High-Dose Lesinurad Deemed Unsuitable as Monotherapy for Gout
Lesinurad is a selective uric acid reabsorption inhibitor.
Despite rapidly lowering serum uric acid (sUA) levels, lesinurad, a selective UA reabsorption inhibitor, cannot be recommended alone at 400 mg per day because of substantial adverse events (AEs). This was the conclusion of the Lesinurad Monotherapy in Gout Subjects Intolerant to Xanthine Oxidase Inhibitors (LIGHT) study.
The LIGHT study consisted of a 6-month, phase 3, multicenter, randomized double-blind placebo-controlled treatment period (core study; Clinicaltrials.gov identifier: NCT01508702), and a follow-up open-label, uncontrolled extended-stage study (extension study; Clinicaltrials.gov identifier: NCT01650246) conducted to examine the short- and long-term safety and efficacy of lesinurad.
Approved for combination therapy with a xanthine oxidase inhibitor (XOI) at 200 mg per day, researchers were interested in whether 400 mg daily of lesinurad monotherapy could demonstrate clinical benefit. Because some patients exhibit a contraindication or intolerance to XOIs (allopurinol or febuxostat), finding a new agent has potential benefit. And since only probenicid (in the US and European Union [EU]) and benzbromarone (in the EU) are approved for use, the researchers hoped to add another. They were particularly focused on renal safety, as kidney impairment is a common comorbidity in gout.
A total of 214 patients with gout (91.1% men; 81.8% white; mean, 11.2 years since diagnosis; average sUA, 9.3 mg/dL) with sUA ≥6.5 mg/dL, and who were intolerant to xanthine oxidase inhibitors, were randomly assigned to receive placebo (n=107) or lesinurad (400 mg orally once daily; n=107). Randomization was stratified by renal function using estimated creatinine clearance and tophus status.
Lesinurad showed an advantage over placebo in sUA reduction, with 29.9% vs 1.9% of patients achieving sUA <6.0 mg/dL at 6 months, the trial's primary outcome (P <.0001). Patients taking lesinurad also achieved secondary sUA end points of <5.0 and <4.0 mg/dL at a rate of 14.0% and 3.7%, respectively. None of the study participants who received placebo attained these levels. Gout flares at 6 months occurred in 11.8% vs 14.6% (P =.68) of patients in the lesinurad and placebo groups, respectively, with both groups demonstrating low rates of gout flares requiring treatment.
Treatment-emergent AEs (TEAEs) were reported by 77.6% and 65.4% of subjects in the lesinurad and placebo groups, respectively. The most frequent TEAEs reported by patients in the lesinurad vs placebo group were elevated blood creatinine level (8.4% vs 0.0%), constipation (5.6% vs 0.0%), diarrhea (9.3% vs 5.6%), nausea (6.5% vs 4.7%), and renal impairment (4.7% vs 0.0%). TEAEs “possibly related to randomized study medication” were 29.9 vs 10.3% in the lesinurad and placebo arms, respectively. Other laboratory results were comparable between groups, and vital signs remained stable throughout the study. Serious TEAEs occurred in 8.4% of those taking lesinurad and in 3.7% of those taking placebo. Renal safety analysis showed kidney-related AEs in 17.8% of the lesinurad group and 0.0% of the placebo group. Of these, 4.7% experienced a serious AE of renal impairment or renal failure. Serum creatinine and estimated creatinine clearance levels were disproportionately increased and reduced, respectively, in the lesinurad vs placebo groups.
The extension study enrolled 88.3% of patients from the core study and involved a daily dose of 400 mg lesinurad for all participants. A total of 58.7% and 24.5% completed 6 and 12 months of treatment, respectively, prior to premature closure because of concerning renal data from the core study that resulted in regulatory intervention.
In the extension study, 73.4% of patients experienced a TEAE, with increased creatinine levels (11.2%), hypertension (7.0%), and upper respiratory infection (9.8%) most commonly reported. AEs possibly related to study medication were reported by 25.2% of patients, and 16.8% experienced renal complications. "Patients receiving lesinurad 400 mg had a higher incidence of TEAEs, grade 3 or 4 TEAEs, serious TEAEs and TEAEs that led to randomized study medication discontinuation compared with placebo," noted the researchers.
Strengths of the LIGHT study included the addition of another uricosuric agent to the regimen, and the proven ability of lesinurad to lower sUA. Limitations included short duration, single dose, limited number of patients with moderate renal impairment, and low percentage of women participants.
Although lesinurad proved effective in rapidly lowering sUA for a sustained period, the high incidence of associated TEAEs prevented the study from continuing. Therefore, the authors do not recommend lesinurad at 400 mg daily for monotherapy of gout.
Editor's Note: This article's headline and content were updated on December 4, 2017.
Tausche AK, Alten R, Dalbeth N, et al. Lesinurad monotherapy in gout patients intolerant to a xanthine oxidase inhibitor: a 6 month phase 3 clinical trial and extension study [published online September 23, 2017]. Rheumatology (Oxford). doi:10.1093/rheumatology/kex350