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Sister Patricia Grasso, CSJ, Continues Progress on Anti-Obesity Peptide
by Aegis Therapeutics, LLC
HIGHLY BIOAVAILABLE ORAL, NASAL AND BUCCAL FORMULATIONS OF [D-Leu-4]OB3
Following the discovery of the hormone leptin and its critical role in curbing appetite in 1995, many believed that the ability to treat obesity was imminent. As a result, several clinical trials ensued to combat obesity with recombinant leptin, but these were unsuccessful. Researchers at Albany Medical College, in Albany NY, made an important discovery in 2000. Using a synthetic peptide strategy to map the entire leptin molecule for active sites, Professor (Sister) Patricia Grasso, CSJ, Ph.D., at the Center for Cell Biology and Cancer Research and Department of Medicine found that a very small piece of the leptin hormone, a peptide representing less than 6% of the total leptin molecule, was responsible for controlling appetite allowing the development of synthetic peptide amides with leptin-like activity.
Recognizing the commercial limitations stemming from poor patient acceptance of, and compliance with, injectable peptide therapeutic regimens, except in severe life threatening conditions, Albany Medical College and Aegis Therapeutics entered into an agreement to combine Aegis’ patented Intravail® non-invasive delivery technologies with Albany Medical College’s patented anti-obesity peptide to 1) assess the technical and commercial potential of the combined technologies and, 2) through Aegis, to seek appropriate partnerships with pharmaceutical companies interested in the obesity and diabetes markets.
Because peptides are most often labile in the GI tract they are usually administered by injection. The principal fragment of interest, D-Leu-OB-3, has been shown to induce significant weight loss upon i.p injection, nasal administration and oral administration. A non-invasive format is preferred in terms of patient compliance, convenience, ease of self administration, and avoidance of needle stick injuries for patients or care givers. While intranasal administration of protein and peptide drugs has shown some limited success with small peptides such as desmopressin and calcitonin, Aegis’ Intravail® absorption enhancement agents provide unmatched bioavailabilities — bioavailabilities comparable to injection for small as well as much larger proteins. Our studies have shown that OB-3 peptide formulated with Intravail® excipients induces significant weight loss upon nasal administration with bioavailability comparable to injection approaching or exceeding 100% compared to s.c. injection. Intravail® excipients have recently been shown to also provide high oral bioavailability of OB-3 as well as concomitant weight loss with bioavailability in excess of 50% in oral gavage studies.
The Intravail® absorption enhancement excipients allow transmucosal delivery – oral, intranasal, buccal, sublingual and rectal – of peptide, protein and non-protein macromolecular therapeutics having molecular weights up to and in excess Aegis Therapeutics LLC – Licensing Opportunity – v1 .4.11 of 20 KDa, with bioavailabilities approaching or equaling injection in some instances. They are also being applied successfully to two small molecule drugs now in human trials.
Intravail® alkylsaccharide excipients are mild and non-irritating to mucosal membranes. They are safe, odorless, tasteless, non-toxic, non-irritating, nondenaturing, and non- mutagenic, chemically synthesized molecules that metabolize to CO2 and H2O. These molecules are closely related to mild surfactants widely used in personal care and food products in significantly higher concentrations than those used in Aegis formulations and are recognized as GRAS substances for many applications. Intravail® absorption enhancement agents provide exceptionally high and unmatched bioavailability performance comparable in efficiency to subcutaneous injection, via the intranasal, buccal, intestinal, and other mucosal membrane administration routes, delivering potent peptide, protein, and large molecule drugs that can currently only be delivered by injection.
Studies conducted at the Albany Medical College by Dr. (Sister) Patricia Grasso, CSJ, and associates have demonstrated excellent oral and nasal bioavailability of the 7-mer OB-3 peptide. Administration of OB-3 by injection and oral gavage in a number of mouse models has been shown to induce significant weight loss with no adverse effects. Serum osteocalcin levels in ob/ob mice treated with [D-Leu-4]-OB3 were elevated by 161.0% over control levels. Depleted osteocalcin levels during weight loss can result in “low bone turnover osteoporosis.” Osteocalcin has been shown to increase insulin sensitivity as well. This, coupled with the reduction in serum glucose, makes the OB3 peptide appear interesting for diabetes as well as weight loss.