A GIP Companion Drug for Enhancing Metabolic Benefits of Long-Acting GLP-1

Project Summary
There is a world-wide “twin epidemic” of obesity and Type 2 Diabetes (T2D), with an urgent need to find
effective new drug treatments for inducing weight loss. Stable derivatives of the endogenous glucoregulatory
hormone, glucagon-like peptide-1 (GLP1) are in clinical use for the treatment of T2D but are also of great interest
as an emerging treatment of obesity. Another closely related glucoregulatory hormone, glucose-dependent
insulinotropic peptide (GIP) has been recently reported to further enhance the weight loss induced by GLP1
based medications. However, for GIP to be clinically useful, this peptide needs to be modified to prevent rapid
enzymatic degradation and to delay clearance from the blood stream. The applicants (Velum, Inc.) have access
to a patent-protected novel strategy to make GIP fully resistant to its main inactivation mechanism of amino-
terminal enzymatic cleavage. This can be achieved by attaching functionally well-tolerated decorations to the
peptide’s first amino acid, together with adding a lipid side chain that further delays peptide
elimination/inactivation. In the current phase II application, the applicants propose to apply this strategy with
the goal of identifying a lead GIP derivative and “backups” that hold therapeutic promise. At the end of the
project period, one to three compounds will be advanced to test safety in humans and enable IND filings.
In collaboration with Tufts University, two Specific Aims will be pursued. Starting with a prototype stable GIP
analogue that has already been engineered, Aim 1 is to further improve on this molecule by introducing
alternative amino-terminal decorations and lipid side chains at feasible residues in the GIP peptide. A total of
83 new follow-up molecules will thus be generated. These will be tested for agonist activity/receptor potency
by receptor signaling assay. Twenty most active derivatives will be further tested for enzyme stability in vitro,
including resistance to DPP4 as well as to trypsin and neprilysin. In Aim 2, six analogues with highest potency
and stability will be selected for studying half-life in the blood stream following s.c. injection in mice. A sensitive
bioassay will be used to monitor peptide activity that has been developed for this project to enable compound
detection regardless of structural modifications. Furthermore, drug-induced weight loss will be quantified in
mice with diet-induced obesity. As the experimental paradigm, GIP analogues will be co-injected daily over a
three-week period together with a latest generation GLP1-based drug, thus enabling the detection of synergistic
effects on weight loss and obesity-related hyperglycemia. The goal is to nominate a lead GIP analogue and two
backup compounds for IND-enabling studies, toward further development of a companion drug that amplifies
GLP1-induced treatment of obesity.PUBLIC HEALTH RELEVANCE STATEMENT
Velum, Inc. has developed a long acting prototype peptide that enhances the activity of the best
currently existing weight loss drugs when applied in combination. Further optimization of the
prototype molecule by minor chemical modifications will further enhance its function as well as
extend its survival in the blood stream, thereby enabling a powerful treatment of obesity and type
2 diabetes (T2D).