AstraZeneca fostamatinib (R788) significantly improved outcomes of patients with rheumatoid arthritis (RA) who responded inadequately to ongoing treatment with methotrexate (MTX).
Phase II Study Published in the New England Journal of Medicine
AstraZeneca's (LSE: AZN) new oral syk inhibitor, fostamatinib (R788), recently in-licensed from Rigel Pharmaceuticals, Inc. (Nasdaq: RIGL), significantly improved outcomes of patients with rheumatoid arthritis (RA) who responded inadequately to ongoing treatment with methotrexate (MTX), according to phase II study data published in The New England Journal of Medicine today.
In the six-month phase IIb study completed by Rigel, known as TASKi2, 67% of patients taking fostamatinib 100mg twice daily achieved the primary efficacy endpoint (ACR 20)at six months, which was significantly higher than placebo. Thirty-six percent of patients achieved an ACR 20 response after just one week. Speed of onset may be an important factor in RA because permanent joint damage can occur when the disease is active. The most common adverse events included diarrhea and upper respiratory infection.
"In this study, we saw a significant clinical benefit in this rheumatoid arthritis population and a manageable safety profile," said Mark C. Genovese, Division of Rheumatology, Stanford University, Palo Alto, CA. "Based on the data, further study of fostamatinib as an oral agent for the treatment of patients with rheumatoid arthritis is certainly warranted."
Patients in the study had active RA despite treatment with MTX alone, and were given either fostamatinib 100mg twice daily (bid), fostamatinib 150mg once daily (qd), or placebo. Significant clinical benefits were reported in both fostamatinib groups in the key efficacy endpoints of the American College of Rheumatology (ACR) patient assessment criteria and Disease Activity Score (DAS) 28*remission criteria.
After six months:
The ACR 20 response was achieved by significantly more patients in both the fostamatinib 100mg bid group and the fostamatinib 150mg qd group (67% and 57% respectively) than the placebo group (35%, p<0.001).
The ACR 50response rates were 43%, 32% and 19% for the fostamatinib 100mg bid group, 150mg qd group and placebo group respectively (p<0.01). The ACR 70response rates were 28%, 14% and 10% for the fostamatinib 100mg bid group, 150mg qd group and placebo group respectively (p<0.001 for fostamatinib 100mg bid, p=0.34 for fostamatinib 150 mg qd).
In addition, the DAS 28 remission rate was significantly higher in both the fostamatinib 100mg bid group and the fostamatinib 150mg qd group (31% and 21% respectively), compared to the placebo group (7%, p<0.01).
The published data indicates that the most common drug-related adverse events in the study were diarrhea (19% in 100mg bid group, 12% in the 150mg qd group and 3% in the placebo group), upper respiratory infection (15%, 7% and 7% respectively) and neutropenia (6%, 7% and 1% respectively). Hypertension (BP>140/90) occurred more frequently in fostamatinib treated patients than placebo (29% across both fostamatinib groups compared to 17% in placebo group) as had been previously reported. The hypertension generally occurred within the first few weeks of therapy and was responsive to conventional anti-hypertensive medications.
There were a similar proportion of patients who had at least one adverse event (AE) among the placebo group and the fostamatinib groups (65%). Ninety-four percent of eligible patients enrolled in an ongoing long-term open label extension study. The low rate of withdrawals is additional evidence that the adverse events were manageable in the patients studied.
AstraZeneca plans to commence the phase III clinical trial program for fostamatinib shortly. The phase III program, called OSKIRA (Oral Syk Inhibition in Rheumatoid Arthritis), is expected to begin in the second half of 2010.
The ACR 20 response criteria is defined as greater than or equal to 20% improvement from baseline in both tender and swollen joints, and greater than or equal to 20% improvement in three of five measures: pain, acute phase reactant, physical function, patient and physician global assessment. ACR 50 and ACR 70 assess greater than or equal to 50% improvement and greater than or equal to 70% improvement in those areas respectively. *DAS 28 is a measure of the activity of Rheumatoid Arthritis assessing 28 joint counts in the body
About Fostamatinib -Fostamatinib (previously referred to as R788), is the first oral syk inhibitor in development as a novel therapeutic approach for RA. It is thought to reversibly block signaling in multiple cell types involved in inflammation and tissue degradation in RA.
In February 2010, AstraZeneca and Rigel Pharmaceuticals announced a worldwide license agreement whereby AstraZeneca will develop and commercialize fostamatinib.
About RA -Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disease, which causes damage to the joints and other organs, affecting approximately 1 in 100 people. It is a major cause of disability and is also associated with reduced life expectancy, especially if not adequately treated.
About the TASKi2 Study Design -TASKi2 was a 6 month, multi-center, randomized, double-blind, placebo controlled, parallel dose clinical trial involving 457 RA patients in the U.S., Latin America and Europe who had active RA despite treatment with MTX alone. Approximately 1/3 of the patients (n=152) studied received 100mg of fostamatinib orally bid. Another third received 150mg of the study drug qd and the final third were given placebo to be taken orally bid or qd (total placebo n=153). Throughout the study all patients continued to receive their stable dose of MTX.
About AstraZeneca -AstraZeneca is a global, innovation-driven biopharmaceutical business with a primary focus on the discovery, development and commercialization of prescription medicines. As a leader in gastrointestinal, cardiovascular, neuroscience, respiratory and inflammation, oncology and infectious disease medicines, AstraZeneca generated global revenues of US $32.8 billion in 2009. For more information please visit: www.astrazeneca.com.
About Rigel -Rigel is a clinical-stage drug development company that discovers and develops novel, small-molecule drugs for the treatment of inflammatory/autoimmune, muscle and metabolic diseases. Rigel's pioneering research focuses on intracellular signaling pathways and related targets that are critical to disease mechanisms. Rigel's productivity has resulted in strategic collaborations with large pharmaceutical partners to develop and market its product candidates. Current product development programs include fostamatinib (R788), an oral syk inhibitor that is expected to enter phase III clinical trials for rheumatoid arthritis in 2010, and R343, an inhaled syk inhibitor that is in clinical trials for asthma.
Rigel Forward-Looking Statements -This press release contains "forward-looking" statements, including, without limitation, statements related to plans to pursue further clinical development of R788 (fostamatinib), including the timing thereof. Any statements contained in this press release that are not statements of historical fact may be deemed to be forward-looking statements. Words such as "estimate," "anticipate" and similar expressions are intended to identify these forward-looking statements. These forward-looking statements are based upon Rigel's current expectations and involve risks and uncertainties. There are a number of important factors that could cause Rigel's results to differ materially from those indicated by these forward-looking statements, including, without limitation, risks associated with the timing and success of clinical trials and other risks detailed from time to time in Rigel's SEC reports, including its Quarterly Report on Form 10-Q for the quarter ended June 30, 2010. Rigel does not undertake any obligation to update forward-looking statements and expressly disclaims any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein.