Cardiac Toxicity Leads SuperGen to Discontinue Development of Phase I PIM Inhibitor
Company says it has already discovered back-up compounds to failed SGI-1776.
SuperGen is discontinuing further development of its early clinical-stage PIM kinase inhibitor anticancer candidate SGI-1776 due to cardiac toxicity issues. The firm said it will, however, push on with its overall PIM inhibitor program, and has already identified more promising compounds.
A Phase I trial evaluating SGI-1776 in patients with refractory prostate cancer and lymphoma had previously highlighted dose-limiting toxicity in the form of cardiac QTc prolongation. SuperGen says more detailed evaluation of the cardiac and pharmacokinetic trial data has failed to identify a safe therapeutic window that would allow clinical development of the drug to continue.
“While we are disappointed with the toxicity seen in patients receiving SGI-1776 and the discontinuation of the development of this specific compound, PIM kinase continues to be an important target for oncology drug development,” notes James S. J. Manuso, Ph.D., SuperGen president and CEO. “The discovery team has identified backup candidates that initially appear to lack some of the liabilities seen in SGI-1776. We continue to pursue inhibitors of PIM that might exhibit a more favourable therapeutic profile.”
SuperGen is using its CLIMB® drug discovery technology to identify small molecule anticancer candidates. The platform combines rapid screening of compound libraries with computational chemistry and systems biology techniques to identify drug leads that bind to target proteins. The firm says its focus is on drug targets that are difficult to screen by traditional methods. The overall aim is to use CLIMB to discover and advance into clinical trials at least one product about every 12 months.
SuperGen’s lead candidate, amuvatinib (MP-470), is a mutant c-Kit inhibitor that has also demonstrated activity against c-Met and c-Ret. The drug is in early clinical trials both as a single agent and in combination with standard chemotherapy regimens as a treatment for a range of tumor types.
Another anticancer candidate, SGI-110, is an inhibitor of DNA methyltransferases that has been granted IND clearance in the U.S. to start in Phase I trials. SuperGen says it aims to start early human studies in patients with myelodysplastic syndromes and acute myeloid leukemia by the end of 2010.
The firm is separately working in collaboration with GlaxoSmithKline to design third-generation epigenetic therapeutics.