Rani Therapeutics (United States)

Abstract Disclosure: A. Dasari: Rani Therapeutics. A. Dhalla: Rani Therapeutics. L. Fung: Rani Therapeutics. M. Hashim: Rani Therapeutics. K. Horlen: ; Rani Therapeutics. K. Kaminskaya: Rani Therapeutics. H. Kennedy: Rani Therapeutics. H. Kim: ProGen. J. Kim: ProGen. J. Kim: ProGen. S. Kim: ProGen. S. Lee: ProGen. D. Mohan: Rani Therapeutics. N. Patel: Rani Therapeutics. K. Song: ProGen. A. Toledo Vo: Rani Therapeutics. A. Yamaguchi: Rani Therapeutics. S. Yang: ProGen. PG-102 is a novel, long-acting bispecific agonist composed of GLP-1 and GLP-2 peptides fused to a central Fc domain. With a favorable safety profile, PG-102 is currently in Phase 2 trials for obesity and type 2 diabetes. As with most incretin mimetics, PG-102 requires injections which can lead to patient discomfort, reduced acceptance, and suboptimal adherence to therapy. To address this challenge, we have developed RT-114, an orally ingestible robotic pill which delivers PG-102 transenterically upon reaching the small intestine. RT-114 is being developed for the treatment of obesity. This nonclinical study was designed to compare the oral delivery of PG-102 via RT-114 with a subcutaneous (SC) injection of PG-102. Sixteen healthy canines were randomized to receive a single 12mg dose of PG-102 either via SC injection (N=6) or orally via RT-114 (N=10). Over a 14-day period, pharmacokinetics (PK; measured as serum drug concentrations by ELISA), pharmacodynamic (PD) outcomes (food intake and body weight), as well as safety, tolerability, and delivery reliability were evaluated. RT-114 was well tolerated and demonstrated high drug delivery reliability achieving systemic drug exposure in 90% (9/10) of the animals. Crucially, PK analysis showed that oral delivery via RT-114 achieved bioequivalence with SC injection, exhibiting comparable serum-drug profiles and 111% average bioavailability relative to SC. Consistent with PK findings, both delivery methods resulted in the same average peak weight loss of 6.7%. Notably, the RT-114 group exhibited less variability in weight loss response compared to the SC group, as indicated by a lower standard deviation (± 1.4% vs ± 5.4%), demonstrating consistent dosing accuracy and suggesting potentially more predictable effects with oral delivery. PK-PD correlation analysis demonstrated a clear positive association between serum PG-102 levels and reduced food intake, consistent with the drug’s expected mechanism of action. Importantly, allometric modeling indicated strong concordance between the canine SC PK data and published human SC PK data, supporting the potential translatability of these RT-114 findings to humans. In summary, this nonclinical study demonstrated that the RT-114 oral robotic pill successfully delivered the bispecific GLP-1/GLP-2 receptor agonist PG-102 to achieve both PK and PD bioequivalence to SC injection. By offering a potentially more convenient alternative to SC injections, RT-114 holds promise for improving patient acceptance and long-term adherence. Moreover, targeted intestinal delivery via RT-114 may better mimic physiologic incretin release, potentially enhancing gut-brain pathway engagement. Collectively, these compelling nonclinical results provide a robust rationale for initiating clinical development of RT-114 as a first in class oral anti-obesity therapy. Presentation: Monday, July 14, 2025

Biotherapeutic agents must be administered parenterally to obtain therapeutic blood concentrations, lowering patient compliance and complicating care. An oral delivery platform (ODP) was developed to deliver drugs into the small intestinal wall. This proof‐of‐concept study was performed in 17 anesthetized, laparotomized swine. In 8 swine weighing 17.4 ± 1.2 kg (mean ± SEM), 20 IU of recombinant human insulin (RHI) were auto‐injected into the jejunal wall by placing the ODP inside the jejunum via an enterotomy. In 9 control swine weighing 17.0 ± 0.4 kg, 20 IU of RHI were injected subcutaneously. In both groups, under a 60‐80 mg/dL euglycemic glucose clamp, blood glucose was measured with a handheld glucometer and serum insulin was measured using ELISA, at 10‐minute intervals between −20 and +420 minutes after RHI delivery. The peak serum concentration of RHI was 517 ± 109 pmol/L in the ODP and 342 ± 50 pmol/L in the subcutaneous group (ns). The areas under the insulin concentration curves (83 ± 18 and 81 ± 10 nmol/L·min) were also similar in both groups. The mean time to peak serum concentration of insulin was 139 ± 42 minutes in the ODP and 227 ± 24 minutes in the subcutaneous group (ns). In conclusion, (a) The bioactivity of RHI was preserved after its delivery into the jejunal wall, (b) the intrajejunal route delivered insulin as rapidly and physiologically as the subcutaneous route, and (c) these pharmacokinetic and pharmacodynamic characteristics of RHI after intrajejunal delivery suggest that drugs currently administered parenterally, such as basal insulin, could be successfully delivered into the proximal intestinal wall via the ingestible capsule.