Chlorolog: Production Scaling and Testing of a Fast-Acting, Ultra-stable Insulin

Award Information
Agency: Department of Health and Human Services
Branch: N/A
Contract: 2R44DK088506-02
Agency Tracking Number: R44DK088506
Amount: $4,469,515.00
Phase: Phase II
Program: SBIR
Awards Year: 2012
Solicitation Year: 2012
Solicitation Topic Code: NIDDK
Solicitation Number: PA11-096
Small Business Information
THERMALIN DIABETES, LLC
10000 Cedar Avenue, CLEVELAND, OH, -
DUNS: 963396747
HUBZone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 BRUCE FRANK
 (317) 846-4233
 bruce@thermalin.com
Business Contact
 RICHARD BERENSON
Phone: (617) 695-0523
Email: rick@thermalin.com
Research Institution
 Stub
Abstract
DESCRIPTION (provided by applicant): 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 basedon 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 thisderivative 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 clampstudies 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, theactive 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.

* information listed above is at the time of submission.

Agency Micro-sites

SBA logo
Department of Agriculture logo
Department of Commerce logo
Department of Defense logo
Department of Education logo
Department of Energy logo
Department of Health and Human Services logo
Department of Homeland Security logo
Department of Transportation logo
Environmental Protection Agency logo
National Aeronautics and Space Administration logo
National Science Foundation logo
US Flag An Official Website of the United States Government