New Approaches Emerge for a Prevalent Nemesis: Gout

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Incidence of gout has increased globally during the past quarter-century, spurring the development of new, more effective therapies aimed at chronic gout.

"Gout is the most common inflammatory arthritis in the world, and existing treatments rarely achieve target serum urate levels,” said Shunqi Yan, Ph.D., founder and chief operating officer of Arthrosi Therapeutics in an interview with BioSpace. “As patients continue to be undertreated with current therapies, monosodium urate crystals (called tophi) continue to accumulate in the joints and tendons, worsening flares, joint erosions and disability.”

An aging, more sedentary population is one of the reasons for the uptick, along with purine-rich diets (such as red and organ meats, anchovies, sardines, mussels, scallops, trout and tuna, as well as alcoholic beverages and drinks high in fructose). Genetic associations may also be involved. These conditions each can cause uric acid levels to increase.

Inhibiting and Degrading Uric Acid

Scientists are exploring three broad ways to address this. The first tries to inhibit the production of uric acid, degrade it or enhance its ability to leave the body.

“One category of treatments uses xanthine oxidase inhibitors, notably allopurinol, to reduce the production of uric acid in your body,” said Roy Wu, SVP of global business development for Atom Bioscience.

Allopurinol is the standard of care, yet “Its efficacy is only about 40 to 45 percent,” Wu said. Its safety profile needs improvement, too. “It’s not very well tolerated, causing a skin reaction (Stevens-Johnson Syndrome) and GI problems. It also requires titration over a long period of time, which means doses can’t be adjusted rapidly," he noted.

While a few companies are investigating iterations of xanthine oxidase inhibitors, a scan of ClinicalTrials.gov shows more activity focused on other approaches.

Metabolizing Uric Acid

Synlogic, for one, is working to metabolize uric acid in the GI tract with an engineered strain of a probiotic bacteria, said Dave Hava, Ph.D., chief scientific officer.

“We hypothesize there is a significant gut component to uric acid metabolism – that uric acid can come from the diet through purine metabolism, but that it also could recirculate in the systemic circulation into the GI tract and be secreted back out, in a kind of loop.

“We hypothesized that if we could design a bacteria that encounters uric acid in the GI tract, breaks it down into something non-toxic and prevents its reabsorption into systemic circulation, it could ultimately lower uric acid levels in the plasma,” Hava explained.

Preclinical data from the prototype strain support that hypothesis. Non-human primate studies show the engineered strain Synlogic designed is active and can reduce systemic levels of uric acid. “We anticipate releasing more preclinical data on SYNB2081 later this year,” Hava said.

Synlogic worked with Ginkgo Bioworks to design the prototype probiotic strain, essentially programming it to be effective under the conditions prevalent in gout.

“Biology is fundamentally programmable,” said Patrick Boyle, Ph.D., head of Codebase, at Ginkgo Bioworks. “If you think about the substrate of biology that we’re engineering, we’re rewriting genetic code. Many of the same principles apply between digital code and software code. While biology is infinitely more complex than computer code, changing an A to a T affects how the cell reads that DNA code and changes its behavior.”

Ginkgo used that approach with Synlogic to design organisms for a particular purpose.

Another company, Allena Pharmaceuticals, has Fast Track designation for its orally-absorbed enzyme to treat gout and chronic kidney disease. When kidneys are impaired, uric acid is eliminated through the GI tract, so ALLN-346 degrades urate there in a way that prevents it from being absorbed systemically. Allena completed enrollment of a Phase IIa outpatient study 202 in July. Results have not been released.

Urate Transporter 1 Inhibitors

A third approach is to cause the system to excrete uric acid more efficiently.

“About 85% of gout patients have a problem eliminating enough uric acid,” Yan said. A urate transporter 1 (URAT1) inhibitor, therefore, could fill a large unmet need. “There is an increasing body of evidence that URAT1 inhibitors may slow the progression of chronic kidney disease and also may have cardiovascular benefits,” he noted.

To that end, Arthrosi is developing AR882 to normalize uric acid excretion through the kidney. This would reduce circulating levels of uric acid throughout the body as well as the formation of monosodium urate crystals. The goal is to reduce serum urate levels below the 6mg/dL needed for disease control and, ideally, below 5mg/dL. AR882 “has been shown to be well-tolerated in clinical trials…and is the only oral therapy evaluating the tophi reduction potential in a Phase II study,” Yan said.

Arthrosi completed enrollment of more than 120 patients with chronic gout in a global Phase IIb study being conducted at 24 sites in the United States, Australia and Taiwan. The three-month study will evaluate dosage. In the earlier Phase IIa study, a 50 mg dose of AR882 reduced serum levels to below 5mg/dL in 93 percent of patients, whereas a 75 mg dose reduced levels below 4mg/dl in 88 percent of patients, suggesting it may also succeed in reducing flares.

Atom Bioscience is also concentrating on uric acid excretion. “ABP-671 is a URAT1 inhibitor, which helps block the reabsorption of uric acid back into the body through the kidney and thus to excrete uric acid,” Wu said. “This is a more direct approach to reducing uric acid from the body than reducing its production.” Early studies showed a nearly 30 percent reduction in uric acid during the first day of treatment, which Wu called significant.

Atom is finalizing the protocols for a Phase IIb/III study for chronic gout that likely will begin in 2023. It’s a six-month treatment and is expected to take six to nine months to enroll, so a readout in mid-2024 seems likely. Atom is thinking of ABP-671 as a possible first-line monotherapy, Wu said.