Eelco de Koning¹, Michael Rickels²

¹Leiden University Medical Center, Leiden, NL;²UPENN Perelman School of Medicine, PHL, PA, USA; e.j.p.de_koning@lumc.nl

Background: VX-880 is an allogeneic stem cell-derived, fully differentiated islet cell therapy being evaluated in a Ph1/2 trial (FORWARD).

Methods: This single-arm, open-label trial evaluates VX-880 as an intra-portal infusion with concomitant steroid-free immunosuppression in participants (18-65yrs) with T1D, impaired hypoglycemia awareness, and ≥2 severe hypoglycemic episodes (SHEs) in the year before enrollment.

Results: Fourteen participants received VX-880: 2 initially received half the dose in Part A and 12 received the full dose in a single infusion in Parts B and C as of May2024. At baseline, participants had multiple SHEs, HbA1c>7%, and no detectable fasting C‑peptide. After VX-880 infusion, all 14 participants demonstrated engraftment and VX-880 function, evidenced by clinically meaningful levels of glucose responsive C‑peptide production on Day (D) 90 MMTT. All 12 participants who received full dose in a single infusion had marked glycemic control improvement (mean HbA1c:baseline=7.8%;D180=6.2%) and glucose time in range (TIR) of >70% (mean TIR:baseline=49.5%;D180=88.3%) and were free of SHEs at >90 days post-infusion. Marked reduction in exogenous insulin use was seen in 11/12 participants (last visit), of which 9/12 stopped using exogenous insulin at/or after D180. Four participants (100%) with ≥1yr follow-up and therefore evaluable for primary and secondary endpoints, had elimination of SHEs with HbA1c<7%, and insulin independence. There were no VX-880-related serious adverse events and two deaths, both unrelated to VX-880: one due to cryptococcal meningitis infection after complications from elective sinus surgery, prolonged high-dose steroid use (protocol prohibited), and immunosuppressive medication; one due to progression of pre-existing neurocognitive impairment from traumatic brain injury from a motor vehicle accident due to a SHE before enrollment. The safety profile was consistent with immunosuppressive regimen, islet infusion procedure, and long-standing T1D.

Discussion/Conclusion: These results demonstrate that a single infusion of VX-880 has curative potential in T1D with elimination of severe hypoglycemia, significantly improved glycemic control, and freedom from exogenous insulin use.