Encouraging results from the phase 1-2 FORWARD-101 clinical trial of zimislecel were shared during the 85^th Scientific Sessions in Chicago. The drug is an investigational stem cell-derived, fully differentiated islet cell therapy for people with type 1 diabetes with impaired hypoglycemic awareness and severe hypoglycemic events (SHEs).

“The 12 participants, at a year follow-up, met the phase 1–2 primary endpoint of elimination of severe hypoglycemia throughout the evaluation period of day 90 to 365, as well as meeting the glycemic control target of under 7%,” explained Michael R. Rickels, MD, MS, the Willard and Rhoda Ware Professor in Diabetes and Metabolic Diseases at the University of Pennsylvania Perelman School of Medicine, during the symposium, Bench to Bedside and Beyond—Bioengineering in Beta-Cell Replacement Therapy.

Each participant in the small cohort demonstrated engraftment with glucose-responsive endogenous C-peptide production that was durable through one year of follow-up, achieved a time in range (TIR) greater than 70%, and reduced exogenous insulin use. Ten of 12 patients no longer required exogenous insulin at month 12.

Dr. Rickels also noted that zimislecel was relatively well tolerated by FORWARD-101 participants. Most adverse effects (AEs) exhibited were of mild to moderate severity. The most common AEs were diarrhea, headaches, and nausea, which were expected because the drug’s safety profile was consistent with the well-established immunosuppressive regimen for deceased donor islet transplantation and infusion procedures for engraftment. No severe AEs were viewed as related to zimislecel.

“The phase 3 study (FORWARD-102), now with a primary endpoint of insulin independence, is well underway and expected to complete enrollment and dosing of approximately 50 individuals by this summer,” Dr. Rickels said.

While Dr. Rickels primarily spotlighted the FORWARD study, Tim Kieffer, PhD, Professor at the University of British Columbia, Canada, provided an overview of the current landscape in macroencapsulated stem cell-derived pancreatic cells in clinical trials. He explained that macroencapsulation can help overcome regulatory barriers associated with cell product heterogeneity, uncontrolled growth, and off-target cells, as well as gene-engineered products. These devices will also, hopefully, address immune rejection.

However, several challenges related to macroencapsulation devices must be overcome, including foreign body responses, limited oxygen diffusion, delayed secretion kinetics, and a restricted number of implant sites.

Islets don’t perform well in macroencapsulation devices that rely on diffusion due to oxygen levels in the subcutaneous space. Therefore, researchers have pivoted to developing protocols to derive islets from stem cells, hypothesizing that the stem cell-derived pancreatic progenitors will be more robust than islets because they’re grown in labs, aren’t isolated, and are less fragile.

The stem cell-derived devices have shown positive results when tested on mice.

“These pancreatic progenitors are surviving in these devices despite the low oxygen, maturing into functional cells that can reverse diabetes in mice,” Dr. Kieffer explained while noting that several attempts to translate these results to human subjects were not successful enough to deliver significant therapeutic benefits.

He highlighted several techniques that could optimize these devices for patients, such as the insertion of holes in the devices to combat the foreign body response and the inadequate diffusion of nutrients observed in previous efforts. Patients who received these altered devices in the PEC-Direct clinical trial showed improved hypoglycemic awareness, reduced insulin requirements, and TIR, despite showing little change in body weight or A1C levels. The most important insights gleaned from this data, according to Dr. Kieffer, were analyses of patients’ C-peptide levels.

“C-peptide was low or undetectable pre-implant, and then we got a progressive increase in C-peptide post-implant,” he said. “Notably, it was meal-regulated, so it’s suggested that those pancreatic progenitor cells were surviving and maturing into functional beta cells.”

Another approach to optimize this technology could be to implant more devices in patients. Patients in the PEC-Direct trial received two to four devices. Another study increased that number to eight devices per patient. The results included an increase in average TIR among patients from 55% pre-implant to 90% by week 44 of the study, less insulin use, and the maintenance of clinically significant A1C decreases.

“There is some encouraging indication that this can work, despite the fact that the survival in these human cells is maybe 1/25 of what you would see with the same implants put into a rodent, so clearly there could be room for improvement,” Dr. Kieffer said.

Other presentations from this session included:

• “Biomaterials to Improve Islet Transplantation,” from Maria Coronel, PhD, Assistant Professor of Biomedical Engineering at the University of Michigan
• “Microencapsulation Strategies for Cell-Replacement Therapy,” from Daniel G. Anderson, PhD, Professor of Chemical Engineering and Institute for Medical Engineering and Science at the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology

On-demand access to recorded presentations from this session will be available to registered participants of the 85^th Scientific Sessions through August 25.