CHICAGO — An investigational allogeneic stem cell-derived islet-cell therapy helped almost all patients with type 1 diabetes achieve insulin independence within the year, a small phase I/II study found.
After a single infusion of zimislecel, all 12 participants had a clinically meaningful and marked improvements in glycemic control, including an HbA1c less than 7%, 76.1% time spent in target glucose range (70-180 mg/dL), and free of severe hypoglycemic events by day 90, reported Michael R. Rickels, MD, of the University of Pennsylvania Perelman School of Medicine in Philadelphia.
By day 365, participants spent 93.3% of time in target glucose range, he said at the American Diabetes Association (ADA) annual meeting.
Also at this time point, average insulin dose decreased by 92% overall. Ten of the 12 participants (83%) were able to achieve insulin independence and no longer required exogenous insulin. In the two participants that continued receiving insulin, doses decreased by 70% and 36%, respectively.
“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,” Rickels and co-authors wrote in the New England Journal of Medicine, where the findings were simultaneously published.
“If you define functional cure by accepting the requirement for immunosuppression, then I think you could call [this] a functional cure,” said Rickels at ADA. “These individuals are maintaining near, if not normoglycemia, without requirement for exogenous insulin therapy. These are terrific results for time spent in target glucose range.”
“As I think about my patients and the unmet need in the type 1 diabetes community, the results we’ve seen so far for restoring endogenous insulin secretion with a stem cell-derived islet therapy bring me hope and confidence for a transformative treatment option for individuals with type 1 diabetes in the not-so-distant future,” he noted in a statement from developer Vertex.
Zimislecel, formerly known as VX-880, was developed for people with type 1 diabetes with recurrent or severe hypoglycemia. It’s an allogeneic stem cell-derived, fully differentiated insulin-producing islet cell therapy that is delivered by infusion into the portal vein over a period of 30-60 minutes. Induction immunosuppressive treatment was also given prior to the infusion, and maintenance immunosuppressive treatment was given after.
The study was split into three parts: parts A, B, and C. In part A, participants received a half dose of zimislecel (0.4 x 109 cells) as a single infusion into the portal vein, with an option for a second half dose within 2 years. This part was focused on establishing safety of zimislecel.
Then in parts B and C — which were focused on establishing efficacy — participants received a full dose of zimislecel (0.8 x 109 cells) as a single infusion. All the participants also received glucocorticoid-free immunosuppressive therapy.
All of the 12 participants enrolled from North America and Europe in the VX-880-101 FORWARD study had to have type 1 diabetes with impaired awareness of hypoglycemia, at least two severe hypoglycemic events in the previous year, and insulin dependence for at least 5 years for eligibility.
Average age was 42.7, 33% were female, 100% were white, and average diabetes duration was 22.3 years. At baseline, all were receiving appropriate diabetes care under a specialist, average HbA1c was 7.8%, mean total daily insulin dose was 39.3 units, and spent half of time in target range.
C-peptide was undetectable in all patients at baseline. But after zimislecel infusion, all had engraftment and islet function, as evidenced by the detection of serum C-peptide during a 4-hour mixed-meal tolerance test.
Most adverse events (AEs) were mild or moderate in severity, and most of the AEs were attributed to immunosuppressive therapy. Some AEs included transient increases in liver function values that generally occurred within 6 days after zimislecel infusion and resolved within 30 days. Decreases in white blood cell counts and renal function were also observed, but were generally consistent with immunosuppressive therapy use.
Two participants died — one during part A and one during part B. The first death was attributed to serious cryptococcal meningitis caused by an extensive sinus surgery that was complicated by prolonged exposure to immunosuppressive medication. The other death was due to severe dementia with agitation. That patient had progression of preexisting neurocognitive impairment caused by a car accident due to a severe hypoglycemic event.
“The phase III study is now well underway and is expected to complete enrollment of approximately 50 total individuals by the end of the summer,” said Rickels.
Disclosures
FORWARD was funded by Vertex Pharmaceuticals. Some co-authors are company employees.
Rickels disclosed relationships with Vertex Pharmaceuticals, Tandem Diabetes Care, Sernova, and Dompe U.S.
Co-authors disclosed multiple relationships with industry including Vertex Pharmaceuticals.
Primary Source
New England Journal of Medicine
Source Reference: Reichman TW, et al “Stem cell-derived, fully differentiated islets for type 1 diabetes” N Engl J Med 2025; DOI: 10.1056/NEJMoa2506549.
