SUN-680 First-in-Class Oral Dual GLP-1/Glucagon Agonist for Patients with Obesity and Metabolic Disorders: In Vivo Pharmacokinetic and Pharmacodynamic Results

Abstract

Disclosure: G. Burshtein: Entera Bio Ltd. C. Itin: Entera Bio Ltd. D. Pery: Entera Bio Ltd. E. Reichman: Entera Bio Ltd. H. Galitzer: Entera Bio Ltd. M. Kushnir: Entera Bio Ltd. A. Bar-Ilan: OPKO Biologics, Ltd. M. Golan: OPKO Biologics, Ltd. L. Moschcovich: OPKO Biologics, Ltd. M. Zakar: OPKO Biologics, Ltd. A. Rivkin: OPKO Biologics, Ltd. M. Levy: OPKO Biologics, Ltd. M. Toledano: Entera Bio Ltd. J. Hsiao: OPKO Health Inc..Oxyntomodulin (OXM) is a naturally occurring peptide hormone secreted by the intestinal L-cells in response to food intake. Acting as a dual agonist of GLP-1 and glucagon receptors, OXM plays a critical role in regulating appetite, energy expenditure, and glucose metabolism. However, due to its short plasma half-life, the therapeutic potential of the native hormone is limited. OPK-88006 is an analog of OXM linked with an acylated long-chain fatty acid to increase its circulating half-life and is suitable for a once-a-week subcutaneous administration. Entera Bio Ltd. in collaboration with OPKO Health Inc. are developing OPK-88006 as the first oral once-daily OXM tablet treatment for patients with obesity and metabolic disorders. Oral bioavailability of peptide drugs is negligible due to the large molecular size, polarity and enzymatic degradation in the gastrointestinal tract. Entera’s N-Tab™ platform minimizes enzymatic degradation while facilitating transcellular permeability, to enable robust oral bioavailability of the peptide drugs. To assess the feasibility of administering OPK-88006 orally, studies were conducted in rats and minipigs. Intravenous administration of OPK-88006 to rats (n=8) and minipigs (n=4), resulted in half-lives of ∼4 h and ∼35 hours, respectively. These half-lives were found to be comparable to the reported half-lives of approved oral semaglutide, Rybelsus®, and support a once daily oral OXM treatment regimen. A PK/PD study was conducted in rats, administered tablets of OPK-88006 (4 mg/rat; n=12 PK and 6 PD) and oral placebo (n=6). Substantial and prolonged systemic exposure along with a significant (p<0.001) reduction in blood glucose (by oral glucose tolerance test) were demonstrated. Finally, oral OPK-88006 tablets at doses of 50 mg/pig were tested in minipigs (n=4). Cmax of ∼0.3 µg/ml, and systemic exposure for more than 96 hours were shown. The obtained plasma levels exceeded those reported in humans for other OXM analogs developed as once daily and once weekly injections. In conclusion, the systemic bioavailability and pharmacologic response, combined with the extended biological half-life of the molecule obtained in rats and minipigs, support further development of oral tablets of OPK-88006 as a potentially first-in-class dual GLP-1/glucagon agonist for the treatment of obesity and metabolic syndromes. A Phase 1 clinical study of this novel oral peptide candidate is currently being planned.Presentation: Sunday, July 13, 2025