Purpose: Xenotransplantation is a promising potential solution to address the critical shortage of available organs for transplantation. Here we describe the study design of the first-ever registration-supporting clinical trial of a xeno-organ, the 10 GE Xenokidney (UKidney™), a xenokidney derived from a 10 gene-edited (10 GE) source pig (GGTA1KO.B4GALNT2/B4GALNT2LKO.CMAHKO.GHRKO.hCD46.hCD55.hTHBD.hPROCR.hCD47.hHMOX1).  
Methods: The EXPAND (GPK-KF-101) study (NCT06878560), “A Prospective Study to Evaluate the Safety and Efficacy of the 10 GE Xenokidney in Patients with End-stage Renal Disease (ESRD),” is a Phase 1/2/3, multicenter, open-label study initially consisting of a cohort of 6 participants across two centers, followed by cohort expansion of up to 50 participants. This first-in-human clinical study will use calcineurin-based immunosuppression and aims to assess the safety and efficacy of the 10 GE Xenokidney in 2 groups of participants: ESRD patients who have been assessed and determined to be ineligible for a conventional allogeneic kidney transplant for medical reasons; and ESRD patients who are on a kidney transplant waitlist but are more likely to die or go untransplanted than receive a deceased donor kidney transplant within five years. Among other eligibility criteria, participants must be 55 to 70 years of age, have been on hemodialysis for at least 6 months, and be negative xeno-crossmatch by complement-dependent cytotoxicity (CDC). After transplant of the 10 GE Xenokidney, participants will be followed for 24 weeks post-transplant where safety and efficacy endpoints will be evaluated, after which, participants will be followed for their lifetime. Efficacy endpoints include participant survival rate, 10 GE Xenokidney survival rate, change in measured glomerular filtration rate, and change in participant quality of life at 24 weeks post-transplant. Overall survival time of participants receiving a 10 GE Xenokidney and survival time of the 10 GE Xenokidney will also be assessed. Safety endpoints will include incidence of adverse events and serious adverse events, all-cause mortality, and the incidence of proteinuria, zoonotic infection, and opportunistic infection. After the initial cohort of 6 participants reaches at least 12 weeks post-transplant, safety and efficacy data will be reviewed. If safety and efficacy results are supportive, the study will proceed and sample size will be increased to a total of up to 50 participants to enable the study to support registration, with additional transplant centers added to the study.
Conclusion: The prospectively designed EXPAND clinical trial is a significant step toward supporting xenotransplantation as a therapeutic option to a large population of ESRD patients who are unlikely to receive an allogeneic kidney transplant.