Clinical Testing of an Insulin Analog

Award Information
Agency:
Department of Health and Human Services
Branch
n/a
Amount:
$254,997.00
Award Year:
2009
Program:
STTR
Phase:
Phase I
Contract:
1R41DK081292-01A1
Award Id:
93694
Agency Tracking Number:
DK081292
Solicitation Year:
n/a
Solicitation Topic Code:
n/a
Solicitation Number:
n/a
Small Business Information
11000 CEDAR AVENUE SUITE 100, CLEVELAND, OH, 44106
Hubzone Owned:
N
Minority Owned:
N
Woman Owned:
N
Duns:
802601570
Principal Investigator:
MICHAEL WEISS
(216) 368-5991
MICHAEL.WEISS@CASE.EDU
Business Contact:
KURT FRETTHOLD
() -
david@venzyme.com
Research Institution:
CASE WESTERN RESERVE UNIVERSITY

CASE WESTERN RESERVE UNIVERSITY
10900 EUCLID AVE
CLEVELAND, OH, 44106 4919

Nonprofit college or university
Abstract
DESCRIPTION (provided by applicant): The central goal of insulin replacement therapy in the treatment of Type 1 diabetes mellitus (T1DM) is tight control of blood glucose concentration. This Phase I STTR application, submitted by Thermalin Diabetes, Inc., in conjunction with Case Western Reserve University, seeks support for the pre-clinical testing and commercial development of an ultra-stable and ultra-fast-acting insulin analog for use in insulin pumps. The novel physico- chemical features of this insul in analog (designated Thermalin) promise to make feasible the long-term use of implantable intraperitoneal insulin pumps. This technology promises to enhance the safety and efficacy of insulin replacement therapy. Clinical trials have established the poten tial of implantable insulin pumps in the treatment of diabetes mellitus, but such pumps are presently regarded experimental by the FDA. A major problem is posed by the limited stability of present insulin formulations as stored for 1-3 months within the pu mp reservoir at 37oC within the peritoneal cavity. Such instability causes aberrant protein aggregation, which frequently impairs insulin delivery due to partial or complete obstruction of the pump. This problem is more severe with use of rapid- acting ins ulin analogs (HumalogTM (Lilly) and NovalogTM (Novo-Nordisk)), whose favorable pharmacokinetic properties otherwise offer significant advantages for use in external insulin pumps. Thermalin is a monomeric single-chain insulin analog refractory to aggregati on and degradation in vitro for gt 6 months on agitation at 37oC. Whereas its thermodynamic stability is markedly higher than wild-type human insulin or insulin analogs currently approved for human use, the receptor-binding affinity of Thermalin and its bi ological activity in diabetic rat model of Type I diabetes mellitus are essentially identical to that of wild-type human insulin. No adverse increase in cross-binding to the IGF receptor or aberrant mitogenicity in cell culture is observed. These prelimina ry results strongly suggest that Thermalin will prove to be a perfect pump insulin for an implantable system, combining rapid pharmacokinetics with long-term stability at high protein concentration as stored in a pump reservoir with gentle agitation at 3 7oC. Design of Thermalin was based on general principles of biophysical chemistry together with analysis of the structure of insulin and its pathways of non-native aggregation and chemical degradation. Support is requested for the GLP manufacture of Therma lin in quantities (10 grams) sufficient (a) to permit rigorous testing of its chemical and physical stability and (b) to enable in vivo assessment of its potency, pharmacokinetics, and pharmacodynamics in pigs, a standard model for studies of insulin analo gs. PUBLIC HEALTH RELEVANCE: We propose to develop an ultra-stable and ultra-fast-acting insulin analog for use in implantable insulin pumps. With this technology, patients with Type I diabetes mellitus may need only 3 or 4 injections per year (to refill t he pump reservoir) rather than 3 or 4 injections per day. Whereas existing insulin formulations tend to degrade at body temperature over a period of weeks, often obstructing the pump, our product (designated Thermalin ) is stable for more than 6 months an d is predicted to have both optimal durability and optimal rapid action for long-term implantable pump therapy.

* information listed above is at the time of submission.

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