SAN DIEGO & CLEVELAND—The diabetes field has seen some changes lately, and that will only continue as newer technologies are entering the therapeutic realm.
ViaCyte recently released preliminary data from its PEC-Direct clinical trial at the Cell & Gene Meeting on the Mesa in Carlsbad, Calif., that show that implanted cells are capable of producing circulating C-peptide.
“These data show that our PEC-01 cells are functioning as intended when appropriately engrafted,” said Dr. Paul Laikind, CEO and president of ViaCyte. “While there is still more work to be done, this is an important milestone. We plan to present additional data in the near future.”
PEC-01 cells are pancreatic precursor cells derived from ViaCyte’s proprietary CyT49 pluripotent stem cell line, and the cells are implanted in both the PEC-Direct and PEC-Encap product candidates. PEC-Direct is a non-immunoprotective device being developed for type 1 diabetes patients who have hypoglycemia unawareness, extreme glycemic lability and/or recurrent severe hypoglycemic episodes. PEC-Encap delivers the same pancreatic islet progenitor cells in an immunoprotective device.
As Dr. Esther Latres, research director at JDRF, tells DDNews, “PEC-01 cells are competent to differentiate further and mature into insulin-producing cells after implantation into people with type 1 diabetes. In nonclinical studies, PEC-01 cells can differentiate into cells that are morphological and functionally similar to pancreatic islets and can restore glycemia in animal models of diabetes.”
Gene-edited immune-evasive PEC-01 cells are being developed for the PEC-QT program in collaboration with CRISPR Therapeutics. The data show initial detection of C-peptide and insulin production through histological and biochemical measurements at multiple time points in multiple patients; detection of C-peptide has correlated with engraftment efficiency.
C-peptide is a standard biomarker in the field for assessing the amount of functional insulin-producing pancreatic beta cells, used because its measurement is not confounded by injected insulin. The PEC-QT study requires patients to be C-peptide-negative upon enrollment.
ViaCyte is also developing immune-evasive stem cell lines from its proprietary CyT49 cell line, which have the potential to further broaden the availability of cell therapy for diabetes and other potential indications. ViaCyte is funded in part by the California Institute for Regenerative Medicine and JDRF (formerly known as the Juvenile Diabetes Research Foundation).
“Next steps and clinical trials would include safety and further demonstration that PEC-01 cells implanted under the skin and properly engrafted, are capable of maturing into functional beta cells and produce the required amount of insulin for controlling blood glucose levels in patients with type 1 diabetes,” Latres reports. “Living with and treating T1D is fundamentally different today than it was even 10 years ago; continued funding and research for project like this are the key to continuing to find cures for the disease and improving the lives of people that live with it. The most exciting part is that these therapies have the potential to eliminate insulin therapy and liberate people from the burdens of managing T1D for months or even years at a time.”
Diasome Pharmaceuticals Inc. has also had good results, with its InSulin Liver Effect (ISLE-1) Phase 2b study results being published recently in the journal Diabetes Care. The study investigated hepatic directed vesicle technology added to rapid-acting insulin in people with type 1 diabetes. The article is entitled “The Divergent Hypoglycemic Effects of Hepatic Directed Prandial Insulin: A Six-Month Phase 2b Study in Type 1 Diabetes Mellitus.”
“Hepatocyte directed vesicle (HDV) technology restores normal glucose metabolism in people with type 1 diabetes (T1D) by delivering injected insulin to the liver,” notes Diasome CEO Robert Geho. “It has been well established that insulin travels to the liver to regulate glucose levels after it is produced by the pancreas in a person without diabetes, but no insulin developer has been able to successfully mimic this process with injected insulin. Once injected under the skin, current insulins are primarily absorbed by fat and muscle cells and struggle to reach the liver’s metabolic cells called hepatocytes.”
“This poor ‘biodistribution’ of injected insulin is a critical challenge, because the liver is the only organ in the entire body that can both store glucose to prevent hyperglycemia and release glucose to prevent hypoglycemia,” he continues. “By simply adding liquid HDV to vials of injected mealtime insulin, we can ensure that insulin will reach the liver and, therefore, mimic the action of endogenous insulin.”
In the ISLE-1 trial, HDV was mixed with insulin Lispro (Humalog) to become HDV-L, and assessed in comparison to Lispro alone. Patients received either HDV-L or Lispro as their mealtime insulin plus standard basal insulin therapy. Across the entire study population, results demonstrated HDV-L to be non-inferior by means of change in HbA1c while significantly reducing total cholesterol, with no severe adverse events and no difference in liver function tests.
“As summarized in the November 2019 issue of Diabetes Care, the ISLE-1 results demonstrate that patients with baseline HbA1c values above 8.5 percent who added HDV therapy to their mealtime insulin experienced decreased hypoglycemia and reduced their mealtime insulin doses, while achieving comparable HbA1c reductions to patients using mealtime insulin alone,” adds Geho. “Specifically, this population experienced about a 30-percent reduction in one measure of hypoglycemia using mealtime insulin with the HDV additive. Blinded continuous glucose monitor data showed that at the end of the study, HDV treated patients spent almost 75 percent less time with blood glucose levels below 54 mg/dL. Bolus mealtime insulin doses were also reduced by about 25 percent for those using HDV-insulin. These results are especially promising to us because they indicate that HDV increases the efficacy of insulin while protecting against hypoglycemia.”
The authors concluded that the outcomes in both groups support the increased liver effect of HDV-L.
“To date, Diasome has competed 21 discrete human clinical studies. Our goal is to make HDV accessible to any person who may need it. We hope to make diabetes management easier for all, regardless of their current insulin supplier,” Geho remarks. “The goal is to improve insulin’s physiological mechanism of action, because even though insulin is life-saving, it can also lead to life-threatening hypoglycemia.
“As someone with T1D myself, I am grateful for the advancements that scientists have made in the last few decades, but insulin administration still carries a great deal of risk related to the constant trade-off between tight control and increased hypoglycemia risk. Diabetes outcomes remain poor despite the adoption of advanced medical devices innovations that focus on how much insulin is delivered and on how quickly it acts, rather than on location or where it acts, which is at the core of our work,” he concludes. “We hope to see that people living with T1D may no longer need to make a trade-off between tight glycemic control and less hypoglycemia risk. These trials are important milestones for the continued development of HDV as a liver-targeting system for insulin.”