Uricase-based combo therapy promising for refractory gout

Half of gout patients receiving novel uricase analogue infusions, along with a proprietary rapamycin formulation, got their serum urate controlled in two phase III studies presented at EULAR 2023.

SEL-212 combines a pegylated form of uricase called pegadricase with “an immune-tolerizing nanoencapsulated rapamycin,” explained study author Dr Herbert Baraf of the Center for Rheumatology and Bone Research in Wheaton, Maryland, US during his presentation.

The rationale was that all uricase products appeared to inherently induce the formation of anti-drug antibodies which diminish their effectiveness. This has been the case with pegloticase, which is US FDA-approved for chronic gout refractory to conventional therapy in adult patients.

This is where the immunosuppressant rapamycin comes in. Rapamycin, administered 30 minutes prior to pegadricase infusion, is intended to forestall any immune reaction to the enzyme.

The two trials tested two doses of pegadricase (0.15 or 0.10 mg/kg) while the rapamycin dose was kept at 0.2 mg/kg. Infusions were given every 4 weeks for 6 months. [EULAR 2023, abstract LB0002]

Patients had gout flares, tophi, or gouty arthritis

The primary efficacy outcome in both studies was serum urate level. Treatment response was defined as serum urate below 6 mg/dL at least 80 percent of the time in multiple measurements taken during the treatment period.

Patients enrolled had at least three gout flares in the previous 18 months, one or more tophi, or a current diagnosis of gouty arthritis.

“Additionally, they must have failed to achieve serum urate control with at least one xanthine oxidase inhibitor and have not been exposed to uricase-based therapy,” Baraf shared. Serum uric acid had to be at least 7 mg/dL. Participants were balanced for age, BMI, and sex across treatment groups.

“Patients received steroids, antihistamines, and other agents around the infusions to suppress short-term reactions. Prophylaxis against gout flares was also provided,” he added.

The first trial, DISSOLVE I, involved 112 patients across 29 sites in the US, while the second, DISSOLVE II, enrolled 153 patients from 37 sites in the US, Russia, Ukraine, Georgia, and Serbia. Patients were randomly assigned to the two active drug doses or placebo. DISSOLVE I continued with a 6-month, blinded safety extension.

Baseline characteristics were similar in both studies. The patients' mean age was 55 years. Most of them were obese. Nearly all were men, with a 10–14-year history of symptomatic gout. Serum urate averaged about 8.5 mg/dL at enrolment.

The only difference was that patients in DISSOLVE II had greater gout severity, with higher mean counts of tender joints (11 vs 3) and swollen joints (5 vs 2), although these varied widely between patients in all study arms.

Better outcomes for SEL-212 than placebo

With the higher dose, the primary endpoint was achieved by 56 percent of patients in DISSOLVE I and 46 percent in the DISSOLVE II trial. The lower dose was less effective, with response rates of 48 percent and 40 percent, respectively.

In both studies, the outcomes were significantly better with SEL-212 than with placebo, which yielded responses in just about 4 percent and 11 percent of patients, respectively.

Results were similar when limited to the subgroup of patients aged 50 and older. However, in DISSOLVE I, there was a larger gap between the dosages (response rate of 65 percent with the high dose and 47 percent with the lower dose). Rates were comparable at 47 percent and 44 percent in DISSOLVE II.

“We also saw significant reductions in serum uric acid for all treatment groups vs placebo,” Baraf said. The mean percentage change was –62.3 percent and –58.3 percent in the high- and low-dose groups, respectively, in DISSOLVE I, and –58.1 percent and –52.2 percent in DISSOLVE II, respectively.

Safety data pooled from the two trials showed that 45 percent of patients irrespective of drug assignment had gout flares. Infections were reported in 23 percent, 18 percent, and 17 percent of the high-dose, low-dose, and placebo groups, respectively.

There were infrequent infusion reactions (7 percent in both active-treatment groups vs 2 percent in the placebo group). Serious adverse events were more common with SEL-212 (15 percent in the low-dose group, 7 percent with the high dose, and 2 percent with placebo). There were four anaphylaxis episodes reported.

The 6-month safety extension of the DISSOLVE I trial showed that 75 percent of patients who completed 6 months of SEL-212 treatment as responders were still on treatment at 12 months, with no infusion reactions or safety signals.

The best is yet to come

Baraf said more data are being awaited with enthusiasm on the clinical secondary endpoints targeted by SEL-212 therapy. This early, its manufacturer is already looking at US license applications next year.