Assistant Managing Editor

Speed was a critical factor when Rigel Pharmaceuticals Inc. signed AstraZeneca plc to a potential $1.2 billion deal back in February, and the big pharma followed through as expected with the launch of a massive Phase III program for oral Syk inhibitor fostamatinib in rheumatoid arthritis.

The start of pivotal studies, plus the transfer of an open-label study to AstraZeneca, also triggered $25 million in milestone payments to the South San Francisco-based biotech and puts fostamatinib (formerly R788) hot on the heels of Pfizer Inc.'s late-stage disease-modifying antirheumatic drug (DMARD) tasocitinib, an oral JAK inhibitor set to unveil its first Phase III data at the upcoming American College of Rheumatology meeting.

Overall, there were no big surprises in the study designs, which are similar both to Pfizer's ongoing program and to Rigel's own earlier Phase II studies showing strong responses in patients whose disease was not adequately treated by methotrexate. (See BioWorld Today, Dec. 14, 2007.)

The OSKIRA (Oral Syk Inhibition in Rheumatoid Arthritis) program will include a total of three studies: two 900-patient, 12-month trials testing fostamatinib on patients responding inadequately to DMARDs, including MTX, and a 450-patient, six-month study testing the drug on patients who previously responded inadequately to treatment with antitumor necrosis factor therapies. Two dose regimens will be tested, the first evaluating 100 mg twice daily and the second testing 100 mg twice daily for four weeks followed by a 150 mg once-daily maintenance dose.

ACR 20 response rates will be the primary endpoints for all three studies.

Based on the drug's earlier data, Oppenheimer & Co. analyst Bret Holley sees a "high probability" that fostamatinib will show improvements in the two studies involving DMARD failures. But the third trial is riskier, since fostamatinib previously missed its mark in a Phase II study enrolling patients who had failed to respond to prior biologic, including anti-TNF, therapy. (See BioWorld Today, July 27, 2009.)

At that time, Rigel executives called those disappointing data "inconsistent" and "confusing," but anticipated no effect on partnering plans. And, sure enough, the firm landed the AstraZeneca collaboration early this year in exchange for $100 million up front. In addition to the recently earned $25 million in milestones, Rigel also is eligible for up to $345 million in development, regulatory and initial sales milestones plus up to $800 million in commercial milestones. On top of that, there's a stepped, double-digit royalty. (See BioWorld Today, Feb. 17, 2010.)

London-based AstraZeneca also provides some much-needed muscle if Rigel hopes to position fostamatinib against Pfizer's tasocitinib (CP-690-550). Though Pfizer's drug, pending Phase III success, would hit the market first, R788's quick onset of action and potential for once-daily dosing could give it a sales advantage. If fostamatinib proves its mettle in Phase III, AstraZeneca has anticipated regulatory filings in 2013.

Pfizer is expected to present further Phase II data at the ACR meeting in Atlanta in November, and analysts are anticipating that initial data from its Phase III monotherapy study as a late-breaker presentation. Data from the Phase III program testing tasocitinib in patients who inadequately respond to MTX are due in 2011.

And the New York-based pharma firm isn't the only one with a JAK program in RA. Last year, Incyte Corp. inked a potential $645 million deal with Eli Lilly and Co. for its Phase IIa JAK1/JAK2 inhibitor. (See BioWorld Today, Dec. 22, 2009.)

But Rigel has the most advanced Syk (spleen tyrosine kinase) inhibitor aimed at RA. Syk is believed to be involved in inflammation and tissue degradation; therefore, blocking Syk signaling could prove attractive in treating RA.

So far, safety data have been fairly promising, though the hypertension risk remains "the key outstanding question," Oppenheimer's Holley wrote in a research note. He added, however, that the risk-benefit ratio likely would be acceptable as long as the drug is positioned as a later-line therapy.

Fostamatinib also has shown early efficacy in other indications, such as lymphoma and idiopathic thrombocytopenic purpura.

Rigel, which boasted about $187 million in the bank as of June 30, also has in its pipeline another Syk inhibitor, R343, in early clinical testing in allergic asthma.

Shares of the company (NASDAQ:RIGL) were flat Wednesday, closing at $8.40.