New Gout Drugs Might Increase Patients at Target Urate Level

VIENNA — Safe and effective options for lowering serum uric acid (sUA) in patients with gout who are refractory to conventional therapies appear to be near, judging from phase 2 and 3 trials that produced positive results at the European Alliance of Associations for Rheumatology (EULAR) 2024 Annual Meeting.

Reports from the meeting included two phase 2 studies with novel urate anion transporter 1 (URAT1) inhibitors for patients with refractory gout, in addition to extension data from the phase 3 trial program for SEL-212. In all cases, efficacy appeared to be on the same order of currently available drugs with potentially better tolerability, an important unmet need for patients with gout refractory to traditional therapies.

12-Month Outcomes With SEL-212

The extension data with SEL-212 follow the 6-month results presented from the DISSOLVE I and II trials at EULAR 2023. Now at 12 months, the benefits have proven to be generally sustained with no new safety signals, according to Herbert S.B. Baraf, MD, The Center for Rheumatology and Bone Research, Wheaton, Maryland.

SEL-212 is a drug platform involving two components delivered by intravenous infusion once monthly in sequence. The first, SEL-110, consists of tolerogenic nanoparticles containing sirolimus. The second, SEL-037, is the pegylated uricase pegadricase.

On the 1-month dosing schedule, most patients who had responded at 6 months were still responding at 12 months, and both of the two study doses of SEL-212 in the DISSOLVE trials were well tolerated over the extension, Baraf reported.

On the basis of the data so far, “this will be an effective and well tolerated therapy for refractory gout over a period of at least 12 months,” Baraf said.

The DISSOLVE I and II trials were identically designed. Patients with refractory gout, defined as failure to normalize sUA or control symptoms with a xanthine oxidase inhibitor, were randomly assigned to receive 0.15 mg SEL-212, 1.0 mg SEL-212, or placebo.

There was a stopping rule for patients who reached a sUA level < 2 mg/dL 1 hour after the infusion.

The primary endpoint was sUA level < 6 mg/dL for at least 80% of the sixth month of the 6-month trial. About 50% of patients on either dose of SEL-212 met this endpoint (vs 4% of those receiving placebo; P < .0001). There was a numerical advantage for the higher dose in both studies.

Patients who completed the 6-month trial were eligible for a 6-month extension, during which they remained on their assigned therapy, including placebo. This phase was also blinded. Patients who met the stopping rule in either the main study or extension did not take the study drug but remained in the study for final analysis.

Of the 265 patients who participated in the main phase of the study, 143 (54%) completed the 6-month extension. Most discontinuations were the result of the stopping rule. Reasons for other patients discontinuing the study included withdrawal of consent in about 10% of each treatment arm and adverse events in 13.8%, 6.8%, and 2.2% of the high-dose, low-dose, and placebo groups, respectively.

At 12 months, when the data from the two trials were pooled, the proportion of patients on therapy and responding remained at about 50% in the high-dose group and 43% in the low-dose group on an intention-to-treat analysis. Relative to the 8% response rate for placebo, the advantage for either dose was highly significant (P < .0001).

In the subgroup of patients with tophi at baseline, representing about half the study group, responses were low at 12 months, whether on high- (41%) or low-dose (43%) SEL-212. The rate of response among placebo patients with baseline tophi was 9%.

Safety of SEL-212; Lack of Infusion Reactions

The safety over the 6-month extension did not differ substantially from that observed during the first 6 months, according to Baraf. This was reiterated in more detail by Alan Kivitz, MD, Altoona Center for Clinical Research, Duncansville, Pennsylvania. He delivered a separate safety presentation focused on DISSOLVE I.

Specifically, there were no serious adverse events thought to be related to treatment. Besides gout flares, which affected approximately 27% of patients regardless of active treatment or placebo assignment, the most common adverse effect was hypertriglyceridemia, which was observed in 5.4% of patients on active treatment vs 0% of those receiving placebo. Independent of the treatment arm, less than 5% of patients developed stomatitis or cellulitis during the 6-month extension period.

Unlike pegloticase, a drug with which SEL-212 might compete, there were no infusion reactions observed after SEL-212 administration, according to Kivitz. This observation is consistent with the randomized COMPARE study, led by Baraf and published last year. In that study, the major advantage of SEL-212 over pegloticase in patients with refractory gout was lower dosing frequency (once vs twice monthly), which along with a reduced risk for infusion reactions reduces the treatment burden, according to Baraf.

New Selective URAT Inhibitors

The other potential advance in the treatment of refractory gout is coming from newer selective URAT1 inhibitors. According to the lead investigators of two phase 2 trials evaluating a novel URAT1 inhibitor, the urate transporter protein has long been considered the most promising target for gout treatment. As this protein regulates the absorption of uric acid from the renal tubule, it has a direct uric acid–lowering effect. However, the adverse events of current agents, such as probenecid, benzbromarone, and sulfinpyrazone, have created a need for drugs with a better benefit-to-risk ratio.

In one of two multicenter phase 2 studies on refractory gout, the experimental agent ruzinurad was tested as an adjunct to the xanthine oxidase inhibitor febuxostat. In the other, the objective was to evaluate whether the experimental agent AR882 or AR882 plus allopurinol is better than allopurinol alone for reducing tophi at 12 months.

Ruzinurad Plus Febuxostat

In the ruzinurad trial, 151 patients with symptomatic gout and elevated sUA (> 6 mg/dL) for at least 6 weeks on stable doses of febuxostat were randomized to receive 5 mg ruzinurad, 10 mg ruzinurad, or placebo. All remained on febuxostat. In the active treatment arms, the starting ruzinurad dose was 1 mg before titrating up to the assigned target.

For the primary endpoint of sUA < 6 mg/dL at 12 weeks, the rates were 56.9%, 53.1%, and 13.7% in the high-dose, low-dose, and placebo groups, respectively (P < .0001 for both ruzinurad arms), reported Huihua Ding, MD, a clinician and researcher at the Shanghai Jiao Tong University, Shanghai.

“Consistently, subgroup analyses based on baseline eGFR [estimated glomerular filtration rate], sUA, and tophus demonstrated superior effective of ruzinurad plus febuxostat over placebo plus febuxostat,” reported Ding, who noted that previous clinical studies suggested the potential for synergism between ruzinurad and febuxostat.

The proportion of patients achieving the more rigorous target of < 0.5 mg/dL was also higher with the higher and lower doses of ruzinurad vs placebo (43.1% and 38.8% vs 9.8%, respectively).

The proportion of patients with treatment-emergent side effects did not differ between the three groups. The most common were gout flares, which were observed in 39.2%, 49.0%, and 45.1% in the high-dose, low-dose, and placebo groups, respectively. Most adverse events were mild or moderate, and none led to treatment discontinuation.

The favorable benefit-to-risk profile of ruzinurad was attributed by Ding to its high relative selectivity and potent inhibition of URAT1, an advantage that might be relevant to avoiding side effects at higher doses.

AR882 in Patients With Tophi

In the trial with AR882, 42 patients with refractory gout and at least one subcutaneous tophus were randomized to receive 75 mg AR882, 50 mg AR882 plus allopurinol, or allopurinol alone. All drugs were taken once daily. Doses of allopurinol of up to 300 mg were permitted.

The changes in the target tophus area and crystal volume at month 6 were compared, and patients who completed this phase were invited into a 6-month extension. In the 6-month extension, 75 mg AR882 was additionally provided to those who had been in the single-agent allopurinol arm. The other arms were unchanged.

Tophi measurements were performed with calipers at regular intervals. Change from baseline in sUA levels was also an efficacy measure, according to Robert Keenan, MD, chief medical officer of Arthrosi Therapeutics, which is developing AR882.

From average baseline sUA levels of > 9 mg/dL, all three treatments reduced sUA levels by an average of at least 4.5 mg by month 3. At month 6, complete resolution of at least one target tophus was observed in 29% of the group randomized to receive 75 mg AR882 alone, 8% of those randomized to receive 50 mg AR882 plus allopurinol, and 8% of those on allopurinol alone.

At month 12, the average sUA levels were 4.3 mg/dL for 75 mg AR882, 3.7 mg/dL for 50 mg AR882 plus allopurinol, and 2.9 mg/dL for the 75 mg AR882 plus allopurinol extension-switch arm.

At the 12-month mark, the proportions of patients with complete resolution of any tophus were 50.0% for 75 mg AR882, 12.5% for 50 mg AR882 plus allopurinol, and 36.4% for the 75 mg AR882 plus allopurinol extension-switch arm, according to Keenan.

Compared with allopurinol alone at 6 months, 75 mg AR882 led to a reduction in total urate crystal volume, and this reduction was sustained at 12 months, he added.

Alone or in combination with allopurinol, AR882 was well tolerated. Gout flares were the most common adverse events, but they declined with continued AR882 treatment, according to Keenan. Diarrhea, headache, and upper respiratory infections were reported but were of mild or moderate severity.

Again, the take-home message from this study, like the other phase 2 study of a novel URAT1 inhibitor, is that these newer drugs might offer a better benefit-to-risk ratio, particularly in those with refractory disease.

“AR882 may offer improved efficacy and better safety compared to existing therapies in the treatment of patients with gout, including those with both clinically visible and subclinical crystal deposition,” Keenan said.

Baraf reported financial relationships with Horizon Therapeutics, Fresenius Kabi, Grünenthal, Olatec, Selecta Biosciences, and Sobi, which provided funding for the trials he discussed. Kivitz also reported a financial relationship with Sobi, which funded the DISSOLVE trials, along with AbbVie, Amgen, Eli Lilly, Flexion, GlaxoSmithKline, and Sanofi-Regeneron. Ding reported no potential conflicts. The study she discussed was funded by Jiangsu Hengrui Pharmaceuticals. Keenan is an employee of Arthrosi Therapeutics, which provided funding for the trial he presented.