Negative adcom vote on Arcalyst puts gout approval in doubt


The writing was on the wall for Regeneron’s Arcalyst in gout when Novartis’ Ilaris was rejected last year. Blocking the pro-inflammatory activity of interleukin-1 has been shown to be an effective way of reducing painful flares, but with use of anti-gout medications expected to rise safety worries have once again trumped efficacy.

In the case of Arcalyst, six cases of cancer proved too much for an FDA advisory committee to back the Regeneron compound, a unanimously negative vote surely ensures the company will not be able to tap a new revenue stream. The outcome did not trouble investors too much, shares fell 3% to $127.29 in early trade; the New York company is far more dependent on the performance of its marketed eye drug Eylea and cancer drug Zaltrap, now awaiting approval.

Safety worries

Like Ilaris, Arcalyst has been approved to treat rare genetic autoimmune conditions grouped under the cryopyrin-associated periodic syndromes (CAPS) banner (Ilaris sucumbs to its fate with FDA gout rejection, August 30, 2011). The New York group launched Arcalyst in 2008 and it achieved sales of $20m in 2011; EvaluatePharma’s forecast puts sales at $225m in 2018, nearly all of it in gout.

Gout is the result of elevated uric acid levels in the bloodstream, causing crystals to form and collect in joints, causing inflammation. Typical treatment for painful periods of symptom flare ups include NSAIDs while preventive treatment involves urate lowering therapies such as allopurinol or Takeda’s Uloric. Paradoxically, the frequency of gout flares following the initiation of maintenance therapy increases.

As an antagonist to IL-1, Arcalyst has been shown to block the joint inflammation characteristic of gout, and Regeneron aimed it at preventing flares during the first 16 weeks of urate lowering therapy.

However, as an immunosuppressant the FDA was always concerned about the risk of opportunistic infection – one of the safety worries that felled Ilaris in gout – and cancer. As Regeneron brought the compound through its clinical programme, the regulator pushed for a larger safety database than the one amassed during the CAPS trials because of the larger gout population; the safety database was expanded from 500 to 1,353 patients.

In briefing materials submitted to the expert panel, the regulator’s staff noted that the overall treatment effect was statistically significant, but modest: a mean of 1 gout flare in the 16 week treatment period for patients taking placebo, compared with 0.3 in patients taking Arcalyst.

Meanwhile, six cases of cancer were reported, the FDA said. There was little safety data beyond the 16 week treatment period, which the FDA characterised as “not typical” for a biological immunosuppressant.

The panel narrowly supported the efficacy claim with a 6-5 vote, but with an 8-3 vote against the adequacy of safety data the ultimate outcome was sealed – a unanimous 11-0 vote against approval. Anything other than a rejection by Arcalyst’s July 30 PDUFA date would be a huge surprise.


If anything, the effective disposal of IL-1 inhibitors in gout could be a glimmer of good news in the otherwise bad-news story that is AstraZeneca. Its acquisition of Ardea BioSciences two weeks ago brought on board the next-most-advanced candidate in the gout space, lesinurad, a novel add-on to allopurinol now in phase III that some reckon could flirt with blockbuster sales in 2018 if it succeeds (AstraZeneca hopes to take off heat with gout acquisition, April 23, 2012).

There is clearly unmet need: gout patient numbers are expected to grow with increases in obesity, dietary changes and metabolic disorders. Meanwhile, allopurinol is thought to be effective in as little as 40% of the patients taking it (Therapeutic focus - Gout pipeline looks thin but holds promise, May 26, 2011).

Thus, patients, specialists and the regulator are all hoping for more effective treatments. But the fates of Ilaris and Arcalyst confirm that the regulator is likely to be just as careful with gout therapies as it is with drugs for obesity or any other condition with a huge addressable population.

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