First patient gains insulin independence with novel stem cell-derived islet cell therapy
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NEW ORLEANS — A man with long-standing type 1 diabetes and no endogenous insulin production achieved insulin independence after an infusion of an investigational stem cell-derived pancreatic islet cell therapy, researchers reported.
In a proof-of-concept study, treatment with half the target dose of VX-880 (Vertex Pharmaceuticals), a novel allogeneic stem cell-derived, fully differentiated, pancreatic islet cell replacement therapy, led to engraftment of islet cells; glucose-regulated increases in fasting and stimulated C-peptide levels; elimination of recurrent, severe hypoglycemia; and improved HbA1c and time in the recommended glucose range for two patients.
“This is the first-in-the-world administration of stem cell-derived islets in this manner, where they are infused into the liver,” James F. Markmann, MD, PhD, chief of the division of transplant surgery and director of clinical operations at the transplant center at Massachusetts General Hospital, and the Claude Welch Professor of Surgery at Harvard Medical School, said during a press conference at the American Diabetes Association Scientific Sessions. “In the experience with cadaveric islets, the only site that was effective in gaining full glycemic control was the liver. This is the first attempt to have an important impact on a patient’s glycemic control.”
Transplantation of islets from human cadavers can eliminate severe hypoglycemia and improve glycemic response in people with type 1 diabetes; however, the treatment is highly limited by quantity and variable quality, Markmann said. Manufactured islets, differentiated from human pluripotent stem cells, represent an alternative potential source of replacement pancreatic islet cells for people with type 1 diabetes.
Markmann presented data for two study participants with severe type 1 diabetes who received the treatment. The first, a man aged 64 years with a 40-year duration of type 1 diabetes who experienced impaired hypoglycemia awareness, was receiving 34 U of insulin daily at baseline. He had a baseline HbA1c of 8.6% and undetectable fasting and stimulated C-peptide.
After a single VX-880 infusion at half target dose, fasting C-peptide was detected by day 29 and increased rapidly; HbA1c and daily insulin decreased in parallel.
At day 90, researchers observed robust increases in fasting and stimulated C-peptide, improved glycemic response and a substantial reduction in exogenous insulin administration, Markmann said.
“At the final interval, day 241 to 270, the patient had a remarkable 99.9% time in range, and at the time he was receiving no insulin and had an HbA1c of 5.2%,” Markmann said. “These are striking results.”
The second participant, a woman aged 35 years with type 1 diabetes for 11 years, a baseline HbA1c of 7.5% and undetectable C-peptide, had a similarly qualitative response to treatment, Markmann said. After the VX-880 infusion, this second patient experienced an increase in time in range from 35.9% at baseline to 51.9% at the day 121 to 150 interval, as well as a reduction in insulin of 18.2 U and an HbA1c of 7.1%.
The therapy was generally safe and well tolerated; most adverse events were mild or moderate and consistent with immunosuppression. The most common adverse events were serious hypoglycemic events that occurred during the perioperative period. There were no severe hypoglycemic events for either patient after day 35.
“We find this to be very encouraging initial results for this new therapy that we believe has real potential to help patients,” Markmann said.
Addressing the issues treatment availability and the risks that may accompany any immunosuppressive treatment, Markmann said optimal candidates for VX-880 are currently those with long-standing, severe disease.
“This is part one of a two-part problem,” Markmann told Healio. “One is to have reliable, consistently effective stem cell therapy. The second is to have an approach that does not require immunosuppression. Right now, the patients being targeted are those with very severe disease, impaired hypoglycemic awareness and severe hypoglycemic events, and that is because of risk-benefit considerations. If we had a way to transplant the cells without the need for immunosuppression, then it could be widely available. That is one of the great opportunities in the future, since these cells could be made in unlimited quantities.”
As Healio previously reported, the FDA placed a clinical hold on the treatment in the U.S. due to insufficient data to support dose escalation. The study remains open for enrollment in Canada and continues to dose patients.
“The team with Vertex is working with the FDA to address the issues that were brought up regarding having enough justification to do dose escalation,” Markmann said during the press conference. “That is in progress, and we hope it will be resolved quickly.”
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Markmann JF. 259-OR. Presented at: American Diabetes Association Scientific Sessions; June 3-7, 2022; New Orleans (hybrid meeting).
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