Biotherapeutics are highly efficacious, but the pain and inconvenience of chronic injections lead to poor patient compliance and compromise effective disease management. Despite innumerable attempts, oral delivery of biotherapeutics remains unsuccessful due to their degradation in the gastrointestinal (GI) environment and poor intestinal absorption. We have developed an orally ingestible robotic pill (RP) for drug delivery, which protects the biotherapeutic drug payload from digestion in the GI tract and auto-injects it into the wall of the small intestine as a safe, pain-free injection since the intestines are insensate to sharp stimuli. The payload is delivered upon inflation of a balloon folded within the RP, which deflates immediately after drug delivery. Here we present results from two clinical studies demonstrating the safety, tolerability and performance of the RP in healthy humans. In the first study, three versions of the RP (A, B and C) were evaluated, which were identical in all respects except for the diameter of the balloon. The RP successfully delivered a biotherapeutic (octreotide) in 3 out of 12 subjects in group A, 10 out of 20 subjects in group B and 16 out of 20 subjects in group C, with a mean bioavailability of 65 ± 9% (based on successful drug deliveries in groups A and B). Thus, reliability of drug delivery with the RP ranged from 25 to 80%, with success rate directly related to balloon size. In a separate study, the deployment of the RP was unaffected by fed or fasting conditions suggesting that the RP may be taken with or without food. These promising clinical data suggest that biotherapeutics currently administered parenterally may be safely and reliably delivered via this versatile, orally ingestible drug delivery platform. Graphical abstract

Purpose Ustekinumab, targeting interleukin (IL)-12 and IL-23, is effective in treating chronic immune-mediated inflammatory diseases, but needs to be dosed via subcutaneous (SC) injection, which impacts patient comfort and treatment adherence. To enable oral dosing of ustekinumab, the utility of a robotic pill (RP) was evaluated in humans. Methods A Phase 1 study was conducted to evaluate the safety, tolerability, and pharmacokinetics (PK) of single doses (0.5 and 0.75 mg) of an ustekinumab biosimilar (CT-P43) delivered via RP (RT-111) in healthy participants compared to ustekinumab (0.5 mg) administered via SC injection. Results RT-111 was well-tolerated with no reported SAEs. Ustekinumab was detected in 35/40 participants dosed with RT-111. At the 0.5 mg dose, RT-111 and SC administration yielded similar C_max (RT-111: 67 ± 7 ng/mL, SC: 56 ± 4 ng/mL), while a dose-proportional increase in C_max was observed at the 0.75 mg dose (92 ± 8 ng/mL). Uptake via oral delivery was faster, with a T_max of 3 vs. 10 days for the SC group. Bioavailability of RT-111 was comparable (81%) to that of SC injection. Conclusion This is the first report of successful oral delivery of a therapeutic antibody via an orally ingestible RP in humans, with bioavailability comparable to SC injection. Clinical trial number Study was registered at Clinicaltrials.gov as NCT05890118 in May 2023.