Stem Cell–Derived Islets Continue to Show Benefit in T1D

 Stem cell–derived beta-cell replacement therapy continues to show benefit in people with type 1 diabetes at a high risk for severe hypoglycemia.

Of a total 17 patients who received a full dose of Vertex Pharmaceuticals, Inc.'s investigational allogeneic stem cell–derived, fully differentiated pancreatic islet cell replacement therapy (VX-880), three, thus far, have achieved the primary study efficacy endpoint of elimination of severe hypoglycemic episodes with A1c < 7% at 1 year and the secondary endpoint of insulin independence.

Others are on the same trajectory, Piotr Witkowski, MD, PhD, professor of surgery at The University of Chicago, Chicago, said at the recent American Diabetes Association (ADA) 84th Scientific Sessions. In his presentation, Witkowski also provided details about the deaths of two study participants that the company had announced in January 2024, neither of which were related to the VX-880 product.

In fact, there have been no severe adverse events related to the product itself, with most due to either the infusion procedure or the immunosuppression. "These data highlight the curative potential of VX-880 in people living with type 1 diabetes and support further evaluation of VX-880 toward pivotal development," Witkowski said.

Stem cell–derived islet cell therapy holds several potential advantages over whole pancreas or deceased donor islet transplantation, including availability in unlimited quantities, the ability to standardize the quality and quantity of the cells, and minimization or elimination of donor-derived infection risk. While there is still a need for immunosuppression, current research efforts are focused on either encapsulating the islets or genetically modifying them so they can evade the immune system, he said.

For now, patients selected for the study are those who experience frequent severe hypoglycemia deemed to be a greater risk to the patient than that of immunosuppression.

In addition, Witkowski told Medscape Medical News, "having the Vertex islet cells on the shelf in unlimited amounts…could gradually replace whole pancreas transplantation, which we often do for patients with type 1 diabetes who need a kidney and are on immunosuppression already…If I had the Vertex cells reimbursed by the patient's insurance, I would transplant the kidney and infuse those cells instead of the whole pancreas."

Asked to contrast the potential of stem cell–derived islet therapy with that of diabetes technology, endocrinologist David T. Ahn, MD, chief of Diabetes Services at Hoag Memorial Hospital Presbyterian, Newport Beach, California, told Medscape Medical News, "Even in its most idealized form, closed-loop technology is an incomplete and suboptimal solution for living with type 1 diabetes because it requires two medical devices worn outside the body, whereas stem cell–derived islet cell transplantation offers the potential to truly cure T1D by re-enabling the human body to make insulin."

However, Ahn pointed out, "With VX-880, the obvious fly in the ointment is the need for immunosuppression which carries significant risk…There are multiple solutions being proposed, but we are still waiting for data as promising as the initial Vertex data is on that front."

He added, "the promising data on achieving insulin dependence in humans in this study represents a crucial step for this type of cure for T1D. In a way, achieving insulin independence is half the battle. The next half is preserving insulin independence."

Patient Benefit With No Harm

The phase 1/2 multicenter FORWARD study investigated VX-880 allogeneic stem cell–derived, fully differentiated, insulin-producing islet cell therapy in people with type 1 diabetes complicated by recurrent severe hypoglycemia. The product is delivered by infusion into the hepatic portal vein.

A steroid-free immunosuppressive regimen is used, involving induction with antithymocyte globulin followed by maintenance with tacrolimus plus sirolimus. Both the cell infusion protocol and the immunosuppressive regimen are the same as have been established with deceased donor islet cell transplants, Witkowski noted.

The open-label phase 1/2 of the FORWARD study enrolled 17 people with type 1 diabetes aged 18-65 years who had impaired hypoglycemic awareness and had experienced two or more severe hypoglycemic episodes in the year prior to screening. The first two patients received a half dose of VX-880 with sequential dosing, the next six full-dose with sequential dosing, and the subsequent 10 full-dose with concurrent dosing.

The 14 patients who have reached at least 6 months post-transplant had an average age of 44 years and diabetes duration of 23 years. Their baseline A1c averaged 7.8%, with total daily insulin dose 39 units (0.54 units/kg/d). All had undetectable fasting C-peptide. They had an average of 2.7 severe hypoglycemic episodes in the year prior to screening.

Thus far, 12 of those 14 patients have received the full VX-880 dose as a single infusion, and all have at least 150 days of follow-up, while three have a year of follow-up. All have demonstrated islet cell engraftment with endogenous insulin production and improved glucose levels by day 90 as assessed by mixed meal tolerance testing, Witkowski said.

All 12 patients achieved reductions in A1c < 7% between day 180 and 1 year, and none experienced severe hypoglycemic events from day 90 onward. Of the 12, 11 had reduction or elimination of exogenous insulin use between day 180 and their most recent visit. The one patient who didn't had used steroids in the peri-infusion period, a study protocol violation.

Of 10 participants who completed the day 180 visit, seven were no longer using exogenous insulin, two had about a 70% reduction in their total daily insulin dose and may be able to stop insulin in the future, and one had about a 24% insulin dose reduction, Witkowski reported.

In all 12, time in range 70-180 mg/dL as measured by continuous glucose monitoring rose from 49.5% at baseline to 76.1% with less than 1% below range by day 90, with further improvements over time. For the three who passed the 1-year mark, time in range averaged 95.5% with zero below range values.

No Adverse Events Due to VX-880

All 14 patients experienced adverse events, with 304 total. However, most were mild to moderate and were related to either the infusion procedure, the immunosuppression, or complications of type 1 diabetes. None of the 23 severe adverse events were related to the VX-880, Witkowski said.

One of the two deaths was due to cryptococcal meningitis arising from an elective sinus surgery in the patient who had used high-dose steroids in the weeks preceding and following the surgery, along with the immunosuppression. The other death was due to progression of a preexisting neurocognitive impairment arising after a traumatic brain injury sustained in a motorcycle accident caused by a severe hypoglycemic episode prior to study enrollment, Witkowski explained.

No adverse events led to study discontinuation.

The FORWARD study has now been expanded to enroll approximately 20 additional patients (37 total). This was done to accelerate registration with the US Food and Drug Administration (FDA) for consideration of VX-880 as an approved drug, Witkowski said.

Improved, No Immunosuppression

Three main strategies are under investigation to protect the stem cell–derived islets from the patient's immune system: Improved immunosuppressant medications, encapsulation as a physical barrier, and gene editing of the islets to make them less immunogenic and thereby evade immune attack, Witkowski explained.

Vertex is currently conducting a phase 1/2 multicenter study of the safety, tolerability, and efficacy of VX-264, a fully differentiated stem cell–derived islet cell therapy encapsulated in an immunoprotective device implanted in the abdominal wall and, therefore, does not require immunosuppression.

In 2022, ViaCyte, a company subsequently acquired by Vertex, initiated an open-label study of gene-edited pancreatic progenitor cells, in partnership with CRISPR Therapeutics' gene editing technology. The first of a planned 10 patients received the cells, but no data have been released.

Transplantation of deceased donor islets is also ongoing but only in a limited capacity in the United States due to the lack of insurance reimbursement and limited research funding, Witkowski said. The deceased donor cell product donislecel (Lantidra, CellTrans) was approved by the FDA in June 2023. CellTrans did not respond to Medscape Medical News' request for a status update.

Witkowski's group at The University of Chicago is conducting ongoing trials involving the Sernova Cell Pouch, with an extrahepatic site for islet engraftment, Tegoprubart (anti-CD40L), a calcineurin inhibitor–free form of immunosuppression, and intraportal islet transplantation in patients who have already received kidney transplants. Other deceased donor islet research is being conducted at the University of California San Francisco; City of Hope, California; University of Illinois Chicago; and The University of Virginia.

Witkowski has served as a consultant to Dompe Pharmaceutical, Sernova, Vertex, and Eledon and is a member of the steering committee for the VX-880 and VX-264 stem cell–derived islet cell transplantation trials. Ahn is a speaker for Abbott, Ascensia, Insulet, Lilly, MannKind, Novo, and Xeris and advisor for Lilly, Ascensia, and MannKind.

https://www.medscape.com/viewarticle/stem-cell-derived-islets-continue-show-benefit-t1d-2024a1000cx1