AstraZeneca’s Gout Drug Lesinurad Hobbled By Renal Risk

Lower dose of oral, uric acid transporter inhibitor shows good efficacy in two of three Phase III trials, but renal safety risk appears to limit lesinurad’s potential market – if it gets approved at all.

AstraZeneca PLC’s oral, selective uric acid re-absorption inhibitor lesinurad demonstrated efficacy in Phase III gout trials, but a kidney safety signal doesn’t bode well.

AstraZeneca’s top-line release of mixed results from three Phase III combination trials testing two doses (200 mg and 400 mg) in about 1,500 gout patients in total – CLEAR1, CLEAR2 and CRYSTAL – on Aug. 13 underscored potential risks with analysts.

The company plans to file only the lower dose, an approach analysts are taking as a sign of discomfort with the drug’s safety profile.

Renal adverse events and kidney stones were reported for the higher 400 mg dose of lesinurad in the CRYSTAL combo trial.

Lesinurad is an oral inhibitor of the uric acid transporter (URAT1) (Also see "Ardea's Phase III Program For Promising Gout Drug Begins To Take Shape" - Pink Sheet, 7 Jan, 2011.). AstraZeneca acquired the drug at high cost – over $1 billion – when it bought Ardea Biosciences Inc. in 2012 (Also see "AstraZeneca’s Ardea Acquisition: A Rich Deal Spurred By Phase III Gout Candidate" - Pink Sheet, 23 Apr, 2012.).

According to the BioMedTracker database, about 10 other drugs are in the global pipeline for gout, of which only one other is in the same class – Chugai Pharmaceutical Co. Ltd. /JW Pharmaceutical’s URC102, an oral Phase I candidate being developed ex-US.

The URAT1 target has been validated, but “because URAT1 is a kidney transporter protein, kidney toxicity is a prominent concern for lesinurad,” Cowen and Company analysts noted in their March 2014 Therapeutic Categories Outlook Report.

The potential market for gout drugs is theoretically large and following decades of little change in the treatment paradigm, new drugs have been introduced in recent years to tap into unmet need and stimulate demand (Also see "Gout Pipeline Looks Past Uloric To Resistant Patients, Acute Flares" - Pink Sheet, 1 Mar, 2009.).

AstraZeneca estimates that there were 15.3 million diagnosed cases of chronic gout in major markets in 2013, a figure that is set to grow to 17.7 million by 2021. However, generics are widely available, notably the xanthine oxidase inhibitor allopurinol, which has been around since the 1960s.

The generic uricosuric agent probenecid is recommended option for those who can’t reach targets with xanthine oxidate drugs. Probenecid is similar to lenisurad but it is “relatively weak and requires multiple daily dosing with large volumes of water,” Sagient analysts pointed out in a review of the latest trial results.

Because the efficacy of lesinurad monotherapy looks on par with a standard 300 mg dose of allopurinol, combination therapy has offered the best opportunity for the drug, Cowen analysts noted.

Mixed Results

The CLEAR1 and CLEAR2 studies evaluated two doses – 200 mg and 400 mg – of lesinurad with standard doses of allopurinol vs. allopurinol and placebo in symptomatic patients not able to reach target uric acid levels. Each trial had about 600 patients

Lesinurad demonstrated efficacy in helping patients reach target levels (6 mg/dlL) after six months of treatment, which was the primary endpoint, AstraZeneca reported. Details, however, were not disclosed.

As for safety, the three most common side effects in the combination arm were upper respiratory tract infection, nasopharyngitis and back pain.

In the CRYSTAL trial, lesinurad (200 mg or 400 mg) was combined with an 80 mg dose of the Takeda Pharmaceutical Co. Ltd.’s xanthine oxidase inhibitor Uloric (febuxostat), a reformulated and more expensive version of allopurinol, vs. febuxostat with placebo in 324 symptomatic gout patients. The 200 mg dose did not meet the primary efficacy endpoint for reducing uric acid levels after six months of treatment, though it did barely show significant efficacy at other time points. The combination with the 400 mg dose of lesinurad did show superior efficacy.

The three most common side effects for the combination arm were nasopharyngitis, arthralgia and upper respiratory tract infection.

Rates of renal adverse events were similar for those taking the 200 mg dose. But renal AEs and kidney stones were more common for the 400 mg arm compared to febuxostat/placebo.

“A full assessment of the safety and tolerability findings of all three studies is ongoing,” the company said.

In the Phase III LIGHT trial disclosed at the end of 2013, investigators had reported increases in serum creatinine levels with the 400 mg dose as a monotherapy in patients who could not take xanthine oxidase inhibitors.

Renal Red Flag May Limit Potential Label

Analysts warned of potential obstacles ahead.

“Whilst the nature of these events has not been disclosed, we are cautious that such a signal with a dose-response will be scrutinized by regulators, and will likely impact commercial potential (especially given that gout patients often have underlying renal disease),” UBS Equities analyst Alexanda Hauber said in an Aug. 13 note.

Even though the lower 200mg dose is being filed, the drug could still pose a risk, for example in patients with renal insufficiency, she said.

The gout market is large and there is unmet need, but on the other hand, given the availability of generics and practice patterns, “lesinurad needs a relatively clean profile to ensure uptake.”

Societe Generale’s analyst Stephen McGarry said in an Aug. 13 note that the results are mixed at best and raise risk for regulatory rejection.

Furthermore, he said that “even if lesinurad is approved either as a mono- or combination therapy, a label with a warning on renal side effects is likely” and the safety profile could limit the commercial market.

Consequently, Societe Generale has reduced its peak sales forecasts from $1.3 billion to $559 million.

The fact that AZ is not planning to submit the 400 mg dose for approval suggests “renal adverse event rates could be more of an issue than it is letting on,” said Mirabaud Equities analyst Nick Turner in an Aug. 13 note.

“This puts the risk/benefit profile of the 200mg dose in the spotlight, unfortunately too little efficacy/adverse event data has been released to allow us to make a valued judgment. However the fact AZN is restricting filing to the 200 mg dose and indication to combination therapy [not including monotherapy] suggests the company has concerns over the drug’s adverse event profile. A label warning on renal toxicity would be expected to compromise the drug’s commercial potential and renal toxicity could be a stumbling block on review.”

“The success of this trio of pivotal studies paves the way for lesinurad to move comfortably into a second-line setting,” BioMedTracker argues.

BioMedTracker looks at the same data through rosier glasses, however: “The success of this trio of pivotal studies paves the way for lesinurad to move comfortably into a second-line setting after initial allopurinol or febuxostat. Current guidelines recommend probenecid, a generic uricosuric agent (like lesinurad) for patients who do not reach sUA targets with allopurinol or febuxostat. However, probenecid is relatively weak and requires multiple daily dosing with large volumes of water. There was no indication of similar issues with lesinurad, although more details on the safety profile are needed,” the analysis notes.“Of course, quantitative efficacy details were not released either, but the success of both doses in the CLEAR studies as well as the efficacy shown as a monotherapy in the LIGHT study suggests that the efficacy will be sufficient for approval in a second-line setting and potentially in a front-line setting in combination with febuxostat,” BioMedTracker noted.