A Trial to Investigate the Non-inferiority of Pegloticase Administered Every 4 Weeks (Q4W) With MTX Compared With Every 2 Weeks (Q2W) With MTX in Participants With Uncontrolled Refractory Gout

Acquired from Horizon in 2024.

• Pegloticase (Biological), also known as Krystexxa: IV infusion
• Methotrexate (Drug): Oral

Primary outcomes

• Percentage of Serum Uric Acid (sUA) Responders (sUA < 6 mg/dL) During Month 6 [Month 6 (Weeks 20, 21, 22, 23, and 24)]: Responders were defined as participants who achieved and maintained sUA levels below 6 mg/dL for at least 80% of the time during Month 6. Responders who met sUA discontinuation criteria (2 consecutive sUA > 6 mg/dL), regardless of treatment status were considered non-responders.

Secondary outcomes

• Percentage of Participants With Complete Resolution of ≥ 1 Tophus at Week 24 in Participants With Tophi at Baseline [Baseline, Week 24]

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Adult men or women ≥ 18 years of age
2. Uncontrolled gout, defined as meeting the following criteria:

   * Hyperuricemia during the Screening Period, defined as sUA ≥ 7 mg/dL, and;
   * Failure to maintain normalization of sUA with xanthine oxidase inhibitors at the maximum medically appropriate dose, or with a contraindication to xanthine oxidase inhibitor therapy based on medical record review or participant interview, and;
   * Symptoms of gout
3. Willing to discontinue any oral ULT for at least 7 days prior to MTX dosing at Week -4 and continue not receiving any oral ULT when receiving pegloticase/placebo for pegloticase infusions
4. Women of childbearing potential must have negative serum/urine pregnancy tests during screening and Week -4.
5. Men who are not vasectomized must agree to use appropriate contraception, so as to not impregnate a female partner of reproductive potential during the trial.

Exclusion Criteria:

1. Severe chronic or recurrent bacterial infections, such as recurrent pneumonia or chronic bronchiectasis
2. Current or chronic treatment with systemic immunosuppressive agents, such as MTX, azathioprine or mycophenolate mofetil; prednisone > 10 mg/day or equivalent dose of other corticosteroid on a chronic basis (3 months or longer)
3. History of any transplant surgery requiring maintenance immunosuppressive therapy
4. Known history of hepatitis B virus surface antigen positivity or hepatitis B DNA positivity
5. Known history of hepatitis C virus RNA positivity, unless treated and viral load is negative
6. Known history of human immunodeficiency virus (HIV) positivity
7. G6PD deficiency (quantitative test at the Screening Visit centrally or locally)
8. Non-compensated congestive heart failure or hospitalization for congestive heart failure within 3 months of the Screening Visit, uncontrolled arrhythmia, treatment for acute coronary syndrome (myocardial infarction or unstable angina) or uncontrolled blood pressure (> 160/100 mmHg) prior to Week -4
9. Pregnant, planning to become pregnant, breastfeeding, planning to impregnate female partner or not on an effective form of birth control, as determined by the Investigator
10. Prior treatment with pegloticase, another recombinant uricase (rasburicase) or concomitant therapy with a PEG-conjugated drug
11. Unable to tolerate MTX 15 mg orally during the MTX Run-in Period
12. Chronic liver disease
13. White blood cell count < 4,000/μL, hematocrit < 32% or platelet count < 75,000/μL
14. Currently receiving systemic or radiologic treatment for ongoing cancer
15. History of malignancy within 5 years other than non-melanoma skin cancer or in situ carcinoma of cervix
16. Diagnosis of osteomyelitis
17. Known history of hypoxanthine-guanine phosphoribosyl-transferase deficiency, such as Lesch-Nyhan and Kelley-Seegmiller syndrome
18. A known intolerance to all protocol-standard gout flare prophylaxis regimens (i.e., participant must be able to tolerate at least 1 of the following: colchicine and/or non-steroidal anti-inflammatory drugs and/or low-dose prednisone ≤ 10 mg/day)
19. Current pulmonary fibrosis, bronchiectasis or interstitial pneumonitis. If deemed necessary by the Investigator, a chest X-ray may be performed during Screening.

Participant flow

Outcome results

• Percentage of Serum Uric Acid (sUA) Responders (sUA < 6 mg/dL) During Month 6 (Primary), Number, percentage of participants: Pegloticase 8mg Q2W + MTX 70.8 (62.2 to 78.4); Pegloticase 16mg Q4W + MTX 56.5 (47.6 to 65.1) (p 0.10)
• Percentage of Participants With Complete Resolution of ≥ 1 Tophus at Week 24 in Participants With Tophi at Baseline (Secondary)

Adverse events

Time frame: For all-cause mortality: from signing of inform consent form (ICF) through database lock (DBL) for primary analysis (up to Week 24); For Serious adverse events and other adverse events: from first dose of MXT through DBL for the primary analysis (up to Week 24).

Serious adverse events by term

Other adverse events by term

• Study Protocol (PDF, 2024-03-06)
• Statistical Analysis Plan (PDF, 2025-08-20)

• MD, Study director, Amgen