Spotlight – Few signs of gout pipeline flaring up
Asian developers dominate biopharma’s gout pipeline, with Selecta and Sobi’s SEL-212 standing out as a rare globally focused project.
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: the mid to late-stage pipeline|
|SEL-212 (pegsiticase)||Selecta/Sobi (3SBio has certain Asian rights)||Pegylated uricase plus mTOR inhibitor||Chronic gout focus: Dissolve 1 and Dissolve 2 topline reported|
|LC350189 (tigulixostat)||LG Chem||Xanthine oxidase inhibitor||Primary gout maintenance: US study Eurelia1 recruiting, PCD Dec 2024; Eurelia2 (vs allopurinol) listed but not yet recruiting|
|SHR4640||Jiangsu Hengrui Pharmaceuticals||URAT1 inhibitor||Primary gout maintenance: China study recruiting, PCD Jul 2024|
|Dapansutrile||Olatec Therapeutics||NLRP3 inflammasome inhibitor||Gout flare pain: ph2/3 enrolling, PCD Sep 2023|
|URC102/SIM0295 (epaminurad)||JW Group/Simcere||URAT1 inhibitor||Company moving into ph3 and then seeking global partners|
|ABP-671||Atom Bioscience||URAT1 inhibitor||Primary gout maintenance: plans to move into global pivotal development this year|
|AR882||Arthrosi Therapeutics||URAT1 inhibitor||Primary gout maintenance: ph2b completed, plans to push on into pivotal development|
|SAP-001||Shanton Pharma||URAT1 inhibitor||Primary gout maintenance: ph2b trial recently started recruiting in the US|
|D-0120||InventisBio||Unclassified||Primary gout maintenance: ph2 programme ongoing in China|
|HP501||Hinova Pharmaceuticals||URAT1 inhibitor||Ph2 ongoing in China|
|SSGJ-613||3SBio||IL-1B MAb and anti-IL1 β MAb||Gout flare pain: ph1/2 China study started mid-2022, PCD Sep 2023|
|DYV-702||Dyve Biosciences||Unclassified||Gout flare pain: ph2 trial completed, further plans unclear|
|Source: Evaluate Pharma, clinicaltrials.gov & company websites.|
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.
A couple of developers are seeking to address gout flares and the associated pain. Novartis's Ilaris is approved in Europe here, although the FDA has long refused to greenlight this interleukin approach in gout, knocking back both Novartis and Regeneron.
Most of the work in Asia is focused on providing safer options to XOIs. Western developers are virtually absent here, likely the result of a series of disappointments that have punctured interest, and the heavily genericised market for these earlier treatments.
One of these disappointments was, in a sense, Krystexxa, despite its status as the biggest-selling branded gout drug. Its tormented development sent Savient into bankruptcy after which, via various owners, the product ended up in Horizon’s hands. Ardea’s lesinurad was an even bigger disaster, being bought and ultimately written off by Astrazeneca at a cost of $1.2bn.
Lesinurad, a URAT-1 inhibitor, was pulled from the market in 2016 by its then owner, Ironwood, for commercial reasons. The drug was linked with kidney failure, prompting the FDA to mandate postmarketing studies, which diminished its prospects even further against cheap generic XOIs.
The search is on for safer URAT-1 inhibitors, which work by increasing the excretion of uric acid through the urine. Atom Bioscience might soon join the late-stage pipeline here, with a project that it claims is a highly potent uric acid lowerer, with no serious side effects reported in its phase 2 programme. The private Chinese group has said it plans to start a global pivotal programme this year.
Another China-based company, Jiangsu Hengrui, is already in phase 3 with another URAT-1 inhibitor, although it is unclear whether this project will be developed for non-domestic markets.
South Korea’s LG Chem and China’s Shanton Pharma have also expressed global ambitions. They will presumably face the same commercial challenges as lesinurad’s developers, although all profess to own safer options.
Either way, it seems that Krystexxa will own the market for chronic gout for some time yet.