EASD: Phase 3 Glucose-Lowering Efficacy of Januvia for Type 2 Diabetes
See Merck’s press release describing a bit of the Phase 3 results from its Januvia trial in patients with previosuly untreated Type 2 diabetes. Januvia (sitagliptin) is now the leading candidate to be the first dipeptidyl peptidase-IV inhibitor (DPP-IV inhibitor) approved for marketing. Since new mechanisms to treat diabetes don’t come along too often, I thought I’d bring these data to your attention.
The data in this release are quite limited, omitting results from some treatment arms, secondary endpoints, and details of adverse events. Nevertheless, they hint at the efficacy and tolerability of the drug when given orally twice daily in combination with metformin (the standard of care, first-line therapy for untreated Type 2 diabetes). The drug appears to work well as an antihyperglycemic therapy, probably comparably to most other add-on therapies to metformin, like TZDs and sulfonylureas, although without the weight gain seen with both of these classes, and without the hypoglycemia that often accompanies sulfonylureas. In this way, Januvia more closely resembles Amylin/Lilly’s injectable GLP-1 analog, Byetta.
Like Byetta, Januvia is believed to act primarily via GLP-1 receptors (by inhibiting metabolism of endogenous GLP-1, thereby increasing its bioavailability) to increase prandial insulin secretion, stimulate gastric emptying and inhibit glucagon secretion. However, the precise mechanism of Januvia’s pharmacological effects to normalize glucose in humans are not known (at least not publicly) and might include, for example, increases in bioavailability of Glucose-dependent Insulinotropic Polypeptide (GIP) and perhaps inhibition/modulation of the metabolism of other peptides involved in glucose homeostasis (e.g. PYY, GRF, GLP-2, etc.).
What investors and potential prescribers need to watch carefully in the near future (Merck is anticipating a mid-October FDA approval for Januvia) is the emerging safety profile of the drug. Unlike GLP-1 and its analogs, DPP-IV inhibitors have the potential for a wide variety of pleiotropic effects, owing in part to their potential ability to alter the bioavailability of many endogenous peptides. So far, the published preclinical data and unpublished clinical data are reassuring.
I would suggest that interested parties look to Merck’s safety package for thorough tests of known DPP-IV-regulated systems, if only indirectly in some cases, by measuring levels of endogenous peptides known to be metabolized by DPP-IV. Probably the most important of these systems from a safety perspective, the immune system, is hypothetically regulated not by DPP-IV’s peptidase activity but rather by its putative role as a costimulator of CD2/CD3-dependent T-cell activation (DPP-IV is also known as CD26).
DPP-IV’s relative importance as a T-cell costimulator in humans hasn’t been elucidated to my knowledge. But assuming DPP-IV’s role is clinically relevant, T-cell costimulation interference would be expected to affect cell-mediated immune function, perhaps subtly. Certainly, a large clinical database will be valuable in detecting adverse events that could signal a cell-mediated immunity dysfunction, but, again, changes would likely be subtle, and safety signals could mistakenly be interpreted as background “noise”. Caution and conservative interpretation is advised. To aid adverse event interpretations, let’s hope that Merck had the good sense to perform supportive studies of cell-mediated immune function. Without actually knowing the program, I’d bet that they did.
I’ll provide an update when details become available.
