Pre-mixed formulations of soluble prandial insulin analogs and NPH micro-crystalline suspensions provide a simplified and cost-effective basal-bolus regimen for patients with Type 2 diabetes mellitus (T2DM) not effectively controlled by basal insulin therapy alone. Such twice-daily products (in vials or pre-filled in pens) account for >$2B in sales in the developed world, and their use is rapidly growing in the developing world. The market leaders are Novo-Nordisk (NovoMix(r) 30 in which insulin aspart is formulated 30% as a soluble zinc hexamer and 70% as an NPH micro-crystalline suspension) and Eli Lilly and Co (Humalog(r) Premixed Insulin in which insulin lispro is formulated 25% as a soluble zinc hexamer and 75% as an NPH micro-crystalline suspension;a 50/50 product is also available). Despite their popularity and clinical utility with appropriate patients, these products are complicated to manufacture, not mixable with other insulin products, fixed in their basal-bolus ratio, and subject to degradation above room temperature. Once opened, pens and vials must be discarded after 10 and 28 days, respectively. We have invented an ultra-stable biphasic insulin analog formulation that would be simpler and less expensive to manufacture, tunable in its pharmacokinetic properties, and ultra-stable at temperatures >100 ?F. Designated Thermalin-biphasic, our product builds on an innovative structural approach based on a single-chain insulin (SCI) platform. Our SCI analog exhibits a pharmacodynamics profile in an animal model that recapitulates the profile of current pre-mixed insulin products. Its ultra-stability would provide convenience during travel, enable mail-order delivery, and enhance emergency preparedness;in the developing world such a product would circumvent the cost and complexity of the cold chain of insulin delivery. Accordingly, we anticipate that this product would be of broad benefit t patients with Type 2 diabetes mellitus in the developed and developing worlds. We anticipate that Thermalin-biphasic will provide a significant cost savings relative to current insulin NPH- mix products. This savings would accrue from three factors: (a) simplification of transport and delivery through elimination of the need for refrigeration, (b) extended shelf life of vials in the hands of patients, and (c) simplification of the manufacturing process through reduction in post-fermentation processing. This Phase I project will take Thermalin-biphasic through proof-of-concept testing. This novel molecular platform, invented at Case Western Reserve University (Prof. M.A. Weiss) and licensed to Thermalin Diabetes, LLC, confers a dramatic extension of shelf life with retention of potency at high temperatures. The applicant, Dr. B. Frank (PI), was co-inventor of Humalog(r) during his prior career at Eli Lilly. Collaborative studies in will be conducted by Prof. C. T. Roberts, Jr. (cellular signaling and mitogenicity;Oregon Health Sciences University) and Prof. A. Cherrington (PK/PD in dogs;Vanderbilt University School). Thermalin Diabetes, LLC has an exclusive license to the IP, which is owned by CWRU.
Pre-mixed formulations which combine soluble prandial insulin analogs with NPH micro-crystalline suspensions (in a 30%/70% ratio in the Lilly lispro product and in a 25%/75% ratio in the Novo-Nordisk aspart product) provide a simple and effective biphasic (bolus/basal) regimen for a significant subset of patients with Type 2 diabetes mellitus. To avoid the limitations of these products (complicated manufacturing &subject to degradation above room temperature), we have invented an ultra-stable biphasic insulin analog formulation that would be simpler and less expensive to manufacture and benefit patients with Type 2 diabetes mellitus in the developed and developing worlds because its ultra-stability would provide convenience during travel, enable mail-order delivery, enhance emergency preparedness, and circumvent the cost, complexity, and impracticality of cold chain delivery and storage in the developing world. This Phase I project will take through proof-of-concept testing a novel molecular platform, invented at Case Western Reserve University and licensed to Thermalin Diabetes, LLC that confers a dramatic extension of shelf life with retention of potency at high temperatures.