Tophus burden reduction with pegloticase: results from phase 3 randomized trials and open-label extension in patients with chronic gout refractory to conventional therapy

Abstract

Introduction: Two replicate randomized, placebo-controlled six-month trials (RCTs) and an open-label treatment extension (OLE) comprised the pegloticase development program in patients with gout refractory to conventional therapy. In the RCTs, approximately 40% of patients treated with the approved dose saw complete response (CR) of at least one tophus. Here we describe the temporal course of tophus resolution, total tophus burden in patients with multiple tophi, tophus size at baseline, and the relationship between tophus response and urate-lowering efficacy.

Methods: Baseline subcutaneous tophi were analyzed quantitatively using computer-assisted digital images in patients receiving pegloticase (8 mg biweekly or monthly) or placebo in the RCTs, and pegloticase in the OLE. Tophus response, a secondary endpoint in the trials, was evaluated two ways. Overall tophus CR was the proportion of patients achieving a best response of CR (without any new/enlarging tophi) and target tophus complete response (TT-CR) was the proportion of all tophi with CR.

Results: Among 212 patients randomized in the RCTs, 155 (73%) had ≥ 1 tophus and 547 visible tophi were recorded at baseline. Overall tophus CR was recorded in 45% of patients in the biweekly group (P = 0.002 versus placebo), 26% in the monthly group, and 8% in the placebo group after six months of RCT therapy. TT-CR rates at six months were 28%, 19%, and 2% of tophi, respectively. Patients meeting the primary endpoint of sustained urate-lowering response to therapy (responders) were more likely than nonresponders to have an overall tophus CR at six months (54% vs 20%, respectively and 8% with placebo).

Conclusions: Pegloticase reduced tophus burden in patients with refractory tophaceous gout, especially those achieving sustained urate-lowering. Complete resolution of tophi occurred in some patients by 13 weeks and in others with longer-term therapy.

Trial registrations: NCT00325195, NCT01356498.

Figure 1

Illustration of a hypothetical patient showing the target tophus responses and overall tophus response. The diagram shows the tophus scoring system for a sample patient with four baseline tophi (three measurable and one unmeasurable). Tophus area was defined for each measurable tophus using the longest dimension and its perpendicular axis. The circle marks the unmeasurable tophus. Each baseline target tophus was rescored at all subsequent study visits. The patient illustrated in the figure had a best “overall” response of complete response (CR) because the patient had at least one target tophus response of CR and no new or progressing tophi at any time during the study. PR, partial response; SD, stable disease.

Figure 2

Consolidated Standards of Reporting Trials Statement (CONSORT) diagram for the pooled tophus-evaluable population. This population flowchart shows the disposition of all patients with baseline tophi pooled from the two randomized, placebo-controlled trials of pegloticase known as GOUT 1 and GOUT 2. OLE, open-label extension; RCT, randomized controlled trial.

Figure 3

Digital images showing complete resolution of tophi in two patients who received pegloticase biweekly. (A) Photograph of patient 1 showing baseline tophus on the medial aspect of the patient’s right third distal interphalangeal (DIP) joint. (B) Photograph of patient 1 showing complete resolution of target tophus at week 13. Note also the reduction in the area of a large tophus on the third proximal interphalangeal joint. (C) Photograph of patient 2 showing baseline tophi on the patient’s right thumb; on the second, third and fourth DIP joints with ulcerations; and on the fifth proximal interphalangeal joint after six months of treatment with placebo in the randomized controlled trials. (D) Photograph of patient 2 showing complete resolution of target tophi on four digits after 25 weeks of treatment with twice-monthly pegloticase in the open-label extension study.