Takeda’s Diabetes Drug Candidate TAK-875 In Phase III Trials
Takeda Pharmaceutical today announced it has begun Phase III clinical trials of TAK-875, a first-in-class drug candidate for treating type 2 diabetes. The experimental therapy activates GPR40, a G-protein-coupled receptor that resides in pacreatic islet cells.
The TAK-875 story is as much about the biology of the target as it is about the molecule itself. And it's a story that owes much to the company's willingness to delve into uncharted territory.
In the early 2000s, scientists knew GPR40 existed, but didn't know what GPR40's purpose was in the body. Plenty of proteins fit this description-- they're called "orphan receptors" in the industry parlance. Much of Takeda's drug discovery strategy is based on figuring out what orphan receptors do.
In a 2003 paper in Nature (DOI: 10.1038/nature01478), Takeda laid out what it learned about GPR40. The receptor responds to a variety of long-chain fatty acids. In response to fatty acid binding, GPR40 activates and boosts insulin secretion from pancreatic beta cells.
GPR40 became a viable drug target for Takeda for several reasons. First, one of the hallmarks of type 2 diabetes is a reduction in insulin secretion from pancreatic beta cells, something GPR40 activation could help counter. Second, G-protein-coupled receptors are established drug targets-- and GPR40 happens to be in the class of GPCRs for which researchers know the most about structure-- the Class A, or rhodopsin-like, GPCRs. (Note: other GPR-type receptors are diabetes targets as well-- C&EN contributing editor Aaron Rowe has written about Arena Pharmaceuticals' activators of GPR119 as diabetes drug candidates.)
Takeda used structural knowledge to its advantage in the discovery of TAK-875 (ACS Med. Chem. Lett., DOI: 10.1021/ml1000855). Researchers were able to build a model of GPR40 based on its similarity to GPCRs of known structure, and dock potential drug candidates inside to see how well they could bind.
This is far from the only drug discovery story that has to do with "de-orphanizing" orphan receptors. In fact, as far back as 1997, pharmaceutical company researchers were writing about orphan receptors as a neglected drug discovery opportunity (Trends Pharmacol. Sci., DOI: 10.1016/S0165-6147(97)90676-3). And of course, just because researchers have "de-orphanized" a receptor doesn't mean all of the complex biology is pinned down. Case in point: the PPAR receptors (J. Med. Chem., DOI: 10.1021/jm990554g). Despite these receptors' promise as targets for obesity and diabetes, drugs designed to target them have tanked in development or had unexpected problems after arrival on the market (read: Avandia).
So as TAK-875 enters Phase III trials, the news might be about the drug candidate's clinical performance, but you can be sure that Takeda's researchers are still working hard to unravel as much of GPR40's basic biology as they can behind the scenes.
TAK-875 docked to a model of GPR40 (ACS Med. Chem. Lett.)