Drug discovery, development, and commercial approval depend on both the strength of a product candidate and a healthy dose
Perhaps the most compelling support for Merck's decision to buck the Big Pharma trend of devoting a majority of R&D resources
to in-licensing later-stage products to fill its pipelines, as opposed to spending those resources on internal development,
is the story of Januvia. Interestingly, Merck's DPP-4 project began with an in-licensed drug candidate, from a privately-held
German biotech called Probiodrug.
In a Probiodrug press release from 2000, Bennett Shapiro, then Merck's EVP, worldwide licensing and external research, said
the agreement marked "an aggressive new focus on external collaborations…bringing the best science to Merck and broadening
our future new product base." The last part of that statement was prescient, even though the Probiodrug candidate was ultimately
terminated. But "it was really the things we'd learned from [the Probiodrug] molecule that resulted in the identification
of sitagliptin, which is the molecule that was discovered internally," says Thornberry.
Merck first became interested in the DPP-4 mechanism based on research conducted in the 1990s, which validated the glucagon-like
peptide 1 (GLP-1) target, the substrate for DPP-4, as a target for diabetes. "The second key piece of data was evidence showing
that DPP-4 was the enzyme involved in the regulation of GLP-1," says Thornberry.
After reviewing preclinical models of diabetes and DPP-4 inhibition published by Probiodrug and Novartis, Merck began its
DPP-4 project in earnest in the summer of 1999. Three years later, in July of 2002, sitagliptin entered into a focused clinical
development program. Thanks to the "full support of the organization," Januvia developers "adopted a somewhat streamlined
clinical development program in that, as others had demonstrated proof of concept, we were able to use a direct to [Phase]
IIb strategy," says Thornberry. "From the initial Phase I studies, we were able to go directly to IIb, and that was one of
the mechanisms we used to move the program more rapidly through development." That and the fact that "there were really no
safety issues at all…either in preclinical studies or in the course of our clinical program, that caused us to slow down."
Merck's sitagliptin development team also realized from the start that "it was going to be critically important to demonstrate
efficacy in combination with metformin," a member of the biguanide class of drugs, and an important first-line therapy, along
with the sulfonylurea drug class, for Type 2 diabetes around the globe. As a result, sitagliptin was developed as a monotherapy
and as a fixed-dose combination with metformin.