AstraZeneca is convinced its new gout therapy lesinurad is effective, but niggling discrepancies in clinical trials have prevented the company from hitting a clinical home run.
The good news for AZ is that data from a phase III trial presented at the European League against Rheumatism (EULAR) meeting in Rome this week showed that lesinurad given in combination Takeda’s xanthine oxidase inhibitor Uloric (febuxostat) was able to reduce levels of serum uric acid (sUA) – a biomarker for gout – better than Uloric alone.
The CRYSTAL study looked at two doses of lesinurad – 200mg and 400mg – and at the higher dose level 76% of patients met sUA targets, compared to 47% with febuxostat alone after six months.
The problem for AZ however is that the 200mg dose – which is the one filed for approval in Europe and the US – did not do so well. Here, while the combination performed better than Uloric alone at most time points, it failed to show a significant improvement at six months, the primary endpoint in the trial.
AZ elected to file the 200mg dose of lesinurad with the European and US regulatory authorities because there was a worrying risk of kidney toxicity at the higher dose.
Added to that, the lesinurad/febuxostat combination did not achieve a significant improvement compared to febuxostat alone in the proportion of subjects achieving a complete resolution of at least one ‘tophus’ – a deposit of uric acid crystals in joints and skin – after 12 months.
AZ insists however that its candidate drug did result in greater total tophus area reduction compared to febuxostat alone, and this view was backed up by a pooled analysis of data from all three phase III trials of lesinurad which collectively showed a reduction in gout flares and tophus area compared to xanthine oxidase inhibitors given alone.
The data inject an extra degree of uncertainty into the regulatory reviews of lesinurad, which at one point had been predicted to become a blockbuster given that between 40% and 80% of patients do not achieve sUA goals with an XO inhibitor alone.
AZ acquired lesinurad as part of its $1.3bn takeover of Ardea Biosciences in 2012. The acquisition also provided a second gout candidate called RDEA3170 that is in mid-stage clinical development.
CymaBay says novel candidate promising
Meanwhile, EULAR also saw new phase II data on a novel candidate for gout in development at CymaBay Therapeutics.
The drug – called arhalofenate – lowers serum uric acid by a uricosuric effect and also has an anti-inflammatory activity that suppresses flares. A once-daily dose of the drug achieved significantly greater reductions in sUA levels when combined with febuxostat than febuxostat alone, according to the trial data.