Synthesis of Lesinurad, AstraZeneca’s potential blockbuster drug
AstraZeneca’slesinurad(formerly known as RDEA-594) is a selective oral Uric Acid Transporter URAT1 inhibitor currently in Phase III development for the treatment of of gout. The regulatory filings for lesinurad in the US and Europe are expected for the first half of 2014.
Gout (also known as podagra when it involves the big toe), while not life-threatening, is an excruciatingly painful condition caused by a buildup of a waste product in the blood called uric acid, which is normally eliminated from the body through urine. Excess Uric acid crystallizes and get deposited in the joints (usually the big toes), creating symptoms similar to an acute arthritis flare. Gout has seen a recent gradual resurgence as a result of rising obesity rates and poor diet according to a study in the journal Annals of the Rheumatic Diseases.
The current Standard treatment for gout works by inhibiting a protein called xanthine oxidase that helps in the formation of the uric acid. These therapies, some of which have been used for more than 50 years, are not effective in all patients. One is a generic drug calledallopurinolthat was approved in the U.S. in 1966. The other isfebuxostat, marketed by Takeda Pharmaceutical Co. in the U.S. asUloricand by Ipsen SA and others in Europe asAdenuricand approved in the U.S. in 2009.
AstraZeneca’s new product Lesinurad, a selective uric acid re-absorption inhibitor (SURI), tackles gout by blocking a protein called Uric acid trasporter 1 (URAT1) that otherwise would cause the body to reabsorb the uric acid. AstraZeneca acquired lesinurad (aka RDEA-594) as part of its $1.26 billion takeouver of San Diego-basedArdea Biosciencesin 2012. RDEA594 is a metabolite of RDEA806, a non-nucleoside reverse transcriptase inhibitor originally developed for HIV.
In top-line results from a Phase III LIGHT study released by AstraZeneca in December 2013 on gout patients who get no benefit from Zyloprim (allopurinol) and febuxostat, lesinurad alone significantly reduced serum levels of uric acid. The company has three other phase III studies ongoing that are testing the use of the drug alongside allopurinol and febuxostat, and these should generate results in the middle of 2014. Analysts at JPMorgan Chase forecast lesinurad alone may have peak sales of $1 billion a year. AstraZeneca also has a second, more potent drug called RDEA3179 to treat elevated levels of uric acid or hyperuricemia. Pfizer’s KUX-1151, licensed from Japan’s Kissei Phmarceuticals, is in early stage development.
Gout is not an automatic success indication of drugmakers. Savient Pharmaceuticalsfiled for Chapter 11 bankruptcy in October 2013 in the face of a severe cash crisis, having spent hundreds of millions of dollars on its would-be flagship — the gout-fighting drugKrystexxa(pegloticase) — with limited results. Krystexxa (pegloticase), a twice-monthly infusion designed to treat severe chronic gout that doesn’t respond to conventional therapy, was approved by the U.S. Food and Drug Administration in September 2010. Crealta Pharmaceuticals acquired Savient for $120.4 million in December 2013.