AstraZeneca’s new oral syk inhibitor, fostamatinib (R788), recently in-licensed from Rigel Pharmaceuticals, Inc, 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 50 response rates were 43%, 32% and 19% for the fostamatinib 100mg bid group, 150mg qd group and placebo group respectively (p<0.01). The ACR 70* response 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 programme for fostamatinib shortly. The phase III programme, called OSKIRA (Oral Syk Inhibition in Rheumatoid Arthritis), is expected to begin in the second half of 2010.