Novel Drug Lowers Urate Levels but Gout Flares Persist

BARCELONA, Spain — The investigational oral compound SAP-001 had a significant and sustained urate-lowering effect in people with refractory gout, according to findings of a phase 2b study reported at the European Alliance of Associations for Rheumatology (EULAR) 2025 Annual Meeting.

The proportion of people achieving a target serum urate level of < 6 mg/dL (360 µ mol/L) after 12 weeks was 10.5% for placebo and ranged from 43.8% to 70.0% for those given one of three different once-daily doses of SAP-001.

A dose response was not seen in the main analysis, however; the proportions of people meeting this primary efficacy endpoint were 43.8% (n = 32) for a 60-mg dose but 56.3% (n = 16) and 70.0% (n = 20) for 10- and 30-mg doses, respectively.

This could have been because of issues with adherence, said the presenting author Kenneth Saag, MD, professor and director of the Division of Clinical Immunology and Rheumatology at The University of Alabama at Birmingham.

Ad hoc analyses, which had not been preplanned, showed that “some subjects had not been exposed to the drug post baseline,” Saag said. “This seemed to strongly correlate with adherence to therapy, as indicated by [a patient’s daily] dosing diary, pill counts, and post-study patient interviews.”

When people with nonquantifiable serum urate levels were excluded from the analyses, there was more of a dose response, particularly if a lower urate level of < 5 mg/dL (300 µ mol/L) had been achieved.

Notably, Saag reported that the urate-lowering effects were maintained until the end of treatment at 6 months, and a good proportion of participants also met the harder target of a serum urate level of < 5 mg/dL.

First-in-Class

“SAP-001 is a drug that has a different renal urate transporter mechanism of action from other urate-lowering drugs that are currently available or are under development,” said Saag, a former president of the American College of Rheumatology.

Although Saag did not present the specific mode of action for the drug, he noted, “it appears to predominantly be targeting GLUT [glucose transporter] 9, which is located on the basal lateral aspect of the renal tubule.” 

This differs from most other uricosuric therapies, which targeted renal transporters on “the apical side of the tubule, such as OAT [organic anion transporters] and URAT [urate transporter]-1,” he added.

“So this drug has the potential as a novel therapeutic option in gout,” Saag said.

Study Design and Patient Population

The study was a 6-month randomized, double-blinded, placebo-controlled investigation of three different doses of SAP-001 for the management of refractory gout.

A total of 403 adults with refractory gout between 18 years and 75 years of age who were living in the US were screened for eligibility, with 87 finally randomized. For inclusion, participants had to either have not responded to at least 4 weeks of standard of care treatment with a xanthine oxidase inhibitor prior to study entry or have a contraindication to its use. They also had to have serum urate levels of ≥ 7 mg/dL at both the screening and randomization visit.

A 1:1:1:2 ratio was used to randomly allocate participants to the four treatment groups: placebo or SAP-001 10 mg, 30 mg, or 60 mg.

Baseline characteristics were reasonably similar among the four groups. The mean ages in each group were 55.9 years, 54.2 years, 50.3 years, and 52.5 years, respectively. The majority were men (89.5%, 87.5%, 90.0%, and 96.9%, respectively), and most identified themselves as White and Hispanic individuals.

The mean BMI was around 32, and baseline serum urate levels were about 8.37 mg/dL (~500 µ mol/L).

The average duration of gout since diagnosis was about 10 years, and 1 in 5 had palpable tophi.

Safety Findings

Saag and associates reported in their abstract that SAP-001 was well tolerated overall.

There were no treatment-emergent serious adverse events in the SAP-001 patients, and all adverse events were of a mild to moderate intensity.

The most frequently reported adverse events were gout flares; these occurred in 26.3% of placebo-treated individuals and in 25%, 30%, and 25% of participants treated with SAP-001 10 mg, 30 mg, and 60 mg, respectively.

The majority of these gout flares occurred within the first few months of the study, although some people taking SAP-001 experienced gout flares up to 4-6 months later.

The longest duration of gout flares in the SAP-001 groups was 11.5 days in the 60-mg SAP-001 group, and the shortest was 6.2 days in the 30-mg group. The mean durations of gout flares in the 10-mg and placebo groups were 6.5 and 7.4 days, respectively.

The time to the first gout flare was shortest in the 30-mg SAP-001 group, at 21.2 days, followed by 40.5 days in the 60-mg group, 50.3 days in the 10-mg group, and 66.4 days in the placebo group.

As for adverse events of special interest, one participant who had taken the 30-mg dose of SAP-001 developed a hepatobiliary disorder, and another who had taken this dose had raised aspartate aminotransferase, an outcome that also occurred in one patient each in the 10- and 60-mg dosing groups.

Increased blood creatinine levels were seen in two participants in the 10-mg group and three in the 60-mg group. Hepatic enzymes were elevated in one patient in the placebo group and one patient in the 30-mg group. One patient in the 60-mg group had acute kidney injury.

Limitations and Conclusion

Saag acknowledged that this was an early-phase study, and its small sample size meant the effect on flares and tophi was limited.

However, he concluded that SAP-001 may be a “novel, efficacious, and generally safe oral urate-lowering treatment option for difficult-to-treat gout populations, and it merits further investigation with a focus on treatment adherence.”

Helga Lechner-Radner, Wien, Austria, who co-chaired the late-breaking abstract session during which Saag had presented these data, questioned whether people with genetic conditions that could cause hyperuricemia had been included or excluded from the study.

Saag responded: “That wasn’t specifically a form of [inclusion]/exclusion in this study; in future studies, that would certainly be reasonable to look at.”

This study was funded by Shanton Pharma. Saag reported acting as a consultant to Shanton Pharma as well as Amgen, Arthrosi, ATOM, Crystalys, LG, and Sobi. He also reported being an investigator for Arthrosi, Crystalys, Inventis, and LG. Several coauthors on the abstract were employees of Shanton Pharma.

Sara Freeman is a freelance medical journalist based in London, England.