Oral delivery of an ustekinumab biosimilar with bioavailability comparable to subcutaneous administration in healthy human participants

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.

Introduction

Translation of medical advances into targeted treatments has led to the development of biologic therapies, which offer high specificity and superior efficacy for many chronic conditions. In particular, biologics that target specific pro-inflammatory cytokines have been life-changing for individuals with chronic immune-mediated inflammatory diseases (IMIDs) like psoriasis. However, due to the size, nature, and structure of biologics, these macromolecules cannot overcome barriers in the gastrointestinal (GI) tract, and therefore can only be administered via parenteral injections. One such molecule is the human IgG1K monoclonal antibody, ustekinumab, which is an effective biologic treatment for individuals with moderate-to-severe psoriasis approved for nearly two decades [1,2,3].

Ustekinumab, like other biologic drugs, must be administered by injection due to its rapid degradation and inactivation in the GI tract [4]. For individuals who are initiating this therapy, the process of performing self-injections can be daunting [5]. Indeed, patients with chronic IMIDs are burdened with repeated administration of injections that interfere with quality of life, can stigmatize, and can elicit behavioral aversions and fear [6, 7]. Predictably, patients who inject biologics on a frequent basis overwhelmingly say they would prefer an oral alternative to their injectable drug [7,8,9]. Surprisingly, 50% of patients whose treatment regimen is more occasional (monthly or biannually) still prefer a pill over an injection, including individuals with moderate-to-severe psoriasis [10, 11]. More specifically, even though ustekinumab is administered via a subcutaneous (SC) injection every 3 months, patients would still prefer an oral ustekinumab option if it was available [11]. Furthermore, both patients and their physicians acknowledge that adherence with therapy would improve with the availability of orally delivered therapy [10, 11].

To address this unmet need for oral delivery of biologics [12, 13], an orally ingestible robotic pill (RP) has been developed that safely delivers biotherapeutics via transenteric injection directly into the small intestine [14,15,16]. The intestines are insensate to sharp stimuli and thus drug delivery via injection is not only painless, but also highly efficient for drug absorption [17, 18]. This oral RP has reliably delivered several biotherapeutics in porcine and canine models with bioavailability nearly identical to SC injections [14, 16, 19, 20]. Further, in human clinical trials, the RP delivered octreotide and teriparatide with high bioavailability and no serious adverse events (SAEs) in both single and repeated daily dosing [15, 21].

Preclinical studies showed that the RP was able to deliver an ustekinumab biosimilar (CT-P43) with bioavailability comparable to SC injections in canines [20]. To confirm these data in humans, a Phase 1 study was conducted to evaluate the safety, tolerability, and pharmacokinetics (PK) of the RP containing CT-P43 (RT-111) in healthy participants. The current report describes the results of this Phase 1 study assessing two doses (0.5 mg and 0.75 mg) of RT-111 compared to SC injections (0.5 mg) of commercially available ustekinumab.

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Clinical trial materials

RT-111 consists of the RP containing CT-P43 and was manufactured by Rani Therapeutics (San Jose, CA, USA). The RP is a versatile drug delivery platform, based on a 000 (31 mm by 11 mm) size capsule, designed to orally deliver biologics that are currently given via SC, intramuscular, or intravenous injections. The enteric coating on the RP is designed to withstand the acidic environment of the stomach. Disintegration of the enteric coating and capsule shell in the small intestine activates the underlying mechanism to actuate the RP whereby the drug is injected transenterically and rapidly absorbed. RP remnants are safely excreted with regular bowel movements. Details of the RP design, operation, reliability and safety have previously been reported.

CT-P43 developed by Celltrion (Yeonsu-gu, Incheon, Republic of Korea) is approved in the European Union, Canada, Australia, and the United States. The CT-P43 drug solution was obtained from Celltrion and was lyophilized into a powder that was compacted into microtablets containing 0.5 mg or 0.75 mg of ustekinumab, inserted and sealed inside the dissolvable needles, and enclosed into the needle chamber under aseptic conditions to maintain sterility. All other components of the RP were assembled in a controlled environment. The sterility of the drug needles was tested and verified by an external CRO (Aemtek Laboratories, Fremont, CA).

Commercially available ustekinumab was purchased and provided to the clinical site for use in the SC injection control group. The drug solution was diluted to be administered at a dose of 0.5 mg/mL.

Myers, J.T., Yamaguchi, A., Horlen, K. et al. Oral delivery of an ustekinumab biosimilar with bioavailability comparable to subcutaneous administration in healthy human participants. Eur J Clin Pharmacol 82, 40 (2026). https://doi.org/10.1007/s00228-025-03969-6