AstraZeneca's PhIII gout data for lesinurad includes a hit, a strikeout and a missing player

Last summer AstraZeneca ($AZN) claimed a major success for its late-stage combination program for lesinurad, a new drug for gout obtained in their $1.26 billion buyout of Ardea. And the company followed through today by detailing the data from two of the three studies investigators heralded, which showed that the treatment hit the desired biomarker for blood levels of uric acid as promised--but added today that it failed to actually reduce the rate of painful flare-ups of the disease for patients in the study. Nevertheless, the pharma giant says it's lining up regulatory submissions in a delayed lunge at gaining marketing approval.

As trumpeted by AstraZeneca last August, the two studies--CLEAR1 and CLEAR2--hit the primary endpoints on a significant reduction of uric acid in the blood. Elevated uric acid levels can trigger gout flares. Combined with generic allopurinol, lesinurad--a uric acid re-absorption inhibitor--registered a clear response among treatment-resistant patients compared to those in the control arm, who received the generic alone. Looked at by dividing the patient groups in the study into allopurinol alone and in combination with 200 mg and 400 mg of lesinurad, the following percentages hit their respective blood level goals: CLEAR1--28%, 54% and 59%; CLEAR2--23%, 55% and 67%.

But the combinations didn't actually reduce the reported number of gout flares--attacks that can damage bone and cartilage as well as the kidney. According to AstraZeneca, "Among the key secondary endpoints of mean gout flare rates and patients with complete tophus resolution, no significant differences were observed for mean gout flare rates (end of month 6 to 12) or patients with complete tophus resolution."

Success for lesinurad is important for AstraZeneca's management team, led by CEO Pascal Soriot, which has been scrambling to prove that the pharma giant can effectively push new products through late-stage development to an approval after years of frustrating setbacks and reorganizations. Bernstein's Tim Anderson has projected potential 2020 sales for this drug at $582 million, making it one of the most valuable contenders in AstraZeneca's pipeline. And the principal investigator in the study says he wasn't surprised by the failure to identify a benefit in the reduction of the rate of flare-ups for patients in the study.

"In gout, we really need a new therapeutic option," says principal investigator Kenneth Saag, a professor at the University of Alabama, Birmingham. Only two drugs, allopurinol and febuxostat, are primarily used to treat the condition, which afflicts millions of people. "Regrettably, measuring flares in trials is exceptionally problematic," he added, as the flare-ups occur at home and aren't captured well in the data.

The primary endpoint in the study, though, is a "great biomarker" that regulators allow to demonstrate that a drug can deliver a better outcome for patients, Saag told FierceBiotech.

David Ginkel

"Gout is more than just flares and there is a great unmet need related to sUA, as we know 40-70% of patients on an XOI do not achieve their sUA goal," noted David Ginkel, who heads the lesinurad project for AstraZeneca, in a written response to a query from FierceBiotech.

"AstraZeneca is excited about lesinurad," he adds. "We are currently preparing regulatory submission packages for lesinurad (200 mg) as the first oral, once-daily chronic combination therapy for gout. It would not be appropriate to speculate on approvability until we complete these discussions with regulators. What I can say is that in this study, where patients were not achieving their sUA target on allopurinol, lesinurad significantly increased the number of patients reaching their target sUA goal. The [American College of Rheumatology] guidelines set a goal of achieving a sUA target (minimum <6), so this is important achievement and great news for gout patients and those who treat them."

The miss on flare-ups, though, could haunt AstraZeneca if it can get to the market, where payers will be forced to consider the benefits of a more expensive medication compared to a much cheaper generic.

AstraZeneca is also likely to face careful scrutiny of potential renal-related effects. Investigators noted that the incidence of renal-related adverse events and kidney stones was higher with lesinurad 400 mg plus allopurinol, which may explain why AstraZeneca is opting to go for an approval of 200-mg doses. Saag added that most renal-related adverse events were reversible, but regulators have an extremely low tolerance for that type of adverse event.

AstraZeneca also compared a combination of lesinurad and febuxostat with febuxostat in a separate Phase III trial, CRYSTAL, which was included in their top-line release with CLEAR1 and CLEAR2. In that study AstraZeneca got mixed results, hitting the primary endpoint with the high dose and missing on the low dose, with no word about gout flares. But there was no mention in AstraZeneca's PR today about that other late-stage study. Saag said he couldn't comment on just why the CRYSTAL data was not included in the data release today.

For his part, Ginkel didn't directly respond to a question about the reason for the delay in filing--AstraZeneca noted in its buyout release that applications were expected in the first half of 2014--and in place of citing actual numbers for flare-ups and the CRYSTAL data he noted that more results would be released at scientific meetings in 2015.

- here's the release