Stem cell-derived, fully differentiated islets for type 1 diabetes

Reichman, T.W.; Markmann, J.F.; Odorico, J.; Witkowski, P.; Fung, J.J.; Wijkstrom, M.; Kandeel, F.; Koning, E.J.P. de; Peters, A.L.; Mathieu, C.; Kean, L.S.; Bruinsma, B.G.; Wang, C.; Mascia, M.; Sanna, B.; Marigowda, G.; Pagliuca, F.; Melton, D.; Ricordi, C.; Rickels, M.R.; Vx-880-101 Forward Study Gr

doi:doi:10.1056/NEJMoa2506549

BACKGROUNDZimislecel 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.METHODSWe 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 x 10(9) 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 x 10(9) 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...Show moreBACKGROUNDZimislecel 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.METHODSWe 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 x 10(9) 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 x 10(9) 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.RESULTSA 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 Cpeptide. 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.CONCLUSIONSThe 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.Show less

Leiden University Scholarly Publications

View statistics

Documents

In Collections

Stem cell-derived, fully differentiated islets for type 1 diabetes