Lesinurad data far from a crystal clear win for Astra

Lesinurad has hardly been the star of AstraZeneca’s vaunted pipeline, and pivotal trial data disclosed today show why. Kidney toxicity has prompted the UK group to drop plans to seek approval for the higher of two doses tested, and the lower dose failed to improve on the efficacy of Takeda's UIoric when the two drugs were tested in combination.

The current consensus suggests that lesinurad’s sales should just about justify the $1bn Astra shelled out to buy Ardea Biosciences in 2012, but today’s news ought to raise doubts over whether the group can achieve even these modest forecasts. The gout space is crowded and heavily genericised, and although many patients are not receiving drug therapy, cheaper and safer drugs will be favoured first over lesinurad if treatment expands.

Can you do better?

Astra announced topline results from three phase III trials of lesinurad, a urate transporter 1 (URAT1) inhibitor. The Clear 1 and 2 trials were in combination with allopurinol, a mainstay of gout treatment for 48 years, and Crystal was in combination with Uloric. The Takeda drug is a xanthine oxidase inhibitor like allopurinol, but is much more potent; it reached the market in 2009.

Both the 200mg and 400mg daily dose of lesinurad, when combined with allopurinol, beat allopurinol alone on the primary endpoint, a statistically significant higher proportion of patients achieving serum uric acid levels of less than 6mg per decilitre of blood after six months of treatment. In the Crystal trials, only the 400mg dose met the endpoint, set at a goal serum uric acid level of 5mg/dl.

Across the three trials, the 400mg dose plus a xanthine oxidase inhibitor resulted in an elevated number of kidney stones and other renal adverse events. Astra did not detail efficacy or safety data beyond the topline findings as it is submitting the studies to a scientific meeting – however, the fact that the group will not file the 400mg dose speaks volumes.

The dose response should certainly raise concerns for regulators, and the compromised renal function in many gout patients will almost certainly limit the commercial promise of lesinurad should it get the backing of the FDA, EMA and other national drug agencies.

Shrinking significance

Astra shares were little moved today after the announcement, a sign that little is expected from this project. Lesinurad was not in the spotlight when the group hyped its pipeline as it fought off the Pfizer takeout bid earlier this year; oncology, anti-inflammatory and respiratory drugs were, on the other hand (Don’t blame Soriot, he’s just doing his job, May 7, 2014).

Nonetheless, this was one of the bigger clinical results the group was expecting before the end of 2014, demonstrating how speculative the Astra bull case remains. Lesinurad sales are forecast at $544m in 2020, giving the project a net present value of $1.2bn, according to EvaluatePharma’s consensus. It would not be surprising to see these numbers slip in the coming weeks as analysts take a more pessimistic view with news of modest efficacy and safety worries.

With gout prevalence expected to grow as obesity rates rise, and many patients receiving suboptimal treatment, there could yet be an opportunity for a drug that can reduce uric acid levels in the blood without testing the kidneys. It is looking less and less like lesinurad is that drug.

To contact the writer of this story email Jonathan Gardner in London at [email protected] or follow @JonEPVantage on Twitter