
  • Patient experienced toxicity with the XO inhibitor/uricosuric. 
  • Patient could not tolerate the XO inhibitor/uricosuric. 
  • Significant drug interaction with the XO inhibitor/uricosuric.
  • Severe renal dysfunction (for allopurinol only).

Continuation of therapy with Krystexxa is considered MEDICALLY NECESSARY when:  

• Positive clinical response to therapy is demonstrated by both of the following:
  • Serum urate level has decreased since initiating therapy (does not have 2 consecutive uric acid levels > 6 mg/dL while on therapy).
  • There is clinical improvement in the signs and symptoms of gout (e.g., decrease in tophi size or frequency of gouty flares per year from baseline or improvement in chronic arthropathy or quality of life).

Krystexxa is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY for all other indications.

Policy Guidelines:
The following requirements should be documented in the medical records: 

• Copies of pharmacy refill data that demonstrate trials and failures of other therapies.
• Uric acid levels will be monitored prior to each infusion.
• For continuation of therapy, two consecutive uric acid levels must NOT be above 6 mg/dL.
• Patients at high risk for glucose 6-phosphate dehydrogenase (G6PD) deficiency (e.g., African or Mediterranean ancestry) must be screened before initiation of therapy and must have negative results.
• Krystexxa will be administered in a health care setting with access to management of severe anaphylaxis and infusion reactions.
• Patient will be premedicated with antihistamines and corticosteroids prior to each infusion.

Benefit Applications:
Benefits may vary between groups/contracts. Please refer to the appropriate Evidence of Coverage, Subscriber Agreement or Benefit Booklet for applicable infusion coverage/benefits.

Rationale:
Pegloticase injection is a PEGylated uric acid specific enzyme indicated for treatment of chronic gout in adult patients refractory to conventional therapy.¹ Pegloticase injection is made up of a recombinant modified mammalian uricase produced by a genetically modified strain of Escherichia coli that is covalently bonded to monomethoxypoly (ethylene glycol) [mPEG]. It achieves a therapeutic effect by catalyzing the oxidation of uric acid to allantoin. Allantoin is then eliminated, mainly by renal excretion, thus lowering serum uric acid (SUA). The recommended dose of pegloticase injection is 8 mg administered every two weeks over no less than 120 minutes as an intravenous (IV) infusion. 

The safety and efficacy of pegloticase injection were evaluated in adult patients with chronic gout refractory to conventional therapy in two randomized, placebo-controlled, double-blind, six-month replicate studies.^1,2 The studies took place in the United States, Canada and Mexico.² In the pivotal trials, randomized patients (n = 225) were between the ages of 23 and 89 years (mean: 55 years of age) with a mean body mass index (BMI) of 33 kg/m².¹ The majority of the patients were male (82 percent, n = 173) and 67 percent were white/caucasian (n = 143).^1,2 The mean duration of gout in the study patients was 15 years with mean baseline SUA level of 10 mg/dL.¹ The most common coexisting conditions with incidence reported included: hypertension (72 percent), dyslipidemia (49 percent), chronic kidney disease (28 percent), diabetes (24 percent), coronary artery disease (18 percent), arrhythmia (16 percent) and cardiac failure/left ventricular dysfunction (12 percent).¹ Eligible patients were required to have a minimum baseline SUA level of at least 8 mg/dL and one of the following conditions: symptomatic gout with a minimum of three self-reported flares in the previous 18 months, at least one gout tophus or gouty arthritis.^1,2 All patients were also required to have a contraindication to allopurinol (e.g., a history of hypersensitivity or an intolerance or toxicity) OR a history of failure with allopurinol, defined as failure to normalize UA with at least three months of therapy at the maximum appropriate dose.^1,2 Major exclusion criteria included certain major cardiac conditions (e.g., unstable angina, uncontrolled arrhythmia, non-compensated congestive heart failure [CHF], uncontrolled hypertension [HTN; e.g., > 150/95]), dialysis, recipients of solid-organ transplants, pregnancy and glucose-6-phosphate dehydrogenase (G6PD) deficiency.² Patients were required to undergo a 1-week washout if receiving urate-lowering therapy (ULT) and were not allowed to take ULT throughout the study period.² 

In both of the pivotal studies, patients were assigned to treatment with pegloticase injection 8 mg every two weeks, pegloticase injection 8 mg every four weeks or placebo in a 2:2:1 ratio.^1,2 Patients were stratified by the presence or absence of tophi. All patients received prophylaxis for infusion reactions with an oral antihistamine, IV corticosteroid and acetaminophen. Gout flare prophylaxis was provided to all patients with colchicine or non-steroidal anti-inflammatory drugs (NSAIDs) beginning one week prior to initiation of pegloticase.² The primary endpoint in both trials was the proportion of responders,² defined as patients achieving plasma uric acid (PUA) < 6 mg/dL for at least 80 percent of the time during Month 3 and Month 6.^1,2 PUA levels at scheduled visits were recorded at specified times in Month 3 and Month 6.² Other endpoints analyzed include tophus resolution; incidence and frequency of gout flares (during Month 1 through 3 and 4 through 6); tender and swollen joint counts; physical function (Health Assessment Questionnaire Disability Index [HAQ-DI]); and health-related quality of life (HRQL; Short Form [SF] 36). 

The modified intent-to-treat (mITT) population included all randomized patients from both studies who received at least one infusion (n = 212); 74 percent of the mITT population from the pivotal studies (Study 1 and Study 2) (n = 157) completed the trials.² In both studies, more patients treated with either pegloticase regimen achieved the primary endpoint of PUA levels less than 6 mg/dL for at least 80 percent of the time during Month 3 and Month 6.¹ The results of the primary endpoint are available in Table 1.

Table 1.  Primary Endpoint Results From Study 1 and Study 2¹

PUA — plasma uric acid; ^∞At least 80 percent of the time during Month 3 and Month 6; ^*Confidence interval is for difference in responder rate between pegloticase and placebo; ^#Composite P-Value (GOUT1 and GOUT2) is < 0.001 compared to placebo; ^{^}Compared to placebo.

The effect of pegloticase on tophi was assessed in Study 1 and Study 2 as a secondary endpoint.^1,2 Seventy-three percent of patients had at least one tophus at baseline.² In patients with tophi at baseline, significantly more patients experienced complete resolution of ≥ 1 tophus (without progression or appearance of any new tophus) at the final visit in the pegloticase 8 mg every two weeks group compared to placebo.^1,2 However, there was not a statistically significant difference in tophi resolution between the patients who received pegloticase every four weeks and patients who received placebo. Results in patients with measurable tophi⁵ are included in Table 2.

Table 2.  Tophus Resolution (in Patients With Measurable Tophi) in Study 1 and Study 2 (at Final Visit)²

The frequency of gout flares increased significantly in both pegloticase treatment groups compared to placebo in Months 1 through 3.^1,2 During Months 4 through 6, there was not a significant decrease in the frequency of gout flares in patients receiving pegloticase when compared to patients receiving placebo.² However, there was a significant reduction in the proportion of patients with gout flare in the biweekly treatment group compared to the placebo group. Gout flare frequency data are reported in Table 3.

Table 3.  Frequency of Gout Flares in Study 1 and Study 2²

n is the number of patients who experienced gout flares;^*Per patient; ^{^}Compared to placebo; SD — standard deviation.

Other Secondary Endpoints
Both treatment groups of pegloticase experienced significant improvements in quality of life and physical function compared to patients treated with placebo.² Using last observation carried forward (LOCF) analysis, treatment with pegloticase every two weeks was associated with reduced pain (visual analog scale [VAS]) and significant changes from baseline in HAQ-DI and SF-36 Physical Component Summary (PCS) scores.

Extension Study
Patients completing Study 1 and Study 2 were eligible for enrollment in an open-label extension study.⁷ Patients (n = 151; 96 percent of completers) chose to receive up to 24 additional months of treatment with pegloticase 8 mg every two weeks (n = 82), pegloticase 8 mg every four weeks (n = 67) or observation (n = 2).³  In the extension study, patients treated with pegloticase continued to experience a decrease in the incidence and frequency of gout flares. After 30 months of therapy, most patients (50 out of 60 patients) who consistently achieved SUA < 6 mg/dL in Study 1 or Study 2 were able to maintain SUA < 6 mg/dL in the open-label extension study.⁴  After one year of treatment, complete tophus resolution (≥ 1 tophus) occurred in 20 additional patients, including 12 patients who were continuing therapy with pegloticase.³ Following 30 months of therapy, 58 percent of baseline tophi had been eliminated.⁴  Tophus progression occurred in 13 patients, all non-responders. 

References:

1. Conway N, Schwartz S. Diagnosis and management of acute gout. Medicine and Health/Rhode Island;2009;92(11);345-358.
2. Pillinger MH, and Keenan RT. Update on the Management of Hyperuricemia and Gout. Bulletin of the NYU Hospital for Joint Diseases;2008;66(3):231-9.
3. Rider TG, Jordan KM. The Modern Management of Gout.Oxford Journals;Medicine;Rheumatology;49(1):5-14. http://rheumatology.oxfordjournals.org/content/49/1/5.full.pdf+html.
4. Smith RG. The Diagnosis and Treatment of Gout. US Pharmacist;May 19, 2009;34(5):40-7. http://www.uspharmacist.com/content/d/feature/i/734/c/13430.

Coding Section

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

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