Date: 2013-06-04
Type of information: Initiation of preclinical development
phase: 3
Announcement: results
Company: AstraZeneca (UK)
Product: fostamatinib
Action
mechanism: enzyme inhibitor/kinase inhibitor. Fostamatinib (previously referred to as R788), is the first kinase inhibitor with selectivity for SYK (spleen tyrosine kinase) in development as an oral treatment for rheumatoid arthritis. Fostamatinib blocks signalling in multiple cell types involved in inflammation and tissue degradation in rheumatoid arthritis and it is hypothesized that it may hinder key steps in the progression of the disease. In February 2010, AstraZeneca and Rigel Pharmaceuticals announced a worldwide license agreement whereby AstraZeneca will develop and commercialise fostamatinib.
Disease: rheumatoid arthritis
Therapeutic area: Autoimmune diseases – Inflammatory diseases - Rheumatic diseases
Country:
Trial
details: OSKIRA-1 randomised 923 patients who had experienced an inadequate response to methotrexate (MTX) and, over a 24 week period, evaluated the effectiveness of two dosing regimens of fostamatinib (100 mg twice daily or fostamatinib 100 mg twice daily for four weeks followed by 150 mg once daily) in combination with MTX versus placebo in combination with MTX. Patients on fostamatinib remained on treatment in OSKIRA-1 for 12 months. (NCT01197521)
The ongoing (Oral SYK Inhibition in Rheumatoid Arthritis) OSKIRA programme, has been designed to investigate fostamatinib as a potential new oral treatment option for rheumatoid arthritis and an alternative to injectable therapies for patients with an inadequate response to conventional Disease Modifying Anti-Rheumatic Drugs (DMARDs), including methotrexate (OSKIRA-1 and OSKIRA-2 (NCT01197534) and those with an inadequate response to TNF-alpha antagonists (OSKIRA-3 - NCT01197755).
Latest
news: OSKIRA1 OSKIRA2 OSKIRA3 100 mg bid 49%, p<0.001 39.6%, p<0.001 36.2%, p=0.004 100 mg bid/150 mg qd 44%, p=0.006 39.6%, p<0.001 27.8%, p=0.168 Placebo 34% 24.5% 21.1%* On June 4, 2013, Rigel Pharmaceuticals and AstraZeneca have announced the topline results from OSKIRA-2 and OSKIRA-3, the remaining pivotal Phase 3 clinical trials investigating fostamatinib, the first oral spleen tyrosine kinase (SYK) inhibitor in development for rheumatoid arthritis.
In the OSKIRA-2 study of patients inadequately responding to disease modifying anti-rheumatic drugs (DMARDs), fostamatinib in combination with DMARDs showed statistically significant improvements in ACR20 response rates at 24 weeks in both the 100 mg twice daily (bid) group and the group receiving 100 mg bid for four weeks followed by 150 mg once daily (qd) compared to placebo.
In the OSKIRA-3 study of patients inadequately responding to methotrexate (MTX) and a single TNF-alpha antagonist, fostamatinib in combination with MTX showed statistically significant improvements in ACR20 response rates at 24 weeks in the 100 mg bid group, but not in the group given 100 mg bid for four weeks followed by 150 mg qd compared to placebo.
In the OSKIRA-2 study of patients inadequately responding to disease modifying anti-rheumatic drugs (DMARDs), fostamatinib in combination with DMARDs showed statistically significant improvements in ACR20 response rates at 24 weeks in both the 100mg twice daily group and the group receiving 100mg twice daily for four weeks followed by 150mg once daily (39.6%, p
In the OSKIRA-3 study of patients inadequately responding to methotrexate (MTX) and a single TNF-alpha antagonist, fostamatinib in combination with MTX showed statistically significant improvements in ACR20 response rates at 24 weeks in the 100mg twice daily group (36.2%, p=0.004) but not in the group given 100mg twice daily for four weeks followed by 150mg once daily (27.8%, p=0.168) compared to placebo (21.1%).
The safety and tolerability findings for fostamatinib observed in the OSKIRA Phase III programme were generally consistent with those previously reported in earlier studies. The most commonly reported adverse events in the OSKIRA programme include hypertension, diarrhoea, nausea, headache and nasopharyngitis (common cold).
Based on the totality of results from the OSKIRA Phase III programme, including the data previously reported from OSKIRA-1, AstraZeneca has decided not to proceed with regulatory filings for fostamatinib. AstraZeneca will return the rights to the compound to Rigel Pharmaceuticals which will decide whether it will continue the ongoing studies and pursue regulatory filings.Fostamatinib ACR20 Scores
Fostamatinib continues to be well tolerated by patients. The safety findings in both the OSKIRA-2 and OSKIRA-3 studies were generally consistent with those observed in the prior OSKIRA-1 study as well as the TASKi Phase 2 program.
Based on the totality of the results of the OSKIRA Phase 3 program in patients with RA, AZ has decided that it will not proceed with regulatory filings and will return the rights to the compound to Rigel.
Fostamatinib remains an important asset for Rigel. It is the most advanced oral SYK inhibitor in development and may have applications in patients with RA as well as other potential indications. Over the next couple of months, Rigel will collect and review the results of AZ's extensive development efforts with fostamatanib and determine the appropriate path forward.
* On April 5, 2013, AstraZeneca has announced top-line results of OSKIRA-1, a Phase III study to assess the efficacy and safety of fostamatinib in development for rheumatoid arthritis (RA). OSKIRA-1 had two primary endpoints: assessing signs and symptoms of RA as measured by ACR20 response rates, and an X-ray endpoint known as mTSS (modified Total Sharp Score).
As a result of this decision, AstraZeneca will incur a pre-tax impairment charge of approximately $140 million to R&D expense in the second quarter of 2013 for the intangible assets relating to fostamatinib. Since intangible asset impairments (except for IS-related intangibles) are excluded from the company’s Core financial measures, this impairment will have no impact on the company’s financial guidance for 2013, which is provided on a Core financial measures basis. As AstraZeneca will continue to incur some Core R&D costs associated with the completion of ongoing studies for fostamatinib, there is no change to the company’s guidance that it expects to hold Core operating costs for 2013 (combined Core SG&A and Core R&D) to a slight increase compared with 2012 on a constant currency basis.
In the OSKIRA-1 study, fostamatinib achieved a statistically significant improvement in ACR20 response rate at 24 weeks in both the 100 mg twice daily group and the group that received 100 mg twice daily for four weeks followed by 150 mg once daily (49%, pThe safety and tolerability findings for fostamatinib observed in the OSKIRA-1 study were generally consistent with those previously reported for the TASKi Phase II programme. The most commonly reported adverse events were typical of those seen in earlier studies, including hypertension, diarrhoea, nausea, headache and nasopharyngitis (common cold).
AstraZeneca will now await the results of the remaining Phase III studies, OSKIRA-2 and OSKIRA-3, to further evaluate and characterise the profile of fostamatinib as a potential treatment for rheumatoid arthritis. Results of these two studies are expected later in the second quarter of 2013.
