LB055 - A FIRST- IN-CLASS ORAL GLP-2 ANALOG FOR TREATMENT OF SHORT BOWEL SYNDROME

LB055

A FIRST- IN-CLASS ORAL GLP-2 ANALOG FOR TREATMENT OF SHORT BOWEL SYNDROME

G. Burshtein¹, C. Itin¹, D. Pery¹, E. Reichman¹, H. Galitzer¹, M. Kushnir¹, A. Bar-Ilan², M. Golan², L. Moschcovich², M. Zakar², A. Rivkin², M. Levy², M. Toledano^1,*, J. Hsiao³

¹Entera Bio Ltd., Jerusalem, ²OPKO Biologics Ltd., Kiryat Gat, Israel, ³OPKO Health Inc., Miami, United States

Rationale: Glucagon-like peptide-2 (GLP-2) is a naturally occurring peptide hormone secreted by the intestinal L-cells, that plays a critical role in regulating gastrointestinal (GI) physiology. Due to a very short plasma half-life (t_1/2), the therapeutic potential of the native hormone is limited. Entera Bio Ltd. in collaboration with OPKO Biologics Inc. is developing OPK-8801003 as the first oral GLP-2 analog for potential therapy of Short Bowel Syndrome (SBS). OPK-8801003 is the analog of endogenous GLP-2, chemically modified to extend its biological t_1/2 while preserving its potency, with the goal of enabling the development of a once-daily tablet treatment. Oral bioavailability of peptide drugs is typically negligible due to their large molecular size and enzymatic degradation in the GI tract. Entera’s N-Tab™ technology platform enables peptides’ permeability and prevents their degradation, allowing therapeutically relevant plasma levels to be reached following oral administration. Given the challenging compliance rates attributed to injectable GLP-2 therapy and heterogeneity of SBS patients, a daily tablet format may address a significant unmet need in treating and titrating patients more effectively.

Methods: To assess the feasibility of oral OPK-8801003 treatment, rat and minipig pharmacokinetic studies were conducted.

Results: Intravenous administration of OPK-8801003 to rats (n=8) and minipigs (n=4) resulted in t_1/2 of ~3 hours and ~15 hours, respectively. These t_1/2 were found to be substantially longer than those reported for teduglutide (an injectable GLP-2 analog, and currently the only approved GLP-2 agonist for SBS treatment) in the same animal models, supporting a once-daily oral OPK-8801003 therapy. Oral administration to minipigs (n=4) of OPK-8801003 tablets of clinically relevant size and dose (50 mg/pig) demonstrated Cmax of ~0.2 µg/ml, and systemic exposure for more than 24 hours. The obtained plasma levels substantially exceeded the Cmax reported in humans for QD SC teduglutide.

Conclusion: The combination of extended t_1/2 and oral bioavailability observed in pre-clinical studies strongly supports further development of this first-in-class, once-daily oral GLP-2 tablet therapy for SBS, offering a potentially transformative treatment option in this underserved area.

Disclosure of Interest: G. Burshtein Other: Employee of and may own stock/options in Entera Bio Ltd., C. Itin Other: Employee of and may own stock/options in Entera Bio Ltd., D. Pery Other: Employee of and may own stock/options in Entera Bio Ltd., E. Reichman Other: Employee of and may own stock/options in Entera Bio Ltd., H. Galitzer Other: Employee of and may own stock/options in Entera Bio Ltd., M. Kushnir Other: Employee of and may own stock/options in Entera Bio Ltd., A. Bar-Ilan Other: Employee of OPKO Biologics Ltd., M. Golan Other: Employee of OPKO Biologics Ltd., L. Moschcovich Other: Employee of OPKO Biologics Ltd., M. Zakar Other: Employee of OPKO Biologics Ltd., A. Rivkin Other: Employee of OPKO Biologics Ltd., M. Levy Other: Employee of OPKO Biologics Ltd., M. Toledano Other: Employee of and may own stock/options in Entera Bio Ltd., J. Hsiao Other: Employee of OPKO Health Inc.