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UNDERSTANDING THE DIFFERENCE
Clinical Trials VS Clinical Practice

In order to better predict the occurrence of infusion reactions, a post hoc analysis of the pivotal clinical trials was completed. This led to the development of the KRYSTEXXA Monitoring Protocol.

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UNDERSTANDING THE SAFETY DATA

FROM PIVOTAL CLINICAL TRIALS TO CLINICAL PRACTICE

Pivotal clinical trials: double-blind protocol masked the causes leading to higher infusion reaction risk1,2

  • During the pivotal clinical trials, the relationship between sUA levels, anti-drug antibodies and infusion reactions was unknown, and therefore not observed1,2
    • Anti-drug antibodies are common to biologic therapies3
    • Identifying the development of anti-drug antibodies is often difficult4
  • Anti-drug antibodies can lead to decreased efficacy and an increased risk of infusion reactions3
    • In the pivotal clinical trials, an sUA >6 mg/dL often reflected the development of anti-drug antibodies to pegloticase2,5
Anti-drug antibodies develop. Increased risk of infusion reactions. Reduced levels of KRYSTEXXA in circulation. sUA levels rebound >6 mg/dL (after initial drop). Anti-drug antibodies develop. Increased risk of infusion reactions. Reduced levels of KRYSTEXXA in circulation. sUA levels rebound >6 mg/dL (after initial drop).

Because of the double-blind protocol, all patients received all doses of KRYSTEXXA regardless of anti-drug antibody formation or sUA level increases1

POST HOC ANALYSIS: UNCOVERING THE LINK BETWEEN ANTI-DRUG ANTIBODIES, sUA LEVELS, LOSS OF RESPONSE, AND RISK OF INFUSION REACTIONS

  • 20/22 patients who experienced infusion reactions had an sUA level >6 mg/dL1,2
  • All patients experienced an initial drop in sUA. Patients whose sUA began to rebound to >6 mg/dL had formed meaningful anti-drug antibodies1,2,6
  • These anti-drug antibodies caused accelerated clearance of pegloticase, leading to a reduced systemic pegloticase level, loss of uric acid lowering effect, and a higher risk of infusion reactions1,2,6

This makes sUA an accurate biomarker to help predict an increased likelihood of infusion reactions

sUA LEVELS THROUGHOUT THE 6-MONTH PIVOTAL CLINICAL TRIALS5,6

sUA reductions efficacy chart: KRYSTEXXA vs placebo

UNDERSTANDING THE SAFETY DATA

FROM PIVOTAL CLINICAL TRIALS TO CLINICAL PRACTICE

Close monitoring of sUA within 48 hours prior to the infusion can significantly reduce infusion reactions1

KRYSTEXXA Monitoring Protocol: sUA can help identify patients at risk for infusion reactions1,6,7

For use after first infusion. Take a preinfusion sUA measurement, preferably within 48 hours prior to each infusion. If the preinfusion sUA level is ≤6 mg/dL, treatment can be continued. If the preinfusion sUA level is >6 mg/dL, consider discontinuing treatment, particularly when 2 consecutive sUA levels >6 mg/dL are observed. For use after first infusion. Take a preinfusion sUA measurement, preferably within 48 hours prior to each infusion. If the preinfusion sUA level is ≤6 mg/dL, treatment can be continued. If the preinfusion sUA level is >6 mg/dL, consider discontinuing treatment, particularly when 2 consecutive sUA levels >6 mg/dL are observed.

sUA: A BIOMARKER THAT INFORMS THE SAFETY AND EFFICACY OF KRYSTEXXA IN CLINICAL PRACTICE

Infusion reactions chart: 95% of infusion reactions occurred when sUA was >6 mg/dL*

Adapted with permission from Baraf HS et al. J Clin Rheumatol. 2014;20(8):427-432.

*Based on infusion reactions per patient.2

TYPES OF INFUSION REACTIONS IN THE PIVOTAL CLINICAL TRIALS

INFUSION REACTIONS Frequency (%)
Hives 10.6
Chest discomfort 9.5
Chest pain 9.5
Reddening of the skin 9.5
Itching of the skin 9.5
Difficulty breathing 7.1

The majority of infusion reactions in the pivotal clinical trials were resolved by slowing or interrupting the infusion and restarting at the same or a slower rate2†

Approximately 75% of infusion reactions with a recorded intervention.2

SEVERITY OF INFUSION REACTIONS IN THE PIVOTAL CLINICAL TRIALS2‡

Incidence of infusion reactions by severity in the randomized controlled trials (RCT)

INFUSION REACTION
SEVERITY
PEGLOTICASE BIWEEKLY
(n=85)
n (%)
PLACEBO
(n=43§)
n (%)
Mild 7 (8) 0
Moderate 11 (13) 2 (5)
Severe 4 (5) 0

These 4 cases of severe infusion reactions identified by investigators were retrospectively reclassified as anaphylaxis by the FDA (n=85)2

Only the most severe episode is showing if a patient had more than 1 event.2
§Thirty-nine of these patients entered the OLE study and were treated with pegloticase.2

CHARACTERIZATION OF SEVERE INFUSION REACTIONS: ALL WERE RESOLVED ON SITE2

PATIENT INFUSION REACTIONS TREATMENT OUTCOME
PATIENT 1 INFUSION REACTIONSDifficulty breathing, swelling of the tongue TREATMENT Infusion discontinued
(Benadryl®: 25 mg IV)
OUTCOME Infusion reaction resolved
PATIENT 2 INFUSION REACTIONS Difficulty breathing, hives, elevated heart rate, elevated blood pressure TREATMENT Infusion discontinued
(Benadryl®, Ventolin®)
OUTCOME Infusion reaction resolved
PATIENT 3 INFUSION REACTIONS Flushing, itchy skin, low blood pressure, elevated heart rate, hives TREATMENT Infusion discontinued
(Benadryl®, Demerol®)
OUTCOME Infusion reaction resolved
PATIENT 4 INFUSION REACTIONS Itchy eye, puffy eye, chest discomfort, throat irritation, joint pain, back pain TREATMENT Infusion discontinued OUTCOME Infusion reaction resolved

Patient did not take full premedication regimen.2

Of the 4 cases reclassified as anaphylaxis, 3 likely would have been prevented using the KRYSTEXXA Monitoring Protocol

In the pivotal clinical trials, no patients with infusion reactions required intubation, mechanical ventilator support, or hospitalization. There were no infusion-related deaths

References
  1. Keenan RT, et al. Rheumatol Ther. 2019;6:299-304.
  2. Baraf HSB, et al. J Clin Rheumatol. 2014;20:427-432.
  3. Strand V, et al. BioDrugs. 2017;31:299-316.
  4. Lombardi G, et al. BMJ Open. 2016;6:1-7.
  5. Sundy JS, et al. JAMA. 2011;306:711-720.
  6. KRYSTEXXA (pegloticase) [prescribing information] Horizon.
  7. Data on file. Horizon, September 2016.
  8. Data on file. Horizon, May 2017.
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Indications and Usage

KRYSTEXXA® (pegloticase) is indicated for the treatment of chronic gout in adult patients who have failed to normalize serum uric acid and whose signs and symptoms are inadequately controlled with xanthine oxidase inhibitors at the maximum medically appropriate dose or for whom these drugs are contraindicated.

Important Limitations of Use: KRYSTEXXA is not recommended for the treatment of asymptomatic hyperuricemia.

Important Safety Information

WARNING: ANAPHYLAXIS AND INFUSION REACTIONS

Anaphylaxis and infusion reactions have been reported to occur during and after administration of KRYSTEXXA. Anaphylaxis may occur with any infusion, including a first infusion, and generally manifests within 2 hours of the infusion. However, delayed-type hypersensitivity reactions have also been reported. KRYSTEXXA should be administered in healthcare settings and by healthcare providers prepared to manage anaphylaxis and infusion reactions. Patients should be premedicated with antihistamines and corticosteroids. Patients should be closely monitored for an appropriate period of time for anaphylaxis after administration of KRYSTEXXA. Monitor serum uric acid levels prior to infusions and consider discontinuing treatment if levels increase to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed.

CONTRAINDICATIONS: G6PD DEFICIENCY ASSOCIATED HEMOLYSIS AND METHEMOGLOBINEMIA

Screen patients for G6PD deficiency prior to starting KRYSTEXXA. Hemolysis and methemoglobinemia have been reported with KRYSTEXXA in patients with G6PD deficiency. Do not administer KRYSTEXXA to these patients.

INDICATIONS AND USAGE

KRYSTEXXA® (pegloticase) is indicated for the treatment of chronic gout in adult patients who have failed to normalize serum uric acid and whose signs and symptoms are inadequately controlled with xanthine oxidase inhibitors at the maximum medically appropriate dose or for whom these drugs are contraindicated.

Important Limitations of Use: KRYSTEXXA is not recommended for the treatment of asymptomatic hyperuricemia.

IMPORTANT SAFETY INFORMATION

WARNING: ANAPHYLAXIS AND INFUSION REACTIONS

Anaphylaxis and infusion reactions have been reported to occur during and after administration of KRYSTEXXA. Anaphylaxis may occur with any infusion, including a first infusion, and generally manifests within 2 hours of the infusion. However, delayed-type hypersensitivity reactions have also been reported. KRYSTEXXA should be administered in healthcare settings and by healthcare providers prepared to manage anaphylaxis and infusion reactions. Patients should be premedicated with antihistamines and corticosteroids. Patients should be closely monitored for an appropriate period of time for anaphylaxis after administration of KRYSTEXXA. Monitor serum uric acid levels prior to infusions and consider discontinuing treatment if levels increase to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed.

The risk of anaphylaxis and infusion reactions is higher in patients who have lost therapeutic response.

Concomitant use of KRYSTEXXA and oral urate-lowering agents may blunt the rise of sUA levels. Patients should discontinue oral urate-lowering agents and not institute therapy with oral urate-lowering agents while taking KRYSTEXXA.

In the event of anaphylaxis or infusion reaction, the infusion should be slowed, or stopped and restarted at a slower rate.

Inform patients of the symptoms and signs of anaphylaxis, and instruct them to seek immediate medical care should anaphylaxis occur after discharge from the healthcare setting.

CONTRAINDICATIONS: G6PD DEFICIENCY ASSOCIATED HEMOLYSIS AND METHEMOGLOBINEMIA

Screen patients for G6PD deficiency prior to starting KRYSTEXXA. Hemolysis and methemoglobinemia have been reported with KRYSTEXXA in patients with G6PD deficiency. Do not administer KRYSTEXXA to these patients.

GOUT FLARES

An increase in gout flares is frequently observed upon initiation of anti-hyperuricemic therapy, including treatment with KRYSTEXXA. If a gout flare occurs during treatment, KRYSTEXXA need not be discontinued. Gout flare prophylaxis with a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended starting at least 1 week before initiation of KRYSTEXXA therapy and lasting at least 6 months, unless medically contraindicated or not tolerated.

CONGESTIVE HEART FAILURE

KRYSTEXXA has not been studied in patients with congestive heart failure, but some patients in the clinical trials experienced exacerbation. Exercise caution when using KRYSTEXXA in patients who have congestive heart failure and monitor patients closely following infusion.

ADVERSE REACTIONS

The most commonly reported adverse reactions in clinical trials with KRYSTEXXA are gout flares, infusion reactions, nausea, contusion or ecchymosis, nasopharyngitis, constipation, chest pain, anaphylaxis and vomiting.

Please see Full Prescribing Information and Medication Guide for more information.

INDICATIONS AND USAGE

KRYSTEXXA® (pegloticase) is indicated for the treatment of chronic gout in adult patients who have failed to normalize serum uric acid and whose signs and symptoms are inadequately controlled with xanthine oxidase inhibitors at the maximum medically appropriate dose or for whom these drugs are contraindicated.

Important Limitations of Use: KRYSTEXXA is not recommended for the treatment of asymptomatic hyperuricemia.

IMPORTANT SAFETY INFORMATION

WARNING: ANAPHYLAXIS AND INFUSION REACTIONS

Anaphylaxis and infusion reactions have been reported to occur during and after administration of KRYSTEXXA. Anaphylaxis may occur with any infusion, including a first infusion, and generally manifests within 2 hours of the infusion. However, delayed-type hypersensitivity reactions have also been reported. KRYSTEXXA should be administered in healthcare settings and by healthcare providers prepared to manage anaphylaxis and infusion reactions. Patients should be premedicated with antihistamines and corticosteroids. Patients should be closely monitored for an appropriate period of time for anaphylaxis after administration of KRYSTEXXA. Monitor serum uric acid levels prior to infusions and consider discontinuing treatment if levels increase to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed.

The risk of anaphylaxis and infusion reactions is higher in patients who have lost therapeutic response.

Concomitant use of KRYSTEXXA and oral urate-lowering agents may blunt the rise of sUA levels. Patients should discontinue oral urate-lowering agents and not institute therapy with oral urate-lowering agents while taking KRYSTEXXA.

In the event of anaphylaxis or infusion reaction, the infusion should be slowed, or stopped and restarted at a slower rate.

Inform patients of the symptoms and signs of anaphylaxis, and instruct them to seek immediate medical care should anaphylaxis occur after discharge from the healthcare setting.

CONTRAINDICATIONS: G6PD DEFICIENCY ASSOCIATED HEMOLYSIS AND METHEMOGLOBINEMIA

Screen patients for G6PD deficiency prior to starting KRYSTEXXA. Hemolysis and methemoglobinemia have been reported with KRYSTEXXA in patients with G6PD deficiency. Do not administer KRYSTEXXA to these patients.

GOUT FLARES

An increase in gout flares is frequently observed upon initiation of anti-hyperuricemic therapy, including treatment with KRYSTEXXA. If a gout flare occurs during treatment, KRYSTEXXA need not be discontinued. Gout flare prophylaxis with a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended starting at least 1 week before initiation of KRYSTEXXA therapy and lasting at least 6 months, unless medically contraindicated or not tolerated.

CONGESTIVE HEART FAILURE

KRYSTEXXA has not been studied in patients with congestive heart failure, but some patients in the clinical trials experienced exacerbation. Exercise caution when using KRYSTEXXA in patients who have congestive heart failure and monitor patients closely following infusion.

ADVERSE REACTIONS

The most commonly reported adverse reactions in clinical trials with KRYSTEXXA are gout flares, infusion reactions, nausea, contusion or ecchymosis, nasopharyngitis, constipation, chest pain, anaphylaxis and vomiting.

Please see Full Prescribing Information and Medication Guide for more information.

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