AMIDEBIO, LLC — Department of Health and Human Services SBIR Phase II: 200

Description

In severe persistent hyperinsulinism (HI), repeated hypoglycemic episodes can ultimately lead to permanent seizure disorders, learning disabilities, cerebral palsy, blindness and even death. Clinical studies have demonstrated the effectiveness of both short-term and long-term treatment with glucagon for severe forms of HI and continuous subcutaneous administration of glucagon has been recommended both because of the potential improvement in patient outcome and high costs of surgical intervention followed by long-term annual care costs. However, the instability of glucagon in solution creates both administration problems and potential complications due to infusion tube blockage. These instability problems have limited the use of glucagon for severe persistent HI. To overcome this problem, in our successful Phase I grant we developed a series of solution stable glucagon analogs using a novel design approach and demonstrated their effectiveness both in vitro and in vivo. These analogs when formulated in a conventional sterile diluent maintain not only the standard 95% potency requirement throughout a 2 year storage period at 4ºC but more importantly offer an extended “in use” stability period of at least 3 months at 40ºC. Such analogs are compatible with implementation in a pump system for the long-term management of severe persistent HI without concern for complications due to glucagon instability and pump clogging issues. In addition, such a product will be suitable for emergency hypoglycemic incidences which result in over 200,000 hospitalizations a year. Finally, the resultant product could be implemented in a bi-hormonal artificial pancreas for T1 and T2 diabetes. In this Phase II project, we aim to develop large scale (gram level) GLP production of the lead candidates, complete toxicology, immunogenicity and formulation studies, and prepare a regulatory package suitable for filing an IND in preparation for clinical trials.In our successful Phase I grant, a series of novel glucagon analogues were designed, produced at milligram levels, tested for solution stability and for both in vitro and in vivo activity. We have identified 3 lead candidates with superior physical properties and biological activity in vivo using a hyperinsulinism model. In this Phase II proposal we aim to complete large scale (gram level) GLP production of the lead candidates, complete toxicology and formulation studies, and prepare a regulatory package suitable for filing an IND in preparation for clinical trials aimed to demonstrate the use of our stable glucagon analogs for treating congenital hyperinsulinism, emergency hypoglycemia and ultimately for treating T1 and T2 diabetics using a bi-hormonal pump.