Spotlight – Few signs of gout pipeline flaring up

Gout has long proved problematic for drug developers, but this week the disease moved into the spotlight for another reason. The FTC pointed to Krystexxa’s monopoly position as a reason for its reluctance to approve Amgen’s takeover of that drug’s owner, Horizon.

A look at the pipeline provides some support for this position. There is only one project that might challenge Krystexxa in the chronic gout setting anytime soon: Selecta and Swedish Orphan Biovitrum’s SEL-212, which will be filed with regulators next year. Otherwise, research is mostly being done by Asian developers running regionally focused programmes that seek to provide new options for earlier stages of the disease.

Gout is treated with different drugs depending on how advanced the painful arthritic disease has become, but toxicity is a widespread problem at all stages. Allopurinol, a 50-year-old drug that remains a mainstay once a patient has moved beyond pain relief or steroids, can cause severe hypersensitivity reactions.

Asian and black populations are particularly prone to these reactions, while people of Asian descent are at a higher risk of developing gout in the first place. This presumably helps explains the heavy presence of Asian developers highlighted below.

Most of these research projects are seeking to offer alternatives to allopurinol or febuxostat, generically available xanthine oxidase inhibitors (XOIs) that work by decreasing the uric acid produced by the body. Febuxostat, sold as Uloric by Takeda before its patent expired, has since 2019 carried a black box warning regarding increased risk of death from heart problems.

Gout, a form of metabolic arthritis, is caused by the buildup of uric acid in the joints, resulting in severe inflammation and pain and the formation of disfiguring lumps called tophi.

Products based on uricase, which can degrade urate crystals in joints that cause tophi, have been developed for refractory or chronic gout. At this stage patients no longer respond to XOIs. Formulating uricase for long-term use has proved far from straightforward, however, with immunogenicity another big issue.

Krystexxa was the first pegylated uricase to prove effective, but it comes at a cost: the product carries a lengthy black box warning of anaphylaxis, infusion reactions and G6PD deficiency-associated haemolysis and methemoglobinemia.

The drug, which requires prophylactic antihistamines and intravenous steroids, is given as an IV infusion over at least two hours every two weeks; on top of the anaphylaxis risk, it frequently causes gout flares to increase in the first few months of treatment. Despite all this Krystexxa is on track to generate sales of $800m this year.

A safer uricase

The opportunity for a safer uricase-based product is clear; this would probably find demand even if it failed to improve on Krystexxa’s efficacy. Topline results from two pivotal trials suggest that Selecta and Sobi’s SEL-212 might fit the bill, with the caveat that full data have yet to be published.

SEL-212 also contains a pegylated recombinant uricase, combined with Selecta’s immune tolerance technology. This is called ImmTor, and is said to reduce immunogenicity. Antidrug antibodies, which reduce the product’s efficacy and contribute to the severe allergic reactions, have been detected in around 40% of Krystexxa-treated patients.

A cross-trial comparison, which comes with the usual caveats, points to similar response rates between a high-dose cohort of SEL-212 versus Krystexxa. Between 47% and 56% of patients met the primary response criteria in the Dissolve trials, compared with a 38-47% response rate on Krystexxa’s label.

Krystexxa combined with methotrexate arguably wins out with a response rate of 71%, although this will not be an option for all patients.

Perhaps more important is SEL-212’s safety profile, with no increase in gout flares reported over the placebo arms. Two cases of anaphylaxis were seen across the programme, however.

Whether these data make the grade will soon be the regulator’s job to decide. Mizuho analysts reckon SEL-212 has sales potential of $500m-1bn in the US, but it worth remembering that the project has previously disappointed, failing to beat Krystexxa in a phase 2 study.