Versartis Focusing On Extending Half Life Of Drugs For Metabolic And Endocrine Diseases

Main Category: Diabetes
Article Date: 14 Jun 2009 - 0:00 PDT

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Versartis, Inc., a new company developing novel biologics with enhanced properties for patients with metabolic diseases, published abstracts for preclinical data on its two product candidates, VRS-859 (exenatide-rPEG) and VRS-808 (glucagon-rPEG), at the American Diabetes Association Scientific Sessions annual meeting beginning today in New Orleans.

Versartis, through a unique licensing agreement with Amunix, Inc., uses the proprietary Amunix recombinant PEGylation (rPEG) technology to extend the half life of established biologics.  The Versartis compounds in development have the potential for significantly less frequent dosing and fewer side effects than those products currently on the market or in development.

"With VRS-859, we have a product candidate that may become a 'best in class' GLP-1 analog for the treatment of type 2 diabetes.  This compound has similar preclinical efficacy to exenatide in animal models; and the pharmacokinetics in four species support monthly dosing in humans.  VRS-859 can also be administered in a small volume with a small gauge needle," said Jeffrey L. Cleland, Ph.D., Founder and Chief Executive Officer of Versartis.

"VRS-808 has the potential to prevent nocturnal hypoglycemia in type 1 diabetes, an unmet medical need," Dr. Cleland continued.  "VRS-859 and VRS-808 did not have significant toxicology at very high doses in preclinical studies, including a lack of immunogenicity in all studies.  We look forward to moving these products rapidly into human clinical trials to benefit diabetes patients."

ABSTRACTS

Exenatide: 1994-PO -- "An Extended Half-life Exenatide Construct for Weekly Administration in the Treatment of Diabetes Mellitus"

The current approved regimen of exenatide for the treatment of type 2 diabetes mellitus requires administration twice a day and is effective in reducing hemoglobin A1c and body weight. Common side effects of this treatment regimen for exenatide include nausea and hypoglycemia, possibly caused by the high peak levels (Cmax) of exenatide after each injection. The ideal dosage form of exenatide would maintain the exenatide blood level in the therapeutic window for at least one week without a high Cmax, which commonly occurs with depot dosage forms. We designed an extended half-life exenatide construct that contains a long unstructured tail of hydrophilic amino acids referred to as rPEG (Exenatide-rPEG; VRS-859). The rPEG tail both increases the serum half-life and provides a slower rate of absorption, thus reducing the peak-trough ratio significantly from the levels seen with twice daily injection of unmodified exenatide. Attachment of rPEG to a model protein (26.9 kDa) increased serum half-life to 75 hrs with a 99% absolute bioavailability following subcutaneous administration in cynomolgus monkeys. A similar half-life extension is expected with exenatide, enabling weekly or every two week dosing in humans. The preclinical efficacy, pharmacokinetics, and immunogenicity of VRS-859 will be presented. The results of these studies will enable rapid progress of the construct into human clinical trials.

Glucagon:  2001-PO -- "An Extended Half-life Glucagon Construct for the Prevention of Nocturnal Hypoglycemia"

Nocturnal hypoglycemia is a common problem for type I diabetics, especially children, often leading to death. Glucagon is typically used to treat acute hypoglycemia, but the short half-life of glucagon ( < 17 minutes) prevents its use in nocturnal applications without complicated pump or depot system approaches. A novel glucagon construct that enables a single dose to maintain basal glucose levels during sleep while minimizing the chance for long term changes in hemoglobin A1c is the ideal approach to preventing hypoglycemia. We designed an extended half-life glucagon construct that contains a long unstructured tail of hydrophilic amino acids referred to as rPEG (Glucagon-rPEG; VRS-808) that increases the serum half-life. Following subcutaneous administration in cynomolgus monkeys, this construct maintains blood levels within the therapeutic window for 10-12 hrs and is completely cleared within 24 hrs. The in vitro potency of the construct is ~20% of natural glucagon, possibly allowing a broader dosing range. A number of characterization experiments will be presented, demonstrating the efficacy and safety of this compound in preclinical models. The data presented will include the results of a dose finding study in fasting beagle dogs, and repeat-administration immunogenicity of the construct in normal mice. The results of these studies will serve as the foundation for moving this novel construct rapidly into human studies.

Source
Versartis