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

Award Information
Agency:
Department of Health and Human Services
Branch
n/a
Amount:
$4,469,515.00
Award Year:
2012
Program:
SBIR
Phase:
Phase II
Contract:
2R44DK088506-02
Agency Tracking Number:
R44DK088506
Solicitation Year:
2012
Solicitation Topic Code:
NIDDK
Solicitation Number:
PA11-096
Small Business Information
THERMALIN DIABETES, LLC
10000 Cedar Avenue, CLEVELAND, OH, -
Hubzone Owned:
N
Socially and Economically Disadvantaged:
N
Woman Owned:
N
Duns:
963396747
Principal Investigator:
BRUCE FRANK
(317) 846-4233
bruce@thermalin.com
Business Contact:
RICHARD BERENSON
(617) 695-0523
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.

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