Good catch. That's a possible buying op in the making. The return of the program to Rigel will likely come before the better news. Hope to have some dry powder at the time . . . I'm not that concerned about the BP, either. Half the pharmacological treatment options for RA have this issue. My take is folks are perhaps unfairly lumping FosD with COX-2 inhibitors , which have cardiovascular risks a bit beyond high BP.
hopkins-arthritis.org
That said, the FDA could be spooked by the different MOA causing a different cardiovascular risk, and requiring some kind of study to convince them otherwise. I haven't seen any preclinical studies on this.
Meanwhile, the protocol for the methotrexate non-responder trial is a bit instructive regarding the ESR/CRP issue:
165.112.8.96
Note also folks with history of cardiovascular issues are not included, so if there's a signal to be had they should get one. I see those two criteria in OSKIRA-3, as well.
For those who are interested and haven't yet looked, here's the program:
165.112.8.96
Just in case my memory is failing me, I did a quick dig into PubMed (keywords: fostamatinib & cardiovascular) & got one abstract. There are teratogenic issues, so we won't see pregnant women taking this, but I'm not get anything that would suggest cardio issues in adults.
>>Birth Defects Res A Clin Mol Teratol. 2009 Feb;85(2):130-6.
Developmental toxicity associated with receptor tyrosine kinase Ret inhibition in reproductive toxicity testing.
Clemens GR, Schroeder RE, Magness SH, Weaver EV, Lech JW, Taylor VC, Masuda ES, Baluom M, Grossbard EB.
Rigel Pharmaceuticals, Inc., 1180 Veterans Blvd., South San Francisco, CA 94080, USA. gclemens@rigel.com
Abstract
BACKGROUND: Urogenital abnormalities are among the most common of all human birth defects. In developmental toxicity studies with the Syk kinase inhibitor R788, a spectrum of findings, including renal agenesis, were observed. R788 has also been found to inhibit the receptor tyrosine kinase Ret. Ret kinase is known to be an essential component in the signaling pathway required for renal organogenesis and ureteric duct formation. Previously known is that mutant mice without the c-ret gene, develop urogenital malformations including renal agenesis.
METHODS: In GLP developmental toxicity studies, gravid rabbits were treated orally with R788 at doses of 0, 10, 22, and 50 mg/kg/day (gestation days 7-19) and gravid rats received 0, 5, 12.5, and 25 mg/kg/day (gestation days 6-17) by the same route. The activity of R406 against Ret kinase was assessed in biochemical and cell-based assays.
RESULTS: A dose-dependent increase in malformations, including renal and ureteric agenesis and a specific major vessel anomaly, retroesophageal right subclavian artery, was observed in both the rat and rabbit. R788 proved to be a potent inhibitor of Ret kinase.
CONCLUSIONS: R788 promoted a spectrum of developmental toxicity, including renal and ureteric agenesis and a specific major vessel abnormality, retroesophageal right subclavian artery, in two different species. These effects are likely the result of inhibition of Ret kinase given its importance in the normal ontogeny of the urogenital and cardiovascular systems across species.<<
I've attempted to understand the implications of RET inhibition. It's a bit beyond me. Depending on the time and place in the body, you might want that. RET can be oncogenic, so inhibiting it if it gets out of hand might be a good idea for certain neoplasms. But it's also neuroprotective. Dunno if FosD penetrates the BBB.
Cheers, Tuck |
