SBIR-STTR Award

A Phase 1 SBIR program of pre-clinical development is proposed focusing on a novel rapid-acting insulin analog for the treatment of diabetes mellitus. Designated Insulin-Cl, our product is a derivative of insulin lispro (the active component of HumalogTM) containing a single chloro-substitution within the aromatic ring of a conserved phenylalanine in the B-chain (PheB24). Insulin-Cl retains the interchange of residues B28 and B29 (substitutions ProB28 .Lys and LysB29.Pro) that confers upon HumalogTM its rapid absorption following subcutaneous injection. Insulin-Cl offers to patients the potential advantages of (i) greater shelf life and stability to degradation at temperatures above room temperature;and (ii) possible formulation as a zinc-free solution to provide ultra- rapid absorption. Current meal-time insulin analogs such as HumalogTM and NovalogTM are less stable than human insulin and must be formulated as zinc insulin hexamers;as a consequence, absorption is in principle not as rapid as could be provided by a zinc-free formulation. Ultra-rapid absorption of Insulin-Cl may offer added patient convenience and also enhanced safety in closed-loop ""smart pumps"" coupled to glucose sensors. We seek to test candidate formulations of Insulin-Cl and to assess its in vivo potency and pharmacokinetics in animal models. Insulin-Cl was invented at Case Western Reserve University and is being developed under license to Thermalin Diabetes, Inc. The principal investigator, who brings to this application four decades of experience in pharmacetical studies of insulin formulations, was co-inventor of insulin lispro. , ,

Public Health Relevance:
Diabetes is an increasingly prevalent disease in the developed and developing worlds;patients seek greater convenience, improved glycemic control, and fewer adverse side-effects, all of which result in greater compliance and lower healthcare costs. This project will complete pre- clinical development of Insulin-Cl, a potentially ultra-stable and ultra-rapid acting insulin analog which could conveniently be stored without refrigeration and taken closer to meal time and could cause less post-meal glucose deficiency.

Thesaurus Terms:
2,4,5,6(1h,3h)-Pyrimidinetetrone;2-Deoxy-2-((Methylnitrosoamino)Carbonyl)Amino-D-Glucose;2-Deoxy-2-(3-Methyl-3-Nitrosoureido)-D-Glucopyranose;2-Deoxy-2-[[(Methylnitrosamino)-Carbonyl]amino]-D-Glucopyranose;28(B)-Lys-29(B)-Pro-Insulin;28(B)-Lysine-29(B)-Prolineinsulin;3-D Structure;3-Dimensional Structure;3d Structure;Absorption;Adverse Effects;Alloxan;Amyloid;Amyloid Substance;Animal Model;Animal Models And Related Studies;Animals;Asparagine;Assay;Bioassay;Biologic Assays;Biological;Biological Assay;Blood Glucose;Blood Serum;Blood Sugar;Budgets;Buffers;C-Terminal;Centrifugation;Chemicals;Chemistry, Pharmaceutical;Chlorine;Chromatography, Exclusion;Chromatography, Gel;Chromatography, Gel Permeation;Cl Element;Clinical;Clinical Trials;Clinical Trials, Unspecified;Common Rat Strains;Coupled;Cresol;Cresols;Crystallography, X-Ray;Crystallography, X-Ray Diffraction;Crystallography, X-Ray/Neutron;Crystallography, Xray;D-Glucose;Development;Dextrose;Diabetes Mellitus;Diabetes Mellitus, Adult-Onset;Diabetes Mellitus, Brittle;Diabetes Mellitus, Insulin-Dependent;Diabetes Mellitus, Juvenile-Onset;Diabetes Mellitus, Ketosis-Prone;Diabetes Mellitus, Ketosis-Resistant;Diabetes Mellitus, Non-Insulin-Dependent;Diabetes Mellitus, Noninsulin Dependent;Diabetes Mellitus, Slow-Onset;Diabetes Mellitus, Stable;Diabetes Mellitus, Sudden-Onset;Diabetes Mellitus, Type 1;Diabetes Mellitus, Type 2;Diabetes Mellitus, Type I;Diabetes Mellitus, Type Ii;Disease;Disorder;Disulfides;Dose;Drug Formulations;Drug Kinetics;Epidemiology;Event;Fplc;Family Suidae;Fast Protein Liquid Chromatography, Tm Pharmacia;Formulation;Formulations, Drug;Fractionation, Centrifugation;Gel Chromatography;Gel Filtration;Gel Filtration Chromatography;Generations;Glucose;Glycohemoglobin A;Glycosylated Hemoglobin A;Group 17 Elements;Halogens;Hb A1;Hb A1a+B;Hb A1c;Hba1;Hba1c;Health Care Costs;Health Costs;Healthcare Costs;Hemoglobin A(1);Humalog;Human;Human, General;Humulin R;Hypoglycemia;Idd;Iddm;Indiana;Insulin;Insulin (Ox), 8a-L-Threonine-10a-L-Isoleucine-30b-L-Threonine-;Insulin, Lispro;Insulin, Lispro, Human;Insulin, Regular;Insulin-Dependent Diabetes Mellitus;Intervention;Intervention Strategies;Ions;Knowledge;L-Asparagine;L-Phenylalanine;Licensing;Life;Link;Mody;Mammals, Rats;Man (Taxonomy);Man, Modern;Mass Spectrum;Mass Spectrum Analysis;Maturity-Onset Diabetes Mellitus;Measurement;Mediating;Medicinal Chemistry;Methods;Methods And Techniques;Methods, Other;Modeling;Niddk;Niddm;Nmr Spectroscopy;National Institute Of Diabetes And Digestive And Kidney Diseases;National Institute Of Digestive Diseases And Kidney Disorders;Non-Insulin Dependent Diabetes;Non-Insulin-Dependent Diabetes Mellitus;Novolin R;Patient Care;Patient Care Delivery;Patients;Pharmaceutic Chemistry;Pharmaceutical Agent;Pharmaceutical Chemistry;Pharmaceuticals;Pharmacokinetics;Pharmacologic Substance;Pharmacological Substance;Phase;Phenylalanine;Phenylalanine, L-Isomer;Photometry/Spectrum Analysis, Mass;Physical Condensation;Physiologic;Physiological;Pigs;Polymers;Principal Investigator;Process Of Absorption;Production;Programs (Pt);Programs [publication Type];Property;Property, Loinc Axis 2;Proteins;Proteomics;Protocol;Protocols Documentation;Pump;Rat;Rat Model Of Diabetes;Rattus;Recombinants;Refrigeration;Replacement Therapy;Resistance;Risk;Sbir;Sbirs (R43/44);Stz;Safety;Sampling;Serum;Single Crystal Diffraction;Small Business Innovation Research;Small Business Innovation Research Grant;Solutions;Spectrometry, Mass;Spectroscopy, Mass;Spectroscopy, Nmr;Spectrum Analyses, Mass;Spectrum Analysis, Mass;Streptozocin;Streptozotocin;Structure;Subcutaneous Injections;Suidae;Surface;Swine;T1 Diabetes;T1d;T1dm;T2d;T2dm;Techniques;Temperature;Testing;Therapeutic;Thermodynamic;Thermodynamics;Time;Timeline;Treatment Side Effects;Tripcellim;Trypsin;Type 1 Diabetes;Type 2 Diabetes;Type Ii Diabetes;Universities;X Ray Crystallographies;X-Ray Crystallography;Zanosar;Zinc;Zn Element;Absorption;Adult Onset Diabetes;Analog;Base;Blood Glucose Regulation;Chemical Stability;Chemical Synthesis;Chlorine Gas;Clinical Investigation;Condensation;Deamidation;Design;Designing;Diabetes;Diabetes Control;Diabetic Rat;Diabetic Rat Model;Dimer;Dipole Moment;Disease/Disorder;Experience;Fast Protein Liquid Chromatography;Gene Product;Glucose Control;Glucose Homeostasis;Glucose Regulation;Glucose Sensor;Glycemic Control;Hemoglobin A1c;Hypoglycemic;Hypoglycemic Episodes;Improved;In Vivo;Innovate;Innovation;Innovative;Insulin Dependent Diabetes;Insulin, Lys(28b)-Pro(29b)-;Insulin, Lysyl(28b)-Prolyl(28b)-;Interventional Strategy;Juvenile Diabetes;Juvenile Diabetes Mellitus;Ketosis Prone Diabetes;Ketosis Resistant Diabetes;Lispro;Maturity Onset Diabetes;Model Organism;Monomer;Novel;Nuclear Magnetic Resonance Spectroscopy;Physical Property;Polypeptide;Porcine;Pre-Clinical;Preclinical;Programs;Protein Function;Public Health Relevance;Receptor Binding;Resistant;Response;Side Effect;Suid;Therapy Adverse Effect;Three Dimensional Structure;Treatment Adverse Effect;Tricresol;Type I Diabetes

We seek to develop a novel insulin analog to enhance the safety and efficacy of insulin pump therapy with broad application to the Artificial Pancreas Project ("smart pumps"). A proprietary approach is proposed based on the favorable physico-chemical properties conferred by chloro-aromatic substitutions in the insulin molecule. This Phase 2 SBIR application thus builds on progress obtain in the Phase 1 program in the characterization of 4-Cl-PheB24-KP-insulin. In this derivative of insulin lispro (the active component of Humalog;Eli Lilly and Co) the para proton of the aromatic ring of PheB24 is substituted by a larger and electronegative halogen atom. Results of Phase 1 studies established that this substitution (i) is compatible with native receptor-binding affinity and natie biological potency;(ii) leads to an accelerated rate of disassembly of the insulin hexamer in vitro;(iii) is associated with foreshortened pharmacodynamics of insulin action in euglycemic clamp studies in a pig model;and (iv) augments the resistance of insulin to physical degradation above room temperature on gentle agitation as in a pump reservoir. This unique confluence of advantageous features predicts significant clinical advantages both with respect to patient convenience and with respect to the performance of control algorithms employed in CGM-coupled closed-loop systems. Accordingly, a Phase 2 development plan is proposed in support of clinical-scale manufacture and optimization of formulation leading to I-GMP production (Aims 1-3) and formal toxicity/tolerance testing in animals in support of an IND application to the FDA (Aim 4). Achievement of these milestones will enable a future Phase 2B application in support of first-in-human trials, anticipated to be a phase 1a clamp study of healthy volunteers. The present application thus provides a logical bridge between highly promising in vitro and animal data, as generated in the Phase 1 SBIR program, and key pre-IND milestones.

Public Health Relevance:
Diabetes is increasing in prevalence;continuous subcutaneous insulin infusion (CSII;pump therapy) can enhance glycemic control and mitigate risk of microvascular complications, thereby improving outcomes and quality and quantity of life and, at the same time, lowering health-care costs. To improve the pharmacokinetics of pump therapy and the efficacy of closed-loop systems, this project will complete pre-clinical development of Chlorolog (a 4-Cl-PheB24 derivative of insulin lispro, the active ingredient of Humalog(R)). The chloro-substitution was designed to accelerate hexamer disassembly at neutral pH (relative to Humalog) and has been demonstrated in a Phase I SBIR program to have ultra-rapid pharmacodynamics.