By John Vandermosten, CFA

NASDAQ:RANI

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On February 5^th, Rani Therapeutics Holdings, Inc. (NASDAQ:RANI) shared its preclinical readout from the RT-116 study demonstrating successful oral delivery of semaglutide using the RaniPill High Capacity (HC) device compared to subcutaneous (SC) injection. The study was conducted in eight canines to generate pharmacokinetic (PK) and pharmacodynamic (PD) data evaluating oral delivery of the glucagon-like peptide-1 receptor (GLP-1) agonist. In the press release, Rani updated stakeholders on the RT-114 program that is being developed with ProGen Co., targeting a start for the GLP-1/GLP-2 dual agonist Phase I study in 2025.

RT-116 Preclinical Results

The RT-116 program is evaluating one of the most important biologics in the market today: semaglutide. It is a successful treatment for weight loss and diabetes and can address other related conditions. An important shortcoming of the product is the lack of an effective oral formulation of the drug. RT-116 seeks to address this shortcoming using the RaniPill HC (RP) for delivery. Semaglutide is a GLP-1 receptor agonist that selectively binds to and activates the GLP-1 receptor mimicking its activity. GLP-1 is an incretin hormone and enterogastrone (hormone that slows stomach motility and secretion) that stimulates insulin secretion, inhibits glucagon secretion, delays gastric emptying and reduces the production of stomach acid serving as a physiological regulator of appetite and food intake.

Study Design

This nonclinical PK and PD study was conducted to examine the effects of RT-116 versus a SC injection comparator group. It was designed as a 2x2 crossover study and was executed in two parts over four weeks. Eight canines were randomized into two equal groups who received either 0.5 mg of semaglutide delivered via the RP or subcutaneous injection. Endpoints include plasma drug concentrations, body weight, food intake, lipid profile and safety.

Results

Semaglutide was successfully delivered in seven of the eight canines that received the RP, which was well-tolerated by all subjects with no serious adverse events (SAEs). C_MAX, T_MAX and area under the curve (AUC) were comparable for both modes of delivery.

Oral administration of the RP generated similar bioavailability and biological activity comparable to subcutaneous administration with RP generating bioavailability of 107% of the subcutaneous method. Both groups produced similar weight loss and decreases in serum triglycerides and cholesterol.

RaniPill Børsen Review

A recent article in the Danish financial publication, Børsen, drew a connection between semaglutide’s sponsor, Novo Nordisk and Rani via a senior executive who previously served at the former and now acts as a Senior Strategic Advisor at the latter. The individual we are referring to is Jesper Høiland who highlighted several synergies between the RaniPill and future opportunities for the semaglutide brands Ozempic, Mounjaro and Wegovy. Mr. Høiland recognizes the potential of the RP and anticipates a significant value inflection point when contracts with major pharmaceutical companies are signed. The article highlighted that the RP has been tested and administered more than 7,000 times in both animal models and humans with no safety problems. There have also been several clinical trials that tested a variety of medicines. Novo acquired the SNAC (Sodium N-[8-(2-hydroxybenzoyl)amino]caprylate) technology which is used in Rybelsus and has developed the LUMI (Luminal Unfolding Microneedle Injector) delivery system. However, Rybelsus is plagued with low bioavailability and LUMI it is in the early stages of development with no clinical data.

The RP could potentially extend the product life for Novo’s semaglutide portfolio through the approval of an oral option with excellent levels of bioavailability. Using the 505(b)(2) pathway, a small trial could relatively quickly submit an RP version of semaglutide to the FDA for approval. Mr. Høiland thinks that 2028 could be an important year for Rani as the semaglutide patent would have expired by then and the RP would have sufficient time to complete clinical trials and gain regulatory approval. The patent on the RP runs until 2044, which would provide many more years of protection for the underlying biologic. While Rani’s Senior Strategic Advisor has not indicated whether or not he has communicated with Novo, he does see a natural fit between semaglutide and oral delivery technology.

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