medwireNews: The stem cell therapy zimislecel restores islet function in patients with type 1 diabetes, reducing the need for exogenous insulin treatment, indicates the VX-880-101 FORWARD trial.
“[T]hese findings provide evidence that pancreatic islets can be effectively produced from pluripotent stem cells and used to treat type 1 diabetes,” write Michael Rickels (University of Pennsylvania Perelman School of Medicine, Philadelphia, USA) and colleagues.
The study was published in The New England Journal of Medicine to coincide with its presentation at the 85th ADA Scientific Sessions in Chicago, Illinois, USA.
Zimislecel is made from allogeneic stem cell-derived, fully differentiated islets with the aim of providing an alternative to islet transplantation, which is typically limited in terms of availability and quality, the researchers say.
The interim analysis of the phase 1/2 trial included 14 adults with long-standing type 1 diabetes. Eligible participants had impaired awareness of hypoglycemia that prevented intense insulin therapy, at least two severe hypoglycemic events in the prior year, undetectable fasting C-peptide levels, and glycated hemoglobin (HbA1c) of at least 7% (53 mmol/mol) at baseline.
The participants were a mean of 42.7 years old, all were White, and two thirds were men. They had a mean type 1 diabetes duration of 22.8 years, took insulin at a daily dose of 39.3 units, and had a mean HbA1c of 7.8% (62 mmol/mol).
Rickels et al gave the patients induction immunosuppressive therapy before infusing them with zimislecel into the portal vein over 30–60 minutes. Patients then received maintenance immunosuppression and were monitored for up to 365 days after treatment.
For part A of the study, two participants received a single half dose of zimislecel (0.4 × 10⁹ cells), with the option of a second dose within 2 years, which one patient received within 9 months. The remaining participants in parts B (n=4) and C (n=8) received a single full dose of zimislecel (0.8 × 10⁹ cells).
Safety, which was the primary endpoint of Part A, showed that the majority of adverse events (AEs) among the 14 study participants who completed 12 months of follow-up were “mild or moderate in severity.” The most AEs common were diarrhea, headache, nausea, COVID-19, mouth ulcers, neutropenia, and rash, with respective rates of 79%, 71%, 64%, 50%, 50%, 43%, and 43%. Mild AEs related to zimislecel were reported in 50% of participants, including transient liver enzyme elevations that resolved within 30 days.
Rickels et al note that serious AEs included neutropenia (three patients) and acute kidney injury (two patients), but none were considered related to zimislecel. Of the two deaths in the study, one was from cryptococcal meningitis linked to immunosuppressive therapy, and the other from severe dementia with agitation due to progression of pre-existing neurocognitive impairment from a traumatic brain injury.
Fasting C-peptide levels were detectable at day 90 in all 14 patients, and C-peptide levels continued to be detectable following a 4-hour mixed-meal tolerance test, with less glucose excursion than at baseline, and improved over time. Indeed, among the 12 patients who received full-dose zimislecel, stimulated C-peptide levels at 90 days were a mean 424 pmol/L 90 minutes after the mixed-meal stimulus, rising to 1036 pmol/L, 1104 pmol/L, and 1274 pmol/L at days 180, 270, and 365, respectively. The threshold peak C-peptide level of at least 100 pmol/L for a functional islet graft was met at all time points.
Insulin independence was achieved by one patient receiving half-dose zimislecel and 10 of those receiving the full dose by 12 months. The remaining two patients in the full-dose group managed to reduce their insulin use by 70% and 36%, respectively. The investigators note that both of these patients had received high-dose glucocorticoids, which was a protocol violation and could have impaired graft success.
“Although elimination of the need for exogenous insulin is desired, the results of this study show clinical benefits from the restoration of islet function, even in the absence of complete elimination of insulin therapy,” the authors say.
The primary endpoint in Part C was freedom from severe hypoglycemic events between days 90 and 365 and an HbA1c of less than 7% or a reduction of at least 1% from baseline during follow-up. In the full-dose group, there were no severe hypoglycemic events between day 90 and 365, and all achieved HbA1c below 7% at day 120, which was maintained for the rest of the follow-up, with a mean reduction of 1.81 percentage points by day 365.
According to continuous glucose monitoring, patients spent an increased time in target glucose range (70–180 mg/dL) following full-dose zimislecel treatment, improving from 49.5% at baseline to 93.3% at day 365.
Rickels and colleagues also found that glucose variability dropped, from 36.3% at baseline to 20.0% at 1 year.
The researchers conclude: “The results of this unplanned interim analysis of our single-group, phase 1–2 study support further investigation of zimislecel in larger, longer studies involving diverse populations.”
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N Engl J Med 2025; doi:10.1056/NEJMoa2506549
ADA 85th Scientific Sessions; Chicago, Illinois, USA: 20-23 June