Stem Cell-Derived, Fully Differentiated Islets for Type 1 Diabetes
- Reichman, Trevor W. M.D.
- Markmann, James F. M.D., Ph.D.
- Odorico, Jon M.D.
- Witkowski, Piotr M.D., Ph.D.
- Fung, John J. M.D., Ph.D.
- Wijkstrom, Martin M.D.
- Kandeel, Fouad M.D., Ph.D.
- de Koning, Eelco J.P. M.D., Ph.D.
- Peters, Anne L. M.D.
- Mathieu, Chantal M.D., Ph.D.
- Kean, Leslie S. M.D., Ph.D.
- Bruinsma, Bote G. M.D., Ph.D.
- Wang, Chenkun Ph.D.
- Mascia, Molly M.D.
- Sanna, Bastiano Ph.D.
- Marigowda, Gautham M.D., M.P.H.
- Pagliuca, Felicia Ph.D.
- Melton, Doug Ph.D.
- Ricordi, Camillo M.D.
- Rickels, Michael R. M.D.
Abstract
Background
Zimislecel is an allogeneic stem cell-derived islet-cell therapy. Data on the safety and efficacy of zimislecel in persons with type 1 diabetes are needed.
Methods
We conducted a phase 1-2 study of zimislecel in persons with type 1 diabetes. In part A, participants received a half dose of zimislecel (0.4×109 cells) as a single infusion into the portal vein, with an option for a second half dose within 2 years. In parts B and C, participants received a full dose of zimislecel (0.8×109 cells) as a single infusion. All the participants also received glucocorticoid-free immunosuppressive therapy. The primary end point in part A was safety. The primary end point in part C was freedom from severe hypoglycemic events during days 90 through 365, with a glycated hemoglobin level of less than 7% or a decrease of at least 1 percentage point from baseline in the glycated hemoglobin level at one or more time points between days 180 and 365. Secondary end points in part C included safety and insulin independence between days 180 and 365. Assessment of the primary and secondary end points in part C involved the participants who received the full dose of zimislecel as a single infusion in part B or C. Detection of serum C-peptide during a 4-hour mixed-meal tolerance test was used to assess engraftment and islet function. All the analyses were interim and not prespecified.
Results
A total of 14 participants (2 in part A and 12 in parts B and C) completed at least 12 months of follow-up and were included in the analyses. C-peptide was undetectable at baseline in all 14 participants. After zimislecel infusion, all the participants had engraftment and islet function, as evidenced by the detection of C-peptide. Neutropenia was the most common serious adverse event, occurring in 3 participants. Two deaths occurred — one caused by cryptococcal meningitis and one by severe dementia with agitation owing to the progression of preexisting neurocognitive impairment. All 12 participants in parts B and C were free of severe hypoglycemic events and had a glycated hemoglobin level of less than 7%; these participants spent more than 70% of the time in the target glucose range (70 to 180 mg per deciliter). Ten of the 12 participants (83%) had insulin independence and were not using exogenous insulin at day 365.
Conclusions
The results of this small, short-term study involving persons with type 1 diabetes support the hypothesis that zimislecel can restore physiologic islet function, warranting further clinical investigation. (Funded by Vertex Pharmaceuticals; VX-880-101 FORWARD ClinicalTrials.gov number, NCT04786262.)
Stem Cell−Derived Islets for Type 1 Diabetes
Zimislecel is an allogeneic stem cell-derived islet-cell therapy. This phase 1-2 study supports the hypothesis that zimislecel can restore physiologic islet function and thus treat persons with type 1 diabetes.