Phase II year
2020
(last award dollars: 2021)
Phase II Amount
$2,994,231
In this Direct-to-Phase II SBIR application we propose to advance development of a first-in-class, stabilized insulin analog, T-1123, that has an ultra-rapid time-action profile in both U-100 and U-500 formulations. The molecular design of T-1123 combines several synergistic stability-enhancing substitutions that enable zinc- free, non-hexamer-based formulations. These formulations demonstrate improved resistance to both physical and chemical degradation compared to marketed insulin products. Our preliminary studies exploited general principles of protein design to tune critical molecular properties of insulin pertinent to its pharmacology: stability, self-assembly, mitogenicity, and potency. In these studies we demonstrated (a) ultra-rapid absorption kinetics for both U-100 and U-500 formulations of T-1123 in swine euglycemic clamp studiesresults that are comparable with U-100 Fiasp®, (b) glucose-lowering potency of T-1123 in animal models that is comparable to human insulin and the prandial insulin analogs, (c) enhanced chemical and physical stability of T-1123, and (d) mitogenic potency of T-1123 that no greater than human insulin. In Phase II we propose to (1) to finalize the formulation of T-1123 in relation to established criteria for ultra-rapid PK/PD and physical/chemical stability; (2) to finalize manufacturing scale-up conditions, transfer this technology to a contract manufacturing organization and produce an engineering lot of T-1123 sufficient to support all IND-enabling toxicology studies; (3) to complete pre-clinical toxicology testing of the finalized T-1123 U-100 formulation. We anticipate that attainment of these Phase II milestones would favorably position Thermalin Inc. to initiate Phase IIb- or investor-funded clinical safety/efficacy trials and to attract a corporate partner to further the development of T- 1123. We envision that both U-100 and U-500 formulations of T-1123 will address important, unmet needs among people with diabetes mellitus. The U-100 formulation of T-1123 will be compatible with existing insulin pumps, including disposable patch pumps. This is of commercial interest because T-1123s markedly augmented stability would enable pre-filling of tubed pump and patch pump reservoirs at the time of manufacture. The U-500 ultra-rapid-acting formulation, enables our co-development of a miniaturized, pre- filled and disposable closed-loop diabetes management system the size of a postage stampStampPump. Initial prototypes of this device have been developed by Thermalin with support from NIDDK (1R43DK121639- 01) and DARPA (STTR W911NF-19-C-0029). Additionally, minor modifications to existing pre-filled pen devices could support sufficiently accurate delivery of U-500 T-1123 to patients with severe insulin resistance, who are required to take very large and thus painful bolus doses of insulin. This latter subset of T2DM patients disproportionately includes underserved minorities and the rural poor of Appalachiapopulations with reduced life spans in an otherwise affluent society. If broadly accessible, T-1123 and its associated delivery devices may therefore mitigate marked disparities in health-care outcomes in all populations with diabetes.
Public Health Relevance Statement: Project Narrative We propose to build on our promising preliminary results to advance a novel insulin analog that is at once ultra-rapid, ultra-concentratable, and more stable than all marketed prandial insulin analogs. This unprecedented confluence of favorable features promises to enable the design and use of miniaturized pre- filled pumps, of potential advantage in the treatment of at-risk populations with T1DM and T2DM. We seek to finalize the formulation, develop and execute a protocol for scaled-up manufacture, and undertake IND- enabling toxicology studies.
Project Terms: absorption; Address; Adherence; Adolescent; Advanced Development; African American; age group; analog; Animal Model; Appalachian Region; base; biophysical properties; Bolus Infusion; Buffers; Canis familiaris; care outcomes; Caring; cell bank; Cell Culture Techniques; Cells; chemical stability; Chemicals; Clinical; clinical material; clinical toxicology; Closure by clamp; Communities; Contracts; design; Development; Devices; diabetes management; Diabetes Mellitus; Diffusion; Dose; Drug Kinetics; efficacy trial; Elements; Engineering; Excipients; Exhibits; Family suidae; Formulation; Funding; Glucose; Glucose Clamp; glycemic control; Glycosylated hemoglobin A; health disparity; Heteronuclear NMR; Hispanic Americans; Human; immunogenicity; improved; in silico; In Vitro; Indigenous American; innovation; Insulin; Insulin Infusion Systems; Insulin Resistance; Insulin, Lispro, Human; Insulin-Dependent Diabetes Mellitus; interest; invention; Kinetics; Lasers; light scattering; Longevity; Malignant Neoplasms; manufacturing scale-up; Maximum Tolerated Dose; member; Metabolic; Methods; miniaturize; Minor; Minority; Modification; Molecular; Mutagenesis; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; novel; Obesity; Pain; patient subsets; Patients; Pharmacodynamics; pharmacokinetics and pharmacodynamics; Pharmacology; Pharmacology Study; Phase; phase 1 study; Polishes; Population; Populations at Risk; Positioning Attribute; Postage Stamps; pre-clinical; Process; Production; Property; Protein Engineering; Proteins; Proteomics; Protocols documentation; prototype; Pump; Recombinants; Research; Resistance; Risk; Rural; Safety; Salts; self assembly; Signal Transduction; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Societies; Spectrum Analysis; Sprague-Dawley Rats; Structure; Subgroup; System; Technology; Technology Transfer; Testing; Time; Toxicology; Tribes; Tube; underserved minority; Underserved Population; Universities; Vulnerable Populations; X-Ray Crystallography; Zinc
