Clinical UM Guideline


Subject: Pegloticase (Krystexxa®)
Guideline #:  CG-DRUG-44 Publish Date:    12/12/2018
Status: Reviewed Last Review Date:    11/08/2018
 
Description

This document addresses pegloticase (Krystexxa, Horizon Pharma Rheumatology LLC, Lake Forest, IL), a pegylated biosynthetic (recombinant DNA) uric acid specific enzyme (urate oxidase/uricase) used in adults with chronic, treatment-refractory gout.

Clinical Indications

Medically Necessary:

Pegloticase is considered medically necessary for an individual with chronic, treatment-refractory gout when the following criteria are met:

  1. Individual is 18 years of age or older; and
  2. Individual has 1 or more of the following:
    1. 3 or more gout flares in the previous 18 months; or
    2. 1 or more tophus; or
    3. History of chronic gouty arthropathy, defined clinically or radiographically as joint damage due to gout; and
  3. Individual has a baseline serum uric acid of 6 mg/dL or greater prior to initiating pegloticase; and
  4. Individual has undertaken lifestyle modifications, such as weight loss for obese individuals (weight control) or avoidance of, or limiting alcohol consumption or dietary intake of meats and fish high in purine content; and
  5. Individual has failed to respond to, is intolerant of, or has a medical contraindication to 1 or more of the following conventional therapies:
    1. A xanthine oxidase inhibitor (allopurinol or febuxostat); or
    2. Combination therapy of 1 xanthine oxidase inhibitor given with a uricosuric agent (for example, probenecid).

Not Medically Necessary:

Pegloticase is considered not medically necessary when the criteria are not met and for all other indications including, but not limited to:

Coding

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

HCPCS

 

J2507

Injection, pegloticase, 1 mg [Krystexxa]

 

 

ICD-10 Diagnosis

 

M1A.00X0-M1A.9XX1

Chronic gout

M10.00-M10.9

Gout

Discussion/General Information

Description of the Condition

Gout is a monosodium urate monohydrate crystal-induced form of arthritis and is the most common rheumatic disease of adults. The condition and it’s complications affects more than 3 million Americans and occurs more often in men over the age of 30, women after menopause, and in individuals with kidney disease. According to the American College of Rheumatology (ACR) guidelines for the management of gout (Khanna, 2012), the prevalence of gout in the United States has risen over the last few decades, “…mediated by factors such as an increased prevalence of comorbidities that promote hyperuricemia, including hypertension, obesity, metabolic syndrome, type 2 diabetes mellitus, and chronic kidney disease (CKD).” 

Gout occurs when excess uric acid, a normal waste product in the blood, deposits needle‐like urate crystals in and around the joints. These crystals can attract white blood cells, leading to severe, painful gout attacks and chronic arthropathy. Uric acid also can deposit in the urinary tract causing kidney stones. Certain foods, such as shellfish and red meats, alcohol in excess, and food and drinks high in sugar (fructose), in addition to some medications, such as low-dose aspirin, certain diuretics (for example, hydrochlorothiazide), and immunosuppressants used in organ transplants (for example, cyclosporine and tacrolimus) may raise uric acid levels and lead to attacks of gout.

Recommendations for Gout Management

The ACR guidelines for gout management (Khanna, 2012) include the following baseline recommendations for managing an individual with an established diagnosis of gout:

Lifestyle modifications include measures to preventing acute flares, including weight control and avoiding or limiting alcohol consumption and dietary intake of meats and fish high in purines. Treatment of an acute attack is directed at relief of joint pain and inflammation with nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, and corticosteroids. Drug therapy to control the underlying hyperuricemia is generally contraindicated until the acute attack is controlled unless the kidneys are at risk because of an unusually heavy uric acid load.

The ACR guidelines (Khanna, 2012) recommend pharmacologic (drug) urate-lowering therapy (ULT) for individuals with an established diagnosis of gout and signs of arthropathy and: (1) tophi or synovitis (evidence A); (2) frequent gout attacks (2 or more attacks per year; evidence A); (3) chronic kidney disease stage 2 or worse (evidence C); or, (4) past urolithiasis (evidence C) as follows:

The American College of Physicians has published a clinical practice guideline on the management of acute and recurrent gout (Qaseem, 2017). The guideline recommends “…that clinicians discuss benefits, harms, costs, and individual preferences with patients before initiating urate–lowering therapy, including concomitant prophylaxis, in patients with recurrent gout attacks. (Grade: strong recommendation, moderate-quality evidence).” There is no specific recommendation for use of pegloticase as a first-line ULT agent for acute or recurrent gout.

Pegloticase for Chronic, Treatment-Refractory Gout

Pegloticase is indicated for the treatment of chronic gout in adults who have failed to normalize serum uric acid and whose signs and symptoms are inadequately controlled with conventional therapy, that is, xanthine oxidase inhibitors at the maximum medically appropriate dose or for whom these drugs are contraindicated. Pegloticase achieves its therapeutic effect by catalyzing the oxidation of uric acid to allantoin, thereby lowering serum uric acid. Pegloticase is not recommended for the treatment of asymptomatic hyperuricemia.

In September 2010, the U.S. Food and Drug Administration (FDA) approved pegloticase after two clinical trials demonstrated the drug lowered uric acid levels and reduced deposits of uric acid crystals in joints and soft tissue. Pegloticase is designated an orphan drug by the FDA for this use and is the first drug approved for this indication. In the two randomized multicenter trials of replicate design (n=225), 8 milligrams (mg) of pegloticase administered every 2 weeks resulted in a significantly greater percentage of individuals achieving plasma uric acid levels less than 6 mg/dL compared with placebo (Krystexxa PI label, 2018; Sundy, 2008; Sundy, 2011). Study participants were adults (mean age, 55 years) with symptomatic gout and at least three gout flares in the previous 18 months or one or more gout tophus or gouty arthropathy, baseline serum uric acid (SUA) levels of 8 mg/dL or greater, and a contraindication to allopurinol or a history of allopurinol treatment failure. Participants were randomized to receive pegloticase 8 mg intravenous every 2 weeks (n=43, Trial 1; n=42, Trial 2), pegloticase 8 mg every 4 weeks (n=41, Trial 1; n=43, Trial 2), or placebo (n=20, Trial 1; n=23, Trial 2). A total of 72% of participants had baseline tophi. All participants received prophylaxis for gout flares with NSAIDs or colchicine and prophylaxis against infusion-related reactions with fexofenadine, acetaminophen, and hydrocortisone. The primary endpoint in both studies was control of plasma uric acid concentrations; the major secondary endpoint was resolution of tophi. During months 3 and 6, the percentage of participants achieving SUA levels less than 6 mg/dL for at least 80% of the time (primary outcome) was significantly greater in the participants treated with pegloticase 8 mg every 2 weeks; 47% in Trial 1 (95% confidence interval [CI], 31% to 62%; p<0.001) and 38% in Trial 2 (95% CI, 24% to 54%; p<0.001) compared with placebo (0%, both trials). Pegloticase 8 mg every 4 weeks demonstrated efficacy with a 20% response rate in Trial 1 (95% CI, 9% to 35%; p<0.04) and a 49% response rate in Trial 2 (95% CI, 33% to 65%; p<0.001). This regimen, however, was associated with an increased frequency of anaphylaxis and infusion reactions and was less effective in reducing tophi. Infusion-related reactions were reported in 26%, 42%, and 5% of participants in the pegloticase biweekly, pegloticase monthly, and placebo groups, respectively. Post hoc analysis revealed that most infusion reactions (79%) were associated with a loss of response to pegloticase. Treatment of tophi was assessed as a secondary outcome. Complete response, defined as 100% resolution of at least one target tophus, no new tophi appearing, and no single tophus showing progression, was achieved in 40%, 21%, and 7% of participants in the pegloticase biweekly, pegloticase monthly, and placebo groups, respectively.

The most commonly reported serious adverse reactions (AEs) reported in the clinical trials were gout flares (77%), infusion reactions (26%) and anaphylaxis (5%). Other common AEs included nausea (12%), contusion or ecchymosis (11%), nasopharyngitis (7%), constipation (6%), chest pain (6%), and vomiting (5%). In addition to AEs occurring in > 5%, exacerbation of preexisting congestive heart failure occurred in 2% of participants. 

Yood and colleagues (2014) retrospectively analyzed data from the two randomized, placebo-controlled phase 3 clinical trials (Sundy, 2011) to determine the effects of 6 months use of pegloticase on renal function in individuals with chronic refractory gout. A total of 49% of participants with stages 3 and 4 chronic kidney disease (CKD) were randomized to pegloticase 8 mg every 2 weeks (n=42), pegloticase 8 mg every 4 weeks (n=41), or placebo (n=20) for 6 months. Renal function was assessed by estimated glomerular filtration rate (eGFR). Participants that completed the randomized trials could participate in an open-label extension study for an additional 2.5 years. The primary endpoint in the trials was plasma uric acid < 6.0 mg/dl for 80% of month 3 and month 6. The mean eGFR in both pegloticase dosing cohorts remained constant over the randomized treatment phase and long-term open-label extension study. The number of participants achieving uric acid response was similar across CKD stages (stage 1 [32%], stage 2 [23%], stage 3 [35%], and stage 4 [39%], respectively, p=0.3). The efficacy and safety of pegloticase was not affected by CKD stage.

Baraf and colleagues (2014) pooled data from the two randomized controlled trials and the open-label extension study to evaluate infusion-related reactions (IR) in study participants. An IR was defined by protocol “as any otherwise unexplained adverse event or cluster of temporally related events occurring during or within 2 hours of infusion.” A total of 94 (45%) of 208 participants who received pegloticase experienced an IR, 10 participants reported IRs at first infusion, and 84 participants during subsequent infusions. Most IRs were reported as mild or moderate; 7% were rated severe. The most common symptoms included chest discomfort (15%), flushing (12%), and dyspnea (11%). No participant required blood pressure or ventilatory support, and all IRs resolved with slowing, interrupting, or stopping the infusion. The authors noted that IRs were associated with loss of pegloticase urate-lowering efficacy, as 91% of all IRs occurred in participants with preinfusion serum uric acid concentrations (sUA) > 6 mg/dL. For participants sustaining preinfusion sUA of < 6 mg/dL, IRs occurred in fewer than 1 per 100 infusions.

FDA Black Box Warning for Pegloticase

The FDA PI label for pegloticase (Krystexxa PI label, 2018) includes the following black box warning:

WARNING: ANAPHYLAXIS AND INFUSION REACTIONS; G6PD DEFICIENCY ASSOCIATED HEMOLYSIS and METHEMOGLOBINEMIA

Contraindications

Adverse Reactions

Definitions

Anaphylaxis: An allergic reaction. In severe cases, this can include potentially deadly anaphylactic shock, a widespread and very serious allergic reaction. Symptoms of anaphylactic shock include dizziness, loss of consciousness, labored breathing, swelling of the tongue and breathing tubes, blueness of the skin, low blood pressure, and heart failure, which can lead to death if immediate emergency treatment is not administered.

Conventional therapy: Treatments that are widely accepted and practiced by the medical community.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency: The most common enzyme deficiency in humans, affecting 400 million people worldwide with a high prevalence in persons of African and Mediterranean descent. It is inherited as an X-recessive chromosome linked disorder.

Hyperuricemia: The presence of abnormally elevated levels of uric acid in the blood.

Refractory disease: Illness or disease that is unresponsive to conventional treatment.

Tophi: Nodular masses of uric acid crystals that deposit in different soft tissue areas of the body in people with chronic gout. Tophi are most commonly found as hard nodules around the fingers, at the tips of the elbows, and around the big toe, but can appear in any part of the body.

Uric acid: A breakdown product of purines that are part of all human tissue and are found in many foods, especially those high in protein.

References

Peer Reviewed Publications:

  1. Baraf HS, Becker MA, Gutierrez-Urena SR, et al. Tophus burden reduction with pegloticase: results from phase 3 randomized trials and open-label extension in patients with chronic gout refractory to conventional therapy. Arthritis Res Ther. 2013; 15(5):R137.
  2. Baraf HS, Yood RA, Ottery FD, et al. Infusion-related reactions with pegloticase, a recombinant uricase for the treatment of chronic gout refractory to conventional therapy. J Clin Rheumatol. 2014; 20(8):427-432.
  3. Becker MA, Baraf HS, Yood RA, et al. Long-term safety of pegloticase in chronic gout refractory to conventional treatment. Ann Rheum Dis. 2013; 72(9):1469-1474.
  4. Lipsky PE, Calabrese LH, Kavanaugh A, et al. Pegloticase immunogenicity: the relationship between efficacy and antibody development in patients treated for refractory chronic gout. Arthritis Res Ther. 2014; 16(2):R60.
  5. Sundy JS, Baraf HS, Yood RA, et al. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials. JAMA. 2011; 306(7):711-720.
  6. Sundy JS, Becker MA, Baraf HS, et al. Reduction of plasma urate levels following treatment with multiple doses of pegloticase (polyethylene glycol-conjugated uricase) in patients with treatment-failure gout: results of a phase II randomized study. Arthritis Rheum. 2008; 58(9):2882-2891.
  7. Yood RA, Ottery FD, Irish W, Wolfson M. Effect of pegloticase on renal function in patients with chronic kidney disease: a post hoc subgroup analysis of 2 randomized, placebo-controlled, phase 3 clinical trials. BMC Res Notes. 2014; 7:54.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Anderson A, Singh JA. Pegloticase for chronic gout. Cochrane Database Syst Rev. 2010;(3):CD008335.
  2. Khanna D , Fitzgerald JD , Khanna PP, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken). 2012; 64(10):1431-1446.
  3. Krystexxa. [Product Information] Lake Forest, IL. Horizon Pharma Rheumatology LLC; July 2018. Available at: https://hznp.azureedge.net/public/KRYSTEXXA_Prescribing_Information.pdf. Accessed on September 25, 2018.
  4. Pegloticase. In: DrugPoints System (electronic version). Truven Health Analytics, CO. Updated August 26, 2018. Available at: http://www.micromedexsolutions.com. Accessed on September 25, 2018.
  5. Pegloticase Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised December 15, 2014. Accessed on September 25, 2018.
  6. Qaseem A, Harris RP, Forciea MA; Clinical Guidelines Committee of the American College of Physicians. Management of acute and recurrent gout: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2017; 166(1):58-68.
  7. Sriranganathan MK, Vinik O, Falzon L, et al. Interventions for tophi in gout: a Cochrane systematic literature review. J Rheumatol Suppl. 2014; 92:63-69.
Websites for Additional Information
  1. National Institutes of Health (NIH). National Institute of Arthritis and Musculoskeletal and Skin Disease (NIAMS). Questions and Answers about Gout. April 2016. Available at: http://www.niams.nih.gov/Health_Info/Gout/. Accessed on September 25, 2018.
Index

Krystexxa
Pegloticase

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

History

Status

Date

Action

Reviewed

11/08/2018

Medical Policy & Technology Assessment Committee (MPTAC) review. Updated Description, Discussion/General Information, References, and Websites for Additional Information sections.

Reviewed

02/27/2018

MPTAC review. The document header wording updated from “Current Effective Date” to “Publish Date.” Updated Description, References and Websites for Additional Information sections.

Reviewed

02/02/2017

MPTAC review. Updated formatting in Clinical Indications section. Updated Discussion/General Information, References, and Websites for Additional Information sections.

Reviewed

02/04/2016

MPTAC review. Updated Discussion/General Information, References, and Websites for Additional Information sections. Removed ICD-9 codes from Coding section.

New

02/05/2015

MPTAC review. Initial document development.