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

There is a world wide twin epidemic of obesity and TypeDiabetesT Dwith an urgent need to find effective
new drug treatments for inducing weight lossStable derivatives of the endogenous glucoregulatory hormoneglucagon like peptideGLPare in clinical use for the treatment of T D but are of equally great interest as
an emerging treatment of obesity and of age related neurodegenerative conditions including Parkinsonandapos s and
Alzheimerandapos s diseaseAnother glucoregulatory hormoneglucose dependent insulinotropic peptideGIPhas
recently been shown to induce a synergistic profile of metabolic and neuroprotective benefit with GLPin
animal studiesHoweverfor GIP to be clinically useful for any of the envisioned combination treatmentse gto further enhance the weight loss induced by GLPbased medicationsGIP needs to be modified to confer
protection from rapid enzymatic degradation in the blood streamThe applicantsVelumInchave access to
a patent protected novel strategy to make GIP fully resistant to its main inactivation mechanism of aminoterminal enzymatic cleavageby attaching functionally well tolerated decorations to the peptideandapos s first amino
acidIn this phase I applicationthey propose to apply this strategyin conjunction with complementary
modifications to stabilize GIPwith the goal of identifying a lead compound that holds promise for future
developmentIn collaboration with Tufts Universitywhere biological assessment of compounds will be
performedtwo Specific Aims will be pursuedStarting with a prototype stable GIP analogue that has already
been engineeredVELAimis to further improve on this molecule by introducing alternative aminoterminal decorations and fatty acid acylations of other selected GIP residuesA total offollow up molecules
to VELwill be generatedThese will be tested for agonist activity receptor potency and enzyme stability in
vitroas well as for survival in the blood stream after subcutaneous injection in miceSerum peptide levels will
be followed using a sensitive bioassay that has been developed for this project to enable compound detection
regardless of structural modificationsIn Aimto establish efficacy in a model of therapeutic applicationtwo
analogues with highest potency and stability will be selected for studying drug induced weight loss in mice with
diet induced obesityAs the experimental paradigmGIP analogues will be co injected every third day over a
three week period with a latest generation GLPbased drugthus enabling the detection of synergistic effects
on weight loss and obesity related hyperglycemiaIt is anticipated that a candidate GIP analogue will be
identified that can be developed in future Phase II studies as a companion drug for GLPagonists for the
treatment of obesity and of neurodegenerative disease The proposed work will identify a candidate molecule that may evolve as a future treatment for obesity and of
age related neurodegenerative conditions including Parkinsonandapos s and Alzheimerandapos s diseaseUsing a new
chemical strategya gut hormone that naturally helps maintain normal blood sugar and body weight will be
stabilized for therapeutic applicationThis drugwhen given as a combination treatmentwill synergistically
enhance the weight reducing effect of currently emerging medications with additional neuroprotective potential