Induced and pre-existing anti-polyethylene glycol antibody in a trial of every 3-week dosing of pegloticase for refractory gout, including in organ transplant recipients

Abstract

Introduction: Pegloticase, a PEGylated recombinant porcine uricase, is approved for treating refractory gout at a dose of 8 mg intravenous (IV) every 2 weeks. However, during phase 1 testing, pharmacokinetics supported less frequent dosing. Also, single doses of pegloticase unexpectedly induced antibodies (Ab) that bound to polyethylene glycol (PEG). We have conducted a phase 2 trial to evaluate every 3-week dosing, and to further define the Ab response to pegloticase. Organ transplant recipients were included, as they are prone to severe gout that is difficult to manage, and because treatment to prevent graft rejection might influence the immune response to pegloticase.

Methods: Plasma uricase activity (pUox), urate concentration (pUA), and clinical response were monitored during up to 5 infusions in 30 patients, including 7 organ transplant recipients. Depending on whether pUA <6 mg/dL was achieved and maintained, patients were classified as non (NR), persistent (PR), or transient (TR) responders. Ab to pegloticase and 10 kDa mPEG were monitored by enzyme linked immunosorbent assay and specificity was further defined.

Results: We observed 17 PR, 12 TR, and 1 NR; 21 patients (16 PR, 5 TR) received all 5 infusions. Over the 15-week trial, pUA in PR averaged 1.0 ± 0.4 mg/dL; T½ for pUox was approximately 13 days, and area under the curve after dose 5 was approximately 30% higher than after dose 1. PR showed clinical benefit and in some, tophi resolved. In 11 of 12 TR, pUox fell rapidly and hyperuricemia recurred before dose 2. In all TR and NR, loss of response to pegloticase was accompanied by Ab to PEG, which was pre-existing in half of those who had no prior exposure to pegloticase. No PR, and 1 one out of 7 organ transplant recipients, had a sustained Ab response to pegloticase.

Conclusions: Every 3-week dosing is effective and may enhance the utility of pegloticase for treating refractory gout. Ab to PEG, which were pre-existing or induced by treatment, caused rapid loss of efficacy and increased the risk of infusion reactions. Organ transplant recipients can benefit from pegloticase, and may be less prone than non-recipients to developing anti-PEG Ab. Investigation of immunosuppressive strategies to minimize anti-PEG Ab is warranted.

Trial registration: ClincalTrials.gov identifier: NCT00111657.

Figure 1

Pharmacokinetics and pharmacodynamics of pegloticase infused at three-week intervals. Panels A and B: Data for the first pegloticase dosing cycle on all 29 patients. (A) Plasma uricase activity (pUox), plotted on a logarithmic scale (y-axis). The dashed line at 1 mU/mL is shown as a reference. (B) Plasma uric acid concentration (pUA). The dashed line at 6 mg/dL is shown as a reference. Symbols: blue = patients with a persistent response to pegloticase (PR); red = patients with a transient response to pegloticase (TR); open red triangles = 3 non-naïve TR, who had received pegloticase >1 year prior to the present trial. P-values shown are for comparison of the means for PR and TR. Panels C and D: Mean pUox and pUA during all five dosing cycles for PR (C) and TR (D). Symbols: blue circles = pUox; red squares = pUA; n = number of patients under treatment in each cycle. Error bars, standard deviation.

Figure 2

Antibody response to pegloticase. Screening ELISAs for Ab to pegloticase (A) and10 kDa mPEG (B). Horizontal axis: N = non, P = persistent, T = transient responder. Symbols: blue = pre-treatment; red = highest A405 during the trial; triangles = the non-responder. (C) Correlation between the anti-pegloticase and anti-10 kDa mPEG ELISAs. The highest A405 values during treatment from 2A and B are re-plotted. Symbols: blue = persistent (P), red = transient (T), green = non-responder (N). (D) Correlation between ELISAs for Ab to pegloticase and PEGylated adenosine deaminase (PEG-ADA). Conditions for the ELISAs were the same except for the plate coating. Two samples, obtained on Day 0 (open symbols) and at the final visit (filled symbols) from six patients (distinguished by symbol shape) were studied. Competition ELISA (see Methods). (E). Pre-treatment. The non-responder (blue underline) and three previously treated patients (blue asterisks) are indicated on the horizontal axis. (F). Post-treatment. The last sample obtained from each Ab-positive patient was tested to minimize competition from circulating pegloticase (pUox was undetectable or <0.3 mU/mL). Data plotted are the mean and SEM for the 13 samples tested.

Figure 3

Evolution of Ab to pegloticase and relation to pUox and pUA in three patients with a transient response to treatment with pegloticase. (A-C) Change during treatment in pUox (left vertical axis) and in the ELISAs for Ab to pegloticase (right vertical axis). (D) Change during treatment in pUA for the same three patients.

Figure 4

Pre-infusion (trough) pUA as a marker for a significant antibody response to pegloticase. All pUA determinations obtained immediately prior to each infusion of pegloticase (nominally 21 days after the preceding infusion) are plotted. The dashed line at 6 mg/dL is shown as a reference. (A) Persistent responders (blue symbols). The open circles and open triangles represent data for the two PR who had single pre-infusion (trough) pUA values >6.0 mg/dL. (B) Transient responders (red symbols). The asterisks represent data for the single TR in whom any pre-infusion (trough) pUA <6 mg/dL was observed.

Figure 5

Resolution of digital tophi in a persistent responder. (A). Prior to treatment with five doses of pegloticase, 8 mg, infused at three-week intervals. (B). At follow-up visit.