SBIR-STTR Award

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 of equally great interest as an emerging treatment of obesity and of age-related neurodegenerative conditions including Parkinson's and Alzheimer's disease. Another glucoregulatory hormone, glucose-dependent insulinotropic peptide (GIP) has recently been shown to induce a synergistic profile of metabolic and neuroprotective benefit with GLP1 in animal studies. However, for GIP to be clinically useful for any of the envisioned combination treatments, e.g. to further enhance the weight loss induced by GLP1 based medications, GIP needs to be modified to confer protection from rapid enzymatic degradation in 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, by attaching functionally well-tolerated decorations to the peptide's first amino acid. In this phase I application, they propose to apply this strategy, in conjunction with complementary modifications to stabilize GIP, with the goal of identifying a lead compound that holds promise for future development. In collaboration with Tufts University, where biological assessment of compounds will be performed, two Specific Aims will be pursued. Starting with a prototype stable GIP analogue that has already been engineered, VEL-42, Aim 1 is to further improve on this molecule by introducing alternative amino- terminal decorations and fatty acid acylations of other selected GIP residues. A total of 12 follow-up molecules to VEL-42 will be generated. These will be tested for agonist activity/receptor potency and enzyme stability in vitro, as well as for survival in the blood stream after subcutaneous injection in mice. Serum peptide levels will be followed using a sensitive bioassay that has been developed for this project to enable compound detection regardless of structural modifications. In Aim 2, to establish efficacy in a model of therapeutic application, two analogues with highest potency and stability will be selected for studying drug-induced weight loss in mice with diet-induced obesity. As the experimental paradigm, GIP analogues will be co-injected every third day over a three week period with a latest generation GLP1-based drug, thus enabling the detection of synergistic effects on weight loss and obesity-related hyperglycemia. It is anticipated that a candidate GIP analogue will be identified that can be developed in future Phase II studies as a companion drug for GLP1 agonists for the treatment of obesity and of neurodegenerative disease.

Public Health Relevance Statement:
The proposed work will identify a candidate molecule that may evolve as a future treatment for obesity and of age-related neurodegenerative conditions including Parkinson's and Alzheimer's disease. Using a new chemical strategy, a gut hormone that naturally helps maintain normal blood sugar and body weight will be stabilized for therapeutic application. This drug, when given as a combination treatment, will synergistically enhance the weight-reducing effect of currently emerging medications with additional neuroprotective potential.

Project Terms:
Clinical; Phase; Biological; Physiologic; Physiological; Mature fat cell; Mature Lipocyte; Lipocytes; Fat Cells; Adipose Cell; Adipocytes; Chemicals; Evaluation; Blood Serum; Serum; analog; Agonist; Collaborations; Therapeutic; Metabolic; Companions; Stream; Clinic; Overweight; Over weight; Neurodegenerative Disorders; neurodegenerative illness; degenerative neurological diseases; degenerative diseases of motor and sensory neurons; Neurologic Degenerative Conditions; Neurodegenerative Diseases; Neural degenerative Disorders; Neural Degenerative Diseases; Nervous System Degenerative Diseases; Degenerative Neurologic Disorders; Degenerative Neurologic Diseases; interest; peptide analog; receptor; Receptor Protein; Animal Model; model organism; model of animal; Animal Models and Related Studies; novel; new technology; novel technologies; Regulation; Modeling; Sampling; Adverse effects; treatment adverse effect; therapy adverse effect; side effect; Treatment Side Effects; insulin secretion; polypeptide; Address; liraglutide; Detection; High Prevalence; in vivo; Endocrine Pancreas Secretion; Pancreatic Endocrine Secretion; C57BL/6 Mouse; Modification; followed up; follow up; Active Follow-up; follow-up; developmental; Development; pathway; Pathway interactions; obesity treatment; age dependent; age related; neglect; clinical efficacy; novel strategy; novel approaches; new approaches; novel strategies; Population; NH2-terminal; N-terminal; resistant; Resistance; novel therapy; novel drugs; novel drug treatments; next generation therapeutics; new therapy; new therapeutics; new drugs; new drug treatments; novel therapeutics; prototype; drug candidate; Phase I Study; phase 1 study; phase II study; phase 2 study; Drug Targeting; metabolic profile; therapeutic candidate; translational spectrum; translational pipeline; Acylation; Aging; Alzheimer's Disease; senile dementia of the Alzheimer type; primary degenerative dementia; dementia of the Alzheimer type; Primary Senile Degenerative Dementia; Alzheimers disease; Alzheimers Dementia; Alzheimer's; Alzheimer syndrome; Alzheimer sclerosis; Alzheimer disease; Alzheimer Type Dementia; Alzheimer; Amino Acids; aminoacid; Animals; Biological Assay; Biologic Assays; Bioassay; Assay; Biological Availability; Physiologic Availability; Biologic Availability; Bioavailability; Blood; Blood Reticuloendothelial System; Blood Glucose; Blood Sugar; Body Weight; Cardiovascular Diseases; cardiovascular disorder; Cell physiology; Subcellular Process; Cellular Process; Cellular Physiology; Cellular Function; Cell Process; Cell Function; Cells; Cell Body; Clinical Trials; Comorbidity; co-morbidity; Diabetes Mellitus; diabetes; Non-Insulin-Dependent Diabetes Mellitus; type two diabetes; type II DM; type 2 DM; maturity onset diabetes; ketosis resistant diabetes; adult onset diabetes; Type II diabetes; Type II Diabetes Mellitus; Type 2 diabetes; Type 2 Diabetes Mellitus; T2DM; T2D; T2 DM; Stable Diabetes Mellitus; Slow-Onset Diabetes Mellitus; Noninsulin Dependent Diabetes Mellitus; Non-Insulin Dependent Diabetes; NIDDM; Maturity-Onset Diabetes Mellitus; MODY; Ketosis-Resistant Diabetes Mellitus; Adult-Onset Diabetes Mellitus; Diet; dietary; Dipeptidyl Peptidases; Dipeptidylpeptide Hydrolases; Dipeptidyl Aminopeptidases; Pharmacotherapy; drug treatment; Drug Therapy; Pharmaceutical Preparations; drug/agent; Pharmaceutic Preparations; Medication; Drugs; Engineering; Enzyme Stability; Epidemic; Fatty Acids; Future; Gastric Inhibitory Polypeptide; gastric inhibitory peptide; Glucose-Dependent Insulinotropic Peptide; Glucose-Dependent Insulin-Releasing Peptide; Glucose; Dextrose; D-Glucose; Goals; Half-Life; Health; Homeostasis; Physiological Homeostasis; Autoregulation; Hormones; Therapeutic Hormone; Endocrine Gland Secretion; Hyperglycemia; hyperglycemic; In Vitro; Industry; Subcutaneous Injections; Intestinal Mucosa; Kidney; renal; Kidney Urinary System; Lead; heavy metal lead; heavy metal Pb; Pb element; Ligands; Light; Photoradiation; Mus; Murine; Mice Mammals; Mice; Nerve Degeneration; neuronal degeneration; neurological degeneration; neurodegenerative; neurodegeneration; neural degeneration; Neuron Degeneration; Obesity; obese population; obese person; obese people; obese; corpulentia; corpulency; corpulence; adiposity; Parkinson Disease; Primary Parkinsonism; Parkinsons disease; Parkinson's disease; Parkinson's; Parkinson; Paralysis Agitans; Legal patent; Patents; Patients; Peptide Hydrolases; Proteolytic Enzymes; Proteinases; Proteases; Protease Gene; Peptidases; Esteroproteases; Peptides; Pharmacology; Physiology; Safety; Testing; Twin Multiple Birth; Twins; United States Food and Drug Administration; USFDA; Food and Drug Administration; Universities; Body Weight decreased; wt-loss; body weight loss; Weight Reduction; Weight Loss; Weight; Work; glucagon-like peptide 1; GLP-1; Generations; Measures; Health Care Costs; Healthcare Costs; Health Costs; base; improved

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:
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).

Project Terms:
Acylation; Amino Acids; aminoacid; Animals; Back; Dorsum; Biological Assay; Assay; Bioassay; Biologic Assays; Biological Availability; Bioavailability; Biologic Availability; Physiologic Availability; Blood; Blood Reticuloendothelial System; Blood Glucose; Blood Sugar; Cardiovascular Diseases; cardiovascular disorder; Cell physiology; Cell Function; Cell Process; Cellular Function; Cellular Physiology; Cellular Process; Subcellular Process; Cells; Cell Body; Clinical Trials; comorbidity; co-morbid; co-morbidity; Diabetes Mellitus; diabetes; Non-Insulin-Dependent Diabetes Mellitus; Adult-Onset Diabetes Mellitus; Ketosis-Resistant Diabetes Mellitus; Maturity-Onset Diabetes Mellitus; NIDDM; Non-Insulin Dependent Diabetes; Noninsulin Dependent Diabetes; Noninsulin Dependent Diabetes Mellitus; Slow-Onset Diabetes Mellitus; Stable Diabetes Mellitus; T2 DM; T2D; T2DM; Type 2 Diabetes Mellitus; Type 2 diabetes; Type II Diabetes Mellitus; Type II diabetes; adult onset diabetes; ketosis resistant diabetes; maturity onset diabetes; type 2 DM; type II DM; type two diabetes; Dipeptidyl Peptidases; Dipeptidyl Aminopeptidases; Dipeptidylpeptide Hydrolases; Pharmacotherapy; Drug Therapy; drug treatment; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Duodenum; Engineering; Enzyme Stability; Enzyme Tests; Expenditure; Fatty Acids; Gastric Inhibitory Polypeptide; Glucose-Dependent Insulin-Releasing Peptide; Glucose-Dependent Insulinotropic Peptide; gastric inhibitory peptide; Glucose; D-Glucose; Dextrose; Goals; Half-Life; Health; Hormones; Endocrine Gland Secretion; Therapeutic Hormone; Human; Modern Man; Hyperglycemia; hyperglycemic; In Vitro; Industry; Kidney; Kidney Urinary System; renal; Lead; Pb element; heavy metal Pb; heavy metal lead; Ligands; Light; Photoradiation; Lipids; Neprilysin; CD10 Antigens; Enkephalinase; Membrane Metalloendopeptidase; Neutral Endopeptidase; Minor; Mucous Membrane; Mucosa; Mucosal Tissue; Mus; Mice; Mice Mammals; Murine; Obesity; adiposity; corpulence; Osteoporosis; Structure of beta Cell of islet; Pancreatic beta Cell; Pancreatic ß-Cell; pancreas beta cell; pancreas ß cell; pancreatic b-cell; Legal patent; Patents; Patients; Peptide Hydrolases; Esteroproteases; Peptidases; Protease Gene; Proteases; Proteinases; Proteolytic Enzymes; Peptides; Pharmacology; Physiology; Safety; Technology; Testing; Trypsin; Tripcellim; Twin Multiple Birth; Twins; United States Food and Drug Administration; Food and Drug Administration; USFDA; Universities; Body Weight decreased; Weight Loss; Weight Reduction; body weight loss; wt-loss; glucagon-like peptide 1; GLP-1; pancreatic secretory trypsin inhibitor I; CCK-releasing factor; Monitor peptide; PSTI-I; cholecystokinin-releasing peptide; growth stimulating-cholecystokinin releasing peptide; luminal CCK-releasing factor; Generations; Health Care Costs; Health Costs; Healthcare Costs; base; improved; Clinical; Phase; Physiological; Physiologic; Adipocytes; Adipose Cell; Fat Cells; Lipocytes; Mature Lipocyte; Mature fat cell; Chemicals; analog; Agonist; Collaborations; Therapeutic; Metabolic; Companions; Weight Loss Agents; Weight-Loss Drugs; Side; Stream; Clinic; Over weight; Overweight; Degenerative Neurologic Diseases; Degenerative Neurologic Disorders; Nervous System Degenerative Diseases; Neural Degenerative Diseases; Neural degenerative Disorders; Neurodegenerative Diseases; Neurologic Degenerative Conditions; degenerative diseases of motor and sensory neurons; degenerative neurological diseases; neurodegenerative illness; Neurodegenerative Disorders; Enteroendocrine Cell; interest; peptide analog; Receptor Protein; receptor; Animal Models and Related Studies; model of animal; model organism; Animal Model; Structure; novel; drug clearance; disease risk; disorder risk; Reporting; Regulation; drug discovery; insulin secretion; preventing; prevent; polypeptide; liraglutide; Detection; Receptor Signaling; in vivo; C57BL/6 Mouse; Modification; follow-up; Active Follow-up; active followup; follow up; followed up; followup; Development; developmental; Pathway interactions; pathway; obesity treatment; obesity intervention; obesity therapy; neglect; Advanced Development; novel strategies; new approaches; novel approaches; novel strategy; Population; N-terminal; NH2-terminal; Resistance; resistant; novel therapeutics; new drug treatments; new drugs; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel therapy; prototype; public health relevance; safety testing; phase 1 study; Phase I Study; phase 2 study; phase II study; Drug Targeting; therapeutic candidate; translational pipeline; translational spectrum; Injections; side effect; Obesity Epidemic; COVID-19; COVID19; CV-19; CV19; corona virus disease 2019; coronavirus disease 2019; diet-induced obesity; diet-associated obesity; diet-related obesity; obese patients; patients with obesity