Pegloticase and Methotrexate Cotherapy in Patients With Uncontrolled Gout With Prior Pegloticase Monotherapy Failure: Findings of an Open-Label Trial
ClinicalTrials.gov identifier: NCT04772313.
Presented in part at the EULAR 2023 annual meeting, Milan, Italy, May 31 to June 3, 2023.
Supported by Amgen, Inc (formerly Horizon Therapeutics).
Qualified researchers may request data from Amgen clinical studies. Complete details are available at https://wwwext.amgen.com/science/clinical-trials/clinical-datatransparencypractices/clinical-trial-data-sharing-request.
Additional supplementary information cited in this article can be found online in the Supporting Information section (https://acrjournals.onlinelibrary.wiley.com/doi/10.1002/acr2.11789).
Author disclosures are available at https://onlinelibrary.wiley.com/doi/10.1002/acr2.11789.
Abstract
Objective
Patients with uncontrolled gout have few treatment options. Pegloticase lowers serum urate (SU) levels, but antidrug antibodies limit SU-lowering response and increase infusion reaction (IR) risk. Methotrexate (MTX) cotherapy increases pegloticase response rates and lowers IR risk in pegloticase-naïve patients. Therefore, the question of re-treating patients with previous pegloticase monotherapy failure has arisen. The ADVANCE open-label trial examined pegloticase plus MTX cotherapy efficacy and safety following pegloticase monotherapy failure.
Methods
Patients with uncontrolled gout (SU levels ≥6 mg/dL, oral urate–lowering therapy failure or intolerance, and ≥1 gout sign or symptom) who previously lost SU-lowering response to pegloticase monotherapy were included. Key exclusion criteria were moderate-to-severe IR or anaphylaxis to pegloticase, MTX contraindication, immunosuppressant administration, glucose-6-phosphate dehydrogenase deficiency, and estimated glomerular filtration rate <30 mL/min/1.73m2. After a 6-week subcutaneous MTX run-in (at 25 mg/wk), patients entered 24-week pegloticase (at 8 mg biweekly) plus MTX treatment. The primary end point was SU-lowering response rate during month 6 (SU levels <6 mg/dL for ≥80% of weeks 20–24). Safety was assessed via adverse events (AEs) and laboratory monitoring.
Results
Eleven patients began pegloticase plus MTX treatment (91% male patients, mean age 58.6 ± 11.3 years, mean ± SD SU levels 8.5 ± 3.2 mg/dL, 91% tophaceous). Previous pegloticase course was 2 to 27 infusions, with the last infusion admins being a mean ± SD of 3.7 ± 2.4 years before. One patient (9%) maintained response during month 6; 10 patients prematurely discontinued treatment (loss of SU lowering [n = 8], IR [n = 2]). Eight patients (73%) experienced ≥1 AE, most commonly gout flare. All AEs were mild or moderate.
Conclusion
Pegloticase plus MTX response rate following failed monotherapy was lower (9% vs 71%) and IR rate was higher (18% vs 4%) than in pegloticase-naïve patients. These findings demonstrate the challenge of overcoming established antipegloticase antibodies and emphasize the importance of initiating immunomodulation before the first pegloticase exposure.
INTRODUCTION
Pegloticase is often the last treatment option for patients with uncontrolled or refractory gout. However, antidrug antibody (ADA) development can lead to loss of serum urate (SU)–lowering response and put patients at risk for infusion reactions (IRs).1, 2 Evidence from both real-world3 and clinical trial3-5 data support the use of immunomodulation as cotherapy to pegloticase to increase urate-lowering response rate and minimize IR risk.
The MIRROR RCT study confirmed a higher treatment response rate to pegloticase (SU levels <6 mg/dL for ≥80% of the time during treatment month 6; 71% vs 39%) and lower IR risk (4% vs 31%) when oral methotrexate (MTX) (at 15 mg/week) versus a placebo was administered as cotherapy in pegloticase-naïve patients.5 Pharmacokinetic and immunogenicity data from this trial support that these safety and efficacy improvements were due to MTX attenuation of ADAs,4, 5 with a higher rate of sustained SU-lowering with MTX cotherapy both in the presence and absence of ADAs.4 Therefore, the question of whether pegloticase coadministered with MTX could be effective in patients who previously lost SU-lowering response with pegloticase monotherapy (presumably due to ADA development) has arisen. A potentially high number of patients are affected because pegloticase was approved as a monotherapy in 2010, but the product label to include MTX cotherapy was not updated until July 2022.
The ADVANCE open-label trial was performed to directly answer this question, examining the efficacy and safety of pegloticase plus MTX (subcutaneous [subQ], at 25 mg/wk) cotherapy in patients with previous loss of SU-lowering response during pegloticase monotherapy. Efficacy, safety, pharmacokinetic, and immunogenicity findings are reported.
PATIENTS AND METHODS
This phase 4 multicenter, open-label study (ClinicalTrials.gov identifier: NCT04772313) was conducted at nine sites in the United States. The trial was reviewed and approved by the WIRB Copernicus Group (WCG) Institutional Review Board (IRB) or the individual site IRB, as required. All patients provided written informed consent to participate in the trial, and the study was conducted in compliance with the ethical guidelines of the Declaration of Helsinki.
Patients
Adult patients with uncontrolled gout, defined as SU levels ≥6 mg/dL, urate-lowering therapy failure or intolerance, and ≥1 ongoing gout symptom (≥1 tophus, ≥2 flares in the past year, and/or chronic gouty arthritis) and previous pegloticase monotherapy treatment failure (loss of SU-lowering response) were included. All patients had received their last pegloticase infusion six or more months before screening. Key exclusion criteria included previous moderate or severe IR or anaphylaxis to pegloticase, MTX contraindication, current immunosuppressant administration, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2. Cohort 1 included patients with treatment failure defined as loss of SU-lowering response to pegloticase and without previous IR. Dependent on cohort 1 meeting study goals, cohort 2 was to include patients with treatment failure who may have experienced a previous mild IR to pegloticase. However, the study was stopped with cohort 1, and cohort 2 was not enrolled.
Study design
This open-label study with a single-treatment group had a 6-week run-in period with subQ MTX followed by a 24-week pegloticase (8 mg infusion every 2 weeks) plus MTX treatment period (Figure 1). Day 1 was defined as the day of first pegloticase infusion. Beginning at week 6 (start of the MTX run-in period), patients began subQ MTX at a dosage of 15 mg/wk for weeks 6 and 5, titrating up to a once-weekly dosage of 25 mg beginning at week 4 (10 mg/wk titrating up to 15 mg/wk if baseline eGFR < 45 mL/min/1.73m2). Compared to previous clinical trials in pegloticase-naïve patients (pegloticase plus 15 mg/wk oral MTX cotherapy; four-week run-in)5, 6 a higher MTX dose and run-in of six weeks was used to produce a more robust immunomodulation in these patients with presumably established ADAs against pegloticase. Patients who were unable to tolerate ≥15 mg/wk of subQ MTX were considered MTX run-in screen failures. Those who began pegloticase, reached the 24-week treatment mark, and may have gained further benefit from continued pegloticase treatment were given the opportunity to extend treatment to 48 weeks at the investigator's discretion. All patients were administered 1 mg/day folic acid during MTX cotherapy (higher doses allowed if needed) and gout flare prophylaxis beginning ≥1 week before first pegloticase infusion. Standard preinfusion prophylaxis, including 125 mg of intravenous (IV) methylprednisolone, was administered before each infusion. Per the study protocol, beginning at week 2, patients who had a postinfusion SU level >50% of the highest pretreatment SU level (between screening and preinfusion day 1) discontinued pegloticase.

Study end points
Study end points were examined in the intent-to-treat population (ITT), defined as all patients who received ≥1 pegloticase infusion. The primary efficacy end point was the proportion of patients with SU-lowering response during month 6 (SU levels <6 mg/dL for ≥80% of the time during weeks 20–24), with the primary objective to demonstrate a response rate during month 6 of ≥20%. Patients with missing SU data in the specified time were considered nonresponders. Secondary efficacy and safety end points (not tiered) included the proportion of patients with SU-lowering response during month 3 (SU levels <6 mg/dL for ≥80% of the time for weeks 10–14), the proportion of patients experiencing an IR, the change from baseline in monosodium urate deposition volume (as measured on dual-energy computed tomography), and the change from baseline in Health Assessment Questionnaire measures (Disability Index [DI], Pain, and Health). Only safety and efficacy end points are presented here. Safety and tolerability were evaluated via adverse events (AEs) and laboratory and vital sign monitoring. AEs of special interest included IR, anaphylaxis, gout flare, and major adverse cardiovascular events (included nonfatal stroke, nonfatal myocardial infarction, cardiovascular death, and congestive heart failure).
Study assessments
The full schedule of assessments can be found in the Supplemental Table 1. Briefly, patients who met all study criteria underwent screening, which included a history and physical (including vital sign measurement), gout assessment (tophi count, gout flare documentation) G6PD-deficiency test, and laboratory measurements (SU, hematology panel, clinical chemistry panel, eGFR, urinalysis, C-reactive protein, serum pregnancy test [female patients of child-bearing potential only]). SU measurement was also performed 1, 4, 7, and 10 days following each of the first four infusions (day 1 through week 6) and 1 and 7 days following each of the next three infusions (weeks 8, 10, and 12). Patients were evaluated with vital sign monitoring and AE assessment every two weeks during the MTX run-in period. Patient quality of life was also measured before MTX exposure (week 6) using several measures, including Health Assessment Questionnaire assessments (DI, Pain, and Health), Global Assessments of Gout (Patient, Physician) European Quality of Life 5 Dimensions 3 Level Version (EQ-5D-3L), Short Form 12, and Patient-Reported Outcomes Measurement Information System 29 (PROMIS-29). During the pegloticase plus MTX treatment period, patients were evaluated at biweekly study visits through week 22 that coincided with pegloticase infusions. Additional noninfusion visits occurred at week 21, week 23, and week 24 or end of treatment. Patients underwent physical examinations every four weeks beginning on day 1 and had regular monitoring of renal function, liver function enzymes, and blood cell counts. Gout flare, concomitant medications, and AEs were assessed at each study visit. An SU-monitoring protocol was followed, and patients who had an SU level >50% of the highest pretreatment value (screening through preinfusion day 1) discontinued pegloticase and MTX, completed the end of treatment visit (within two weeks of the last infusion), and remained in the study on observation. All patients had a follow-up phone call, email, or visit approximately 30 days after the last dose of pegloticase or MTX, whichever was later.
Pharmacokinetic and immunogenicity analyses
Samples were collected for pharmacokinetic measurements before and after pegloticase infusion on day 1 and weeks 2, 6, 14, 22, and 24 (or end of treatment). Pegloticase concentrations in serum were measured (both before and after infusion during the treatment period) using a validated liquid chromatography-mass spectrometry (LC-MS/MS) assay (AIT Bioscience; calibration range: 0.0500–5.00 μg/mL). Concentrations below the quantitation limit (<0.0500 μg/mL) were imputed as half of the lower limit (0.025 μg/mL) for pegloticase concentration analyses. Preinfusion blood samples were also used to evaluate MTX polyglutamates (MTX-PG1–5) in red blood cells using a validated LC-MS method (performed by Exogen Inc. [AVISE® MTX test]).7
Preinfusion samples were collected for ADA assessments at week 6, day 1, and weeks 2, 6, 14, 22, and 24 (or end of treatment) to examine pegloticase immunogenicity in this study population. Both anti–polyethylene glycol (PEG) and anti-uricase IgG antibodies in serum were assessed for detection and titer quantification. ADAs were evaluated using validated enzyme-linked immunosorbent assays (anti-uricase assay: Precision for Medicine; anti-PEG assay: BioAgilytix).
Statistical analysis
A planned sample size of 30 patients would demonstrate meeting the study's primary efficacy end point of statistically >20% response rate during month 6 (SU level <6 mg/dL for ≥80% of the time during weeks 20–24) if at least 12/30 (40%) patients were treatment responders. In that case, the lower bound of a 95% confidence interval (CI) for the proportion of responders would be approximately 23%.
Data were presented as means ± SDs and as counts with percentages, as appropriate. Kaplan-Meier analyses were used to estimate median (95% CI) time to first SU level >6 mg/dL. All analyses were conducted after all enrolled patients had completed the study. Efficacy and safety end points are presented in the ITT population (≥1 pegloticase infusion received). Safety analyses were also performed during the MTX run-in period in patients who received ≥1 dose of MTX. No statistical testing was performed.
RESULTS
Patients
A total of 17 patients were screened for study inclusion, 4 of whom had failed screenings. Thirteen patients received ≥1 dose of MTX, but two patients withdrew after two MTX doses; both patients had an eGFR measurement <30 mL/min/1.73 m2 during the run-in period. Therefore, 11 patients entered the pegloticase plus MTX treatment period and made up the ITT for cohort 1 (loss of SU-lowering response and no previous IR). Ten of the 11 patients discontinued treatment before week 24, 8 due to loss of SU-lowering efficacy and 2 due to an IR. Only one patient completed treatment through week 24 and entered the optional extension period. Preliminary ongoing efficacy assessment by the sponsor led to enrollment halting of cohort 1, and cohort 2 was not enrolled. Therefore, all reported findings are of cohort 1. Patients were mostly male patients (90.9%) and White (63.6%), with a mean ± SD age of 58.6 ± 11.3 years (3 patients [27.3%] ≥65 years). Patients had long-standing gout (mean ± SD 25.2- ± 8.5-year history) and high disease burden (90.9% had tophi, mean ± SD SU level 8.5 ± 3.2 mg/dL, mean ± SD 4.5 ± 3.8 flares in the previous six months). Patient characteristics are fully summarized in Table 1.
Characteristics | Patients (n = 11) |
---|---|
Patient characteristics | |
Male patients, n (%) | 10 (90.9) |
Age, mean ± SD, yr | 58.6 ± 11.3 |
Race, n (%) | |
White | 7 (63.6) |
African American | 1 (9.1) |
Asian | 1 (9.1) |
Multiracial | 1 (9.1) |
Other | 1 (9.1) |
Ethnicity, n (%) | |
Hispanic or Latino | 3 (27.3) |
Not Hispanic or Latino | 8 (72.7) |
Current tobacco user, n (%) | 2 (18.2) |
hs-CRP | 0.95 ± 1.47 |
Body mass index, mean ± SD | 31.8 ± 5.4 |
eGFR, mean ± SD, mL/min/1.73m2 | 71.5 ± 14.6 |
eGFR ≤60 mL/min/1.73 m2, n (%) | 2 (18.2) |
Comorbidities, n (%) | |
Hypertension | 11 (100) |
Hypercholesterolemia/hyperlipidemia | 4 (36.4) |
Diabetes | 3 (27.3) |
Anxiety | 3 (27.3) |
Back pain/spinal fusion surgery | 3 (27.3) |
Nephrolithiasis | 3 (27.3) |
Deep vein thrombosis | 2 (18.2) |
Coronary artery disease | 2 (18.2) |
Gout characteristics | |
Gout duration,a mean ± SD, yr | 25.2 ± 8.5 |
Tophi, n (%) | 10 (90.9) |
Prepegloticase SU level, mean ± SD, mg/dL | 8.5 ± 3.2 |
Number flares in previous 6 months, mean ± SD | 4.5 ± 3.8 |
- * Baseline hs-CRP and eGFR are last observation before first dose of methotrexate. CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; hs-CRP, high sensitivity C-reactive protein; SU, serum urate.
- a Time between date of informed consent and first gout diagnosis.
Previous pegloticase course range was 2 to 27 infusions (mean ± SD 6.0 ± 7.4 infusions), with last infusion received 0.7 to 9.2 years (mean ± SD 3.7 ± 2.4 years) before screening. Most patients had received biweekly pegloticase (nine patients [81.8%]), but one patient (9.1%) each had received weekly and monthly dosing, respectively. All 11 patients in the ITT had discontinued their previous course of pegloticase therapy because of documented loss of SU-lowering response, and none had experienced an IR.
Efficacy outcomes
One patient (9.1%) met treatment response criteria during month 6. Therefore, this study did not meet its primary efficacy end point. This response rate of 9.1% was lower than what has been previously shown in pegloticase-naïve patients both in the presence and absence of MTX cotherapy (MIRROR RCT modified ITT population [≥1 pegloticase infusion] with MTX: 74.0%; without MTX: 40.8%; Figure 2).5 The remaining 10 patients discontinued pegloticase before week 24, with 8 patients (72.7%) discontinuing due to loss of SU-lowering response and 2 patients (18.2%) discontinuing due to IR (further detail below). All 11 patients had ≥1 SU level >6 mg/dL after receiving pegloticase, even the one treatment responder, with the first SU level >6 mg/dL occurring a mean ± SD of 20.8 ± 18.3 days (range 6.7–59.9 days) after first documented SU-lowering (<6 mg/dL; Kaplan-Meier estimated median 13.8 days [95% CI 7.0–27.8]). The single-treatment responder during month 6 was also the only patient who met treatment response criteria during month 3 (9.1% response rate during month 3). It should be noted that MTX compliance during treatment was high, with a mean ± SD weekly dosage of 22.3 ± 4.7 mg/wk (range 16–25 mg/wk).

Observed SU values while receiving therapy are shown for each patient in Figure 3. In the single-treatment responder, the change from baseline in SU was −6.90 g/dL at week 24.

Pharmacokinetic and ADA findings
The MTX-PG concentrations were maintained during treatment and in the expected range for weekly low-dose MTX just before initiating pegloticase.7 Because of the small number of patients, pegloticase exposures reported here should be interpreted with caution in both treatment nonresponders with pharmacokinetic data (n = 6) and the single-treatment responder. In the treatment responder, pegloticase concentration was comparable to that of pegloticase-naïve MIRROR RCT participants at all time points examined. However, pegloticase concentrations in treatment nonresponders were highly variable. The mean peak concentration at week 2 in nonresponders (n = 6) was lower compared to the single-treatment responder and MIRROR RCT participants. Mean pegloticase concentrations over time are shown in Figure 4.

No patient was positive for anti-uricase antibodies before MTX and pegloticase exposure (week 6). Eight patients (72.7%) screened positive for anti-uricase antibodies during treatment, of whom four were confirmed positive with low levels of antibody titer (≤1:90). All four of these patients discontinued pegloticase: three due to loss of treatment response (met protocol stopping rule) and one due to IR. The single patient who was a treatment responder did not have a positive anti-uricase antibody screen.
All 11 patients were positive for anti-PEG antibodies before MTX and pegloticase exposure (week 6), with 8 patients (72.7%) having a titer ≥1:320. Following the first pegloticase infusion, anti-PEG antibody titer increased in nine patients (81.8%), all of whom were treatment nonresponders (seven loss of urate-lowering response, two IR; Figure 5). The single patient who was a treatment responder had a steady decline in anti-PEG antibody titer during treatment (from 1:2,560 on day 1 to 1:320 at week 24). In the two patients who experienced an IR, anti-PEG antibody titer sharply increased following first pegloticase infusion, with titers of 1:320 and 1:160 at day 1 and 1:5,120 and 1:81,920, respectively, at week 2, the time of IR in both patients.

Safety
No new safety signals were identified during the study (Table 2). During the MTX run-in period, 53.8% of patients (7/13) experienced ≥1 AE, most commonly gout flare (46.2%) and fatigue (15.4%). Additionally, one patient (7.7%) experienced a serious adverse event (SAE) of perineal abscess that was deemed unrelated to MTX. During the pegloticase plus MTX treatment period, 72.7% of patients (8/11) experienced ≥1 treatment-emergent AE, most commonly acute gout flare (63.6%), arthralgia (18.2%), extremity pain (18.2%), and IR (18.2%). All AEs were mild or moderate in severity (Rheumatology Common Toxicity Criteria [CTC]8 grade 1 or 2) except for one grade 3 AE of lymphocyte count decrease and one grade 4 SAE of septic shock, both of which were deemed unrelated to MTX or pegloticase.
MTX, run-in (n = 13) | Pegloticase plus MTX treatment (n = 11) | |
---|---|---|
Treatment-emergent AEs occurring in >1 patient | ||
≥1 AE, n (%) | 7 (53.8) | 8 (72.7) |
Gout flarea | 6 (46.2) | 7 (63.6) |
Arthralgia | 1 (7.7) | 2 (18.2) |
Infusion reactiona,b | 0 | 2 (18.2) |
Pain in extremity | 0 | 2 (18.2) |
Fatigue | 2 (15.4) | 0 |
Anaphylaxisa | 0 | 0 |
Cardiovascular eventa,c | 0 | 0 |
Serious AEs | ||
≥1 serious AE, n (%) | 1 (7.7) | 1 (9.1) |
Septic shock | 0 | 1 (9.1)d |
Perineal abscessd | 1 (7.7) | 0 |
- * All serious AEs and AEs of special interest are shown. AE, adverse event; MTX, methotrexate.
- a AE of special interest.
- b Throat tightness, erythema, itching, urticaria in 1 patient; back pain in 1 pt.
- c Included nonfatal stroke, nonfatal myocardial infarction, cardiovascular death, and congestive heart failure.
- d Perineal abscess (not related to MTX) developed during MTX run-in (two days before the first pegloticase infusion), the same patient developed septic shock five days after their last pegloticase infusion at week 2.
Rates of AEs of special interest (gout flare, IR or anaphylaxis, and cardiovascular events) were similar to what was observed in the MIRROR RCT trial, with the exception of IR rate, which was lower than with pegloticase monotherapy (31%) and higher than with pegloticase plus MTX cotherapy (4%) in pegloticase-naïve patients (Figure 2).5 Two patients (18.2%) each experienced one IR during the second pegloticase infusion (day 15), both of which were graded as moderate in severity (Rheumatology CTC8 grade 2). One patient experienced lower back pain that radiated down both legs. No treatment was administered. The other patient experienced erythema, itching, hives, and throat tightness. The patient was administered IV diphenhydramine HCl (50 mg), IV hydrocortisone (100 mg), and inhalation albuterol at the time of IR. The patient also took oral diphenhydramine HCl (25 mg), hydroxyzine HCl (25 mg), and dexamethasone (8 mg) as needed for hives from day 34 to 38. No AEs of an anaphylaxis or cardiovascular event were observed during the study.
DISCUSSION
In this small open-label study, the treatment response rate with pegloticase plus MTX following failed pegloticase monotherapy was 9%, markedly lower than in pegloticase-naïve patients both in the presence5 (74.0%) and absence2, 5 (40.8–43.5%) of MTX cotherapy. The majority of treatment failures (80%) occurred within the first three infusions, including in the two patients who experienced an IR (both at week 2 during infusion 2). The one treatment responder had high-titer anti-PEG antibodies before initiating MTX. Interestingly, SU levels did not fall to near zero, as is typically seen after the first infusion in SU-responders receiving their first pegloticase course.2, 5 Rather, SU levels gradually decreased and became somewhat variable around week 6, decreased to near zero by week 10, and remained near zero for the remainder of treatment. Interestingly, anti-PEG antibody titers gradually decreased over the course of treatment. Together, the SU and anti-PEG antibody titer profiles suggest that this patient may have developed immune tolerance to pegloticase, presumably due to MTX cotherapy. However, as this trial demonstrates, this seems to be a rare occurrence.
Treatment safety profile was similar as previously observed with pegloticase plus MTX cotherapy, with the exception of IR rate, which was higher in retreated patients (18%) than in pegloticase-naïve patients who received pegloticase plus MTX cotherapy (4%).5 Both IRs that occurred in the current study were moderate in severity, and no anaphylaxis was observed. Interestingly, the observed IR rate in retreated patients was lower than that observed with pegloticase monotherapy in pegloticase-naïve patients2, 5 (26–31%), although the sample size of the current study was small. As in other studies examining pegloticase plus MTX, safety signals related to the liver, bone marrow, and kidneys were not observed.
The efficacy and safety findings from this study demonstrate the challenge of overcoming established ADAs against pegloticase once the treatment response is lost. This is consistent with the action of the humoral immune system and the robustness of the memory (anamnestic) immune system. On first exposure to an antigen, B and T cells (humoral immune system) become activated, resulting in plasma cell differentiation and antibody creation. Once established, plasma memory immune cells migrate to the bone marrow, where antibodies are secreted for months to years after antigen elimination.9 On re-exposure to that antigen, additional antibodies are rapidly produced. MTX selectively induces apoptosis of activated T cells (nonactivated T cells are not affected),10 attenuating both short-term and subsequent long-term ADA development when the initial drug exposure occurs. Therefore, it is immunologically simpler and more effective to prevent immune activation than to try and overcome already-established ADA-producing memory immune cells. Given the lower IR rate observed here than with pegloticase monotherapy and the fact that the one treatment responder was able to tolerate pegloticase in the presence of anti-PEG antibodies, MTX may have some action on existing ADAs and prevent the anamnestic immune response. However, the overall trial findings emphasize the importance of initiating immunomodulation before initial pegloticase treatment to prevent ADA development and maximize the number of patients who may fully benefit from pegloticase therapy more effectively.
This study was mainly limited by its open-label design and small sample size. However, the findings of this study are informative, and larger studies in this population are unlikely to be conducted. Additionally, this study was not designed to examine pegloticase retreatment response rates following a successful course of treatment with either pegloticase monotherapy or pegloticase plus MTX cotherapy. Further study is needed to better understand how MTX cotherapy influences a patient's ability to receive multiple courses of pegloticase.
In conclusion, ADA attenuation with MTX has emerged as an important advancement for improving both the efficacy and safety of pegloticase. These results of the ADVANCE open-label trial demonstrate the challenge of overcoming established ADAs against pegloticase in patients with previous loss of urate-lowering response. Given that pegloticase is often the last treatment option for patients with uncontrolled gout, maximizing treatment benefit is of the utmost importance in this patient population. The current study supports the importance of MTX coadministration during initial pegloticase treatment course in achieving this in patients without contraindication to MTX.
AUTHOR CONTRIBUTIONS
All authors contributed to at least one of the following manuscript preparation roles: conceptualization AND/OR methodology, software, investigation, formal analysis, data curation, visualization, and validation AND drafting or reviewing/editing the final draft. As corresponding author, Dr LaMoreaux confirms that all authors have provided the final approval of the version to be published and takes responsibility for the affirmations regarding article submission (eg, not under consideration by another journal), the integrity of the data presented, and the statements regarding compliance with institutional review board/Declaration of Helsinki requirements.
ROLE OF THE STUDY SPONSOR
Amgen, Inc (formerly Horizon Therapeutics) played a role in the study design, analysis and interpretation of the data, the writing of the manuscript, and the decision to submit the manuscript for publication. Publication of this article wascontingent upon approval by Amgen Inc.