PharmaIN | PGC GLP-1

PGC GLP-1

Introduction

Glucagon-like Peptide-1 (GLP-1) is a 3.5 kDa peptide excreted in the gut which is known to regulate insulin production, decrease glucagon secretion, and increase beta cell mass. It also acts to inhibit acid secretion in the gut and decrease appetite. Because of these functions, GLP-1 is a candidate as a therapy for type-1 and type-2 diabetes and obesity. However, its sensitivity to enzymatic cleavage by Dipeptidyl peptidase-4 (DPP-IV) results in a plasma half-life of only a few minutes. Constant subcutaneous infusion studies suggest that if the natural metabolic degradation of GLP-1 can be decreased without affecting its activity, it would be a very promising therapy for diabetes. Therefore, PGC GLP-1 formulations using the Hydrophobic Core platform have been developed with the intent of increasing the serum half-life of native human GLP-1 to create a viable therapeutic drug.

GLP-1 is involved in blood glucose regulation

Formulation

PGC GLP-1 is formulated with PharmaIN's Hydrophobic Core technology platform, which takes advantage of it's α-helical structure.

In Vivo Results

As shown in the figure below, PGC GLP-1 significantly extends GLP-1 half-life in the blood of Sprague-Dawley rats upon subcutaneous injection. This result is confirmed in the following figure by efficacy experiments in T2D models, where PGC GLP-1 is compared directly to Byetta 2/day.

PGC protects GLP-1 from DPP4 degradation and excretion from the kidneys, dramatically extending its circulation time

PGC GLP-1 is as effective at lowering HbA1c levels when dosed 1/week compared to Byetta® dosed BID

The angiograph below visually shows the ability of PGC to accumulate in inflamed tissues. It is known that a degree of inflammation is present in the pancreas of diabetic patients, allowing for accumulation of an imaging agent bound to PGC in the diabetic pancreas.

PGC bound to an imaging agent accumulates in the diabetic pancreas of an STZ-induced Type 1 diabetes murine model

Comparison to PEGylation

PGC GLP-1 performs favorably to PEGylation in pre-clinical animal models, providing many times the total benefit.

Comparative Pharmacokinetic and Pharmacodynamic Parameters for PEGylated Molecules and their PGC counterparts

Advantages of PGC GLP-1

  • Delivers fully active native human GLP-1
  • Highly soluble in water, a "true solution"
  • Passive accumulation to inflamed pancreas
  • Simple manufacture, very stable in solution
  • 505(b)2 regulatory path is possible as the FDA perceives PGC as an excipient
  • Induces islet cell proliferation in T1D animal models