Donislecel: First Cellular Therapy to Treat Patients With Brittle Type 1 Diabetes

Donislecel is indicated for the treatment of type 1 diabetes in adults who are unable to approach their target A1C because of repeated episodes of severe hypoglycemia despite intensive diabetes management and education. It is intended to be used in conjunction with concomitant immunosuppression and to be delivered via infusion into the hepatic portal vein only (6).

Currently, there are no off-label uses for donislecel. The use of this new therapy should be limited to individuals with brittle type 1 diabetes because of risks associated with the infusion procedure and long-term immunosuppression. There is no evidence to show that it would benefit patients whose diabetes is well controlled with insulin therapy or those with hypoglycemia unawareness who are able to prevent repeated severe (level 3) hypoglycemia.

Repeated intraportal islet infusions are not recommended for patients who have experienced prior portal thrombosis unless the thrombosis was limited to second- or third-order portal vein branches. There is no evidence that the use of donislecel would be safe and effective in patients with liver disease or renal failure or in those who have received a kidney transplant (6).

Donislecel should be stored in an insulated container at 15–25°C (59–77°F) for no longer than 6 hours from time of product release (6).

The recommended minimum dose is 5,000 equivalent islet number (EIN)/kg for initial infusion and 4,500 EIN/kg for subsequent infusion in the same recipient, if required. The maximum dose per infusion is dictated by the estimated tissue volume, which should not exceed 10 cc per infusion and the total EIN present in the infusion bag (up to a maximum of 1 × 10⁶ EIN per bag). A second infusion may be performed if the patient does not achieve or loses independence from exogenous insulin within 1 year of infusion. A third infusion may be given using the same criteria. There are no data regarding the effectiveness or safety of patients receiving more than three infusions (6).

Patients will receive pre-procedural induction immunosuppression 30–360 minutes before donislecel infusion. The immunosuppression regimen for islet cell transplantation will include nondepleting monoclonal anti-interleukin-2 (anti-IL-2) receptor antibody therapy 120 minutes before islet infusion or polyclonal T-cell–depleting antibody if the patient is sensitized to donor HLA antigens or anti-IL-2 receptor antibody therapies. Calcineurin inhibitor, mammalian target of rapamycin inhibitor, tumor necrosis factor blocker, and periprocedural antibiotic prophylaxis will also be given (6).

Donislecel is contraindicated in patients who have concomitant disease or conditions, including pregnancy, that contraindicate the procedure for infusion or immunosuppression (6).

Pancreatic islets regulate blood glucose levels through secretion of multiple hormones in response to increases and decreases in blood glucose levels. Donislecel’s primary mechanism of action is the secretion of insulin by infused allogeneic pancreatic β-cells (6).

The safety and effectiveness of donislecel have been demonstrated in two nonrandomized, open-label, single-arm clinical studies (UIH-001 and UIH-002), in which 30 participants with brittle type 1 diabetes received at least one and a maximum of three islet infusions. Of the 30 participants, 25 achieved insulin independence at some point during the study. Four subjects were insulin-independent for <1 year, 12 for 1–5 years, and 9 for >5 years. Among those who achieved durable insulin independence (i.e., not requiring exogenous insulin and maintaining adequate glycemic control, with an A1C <6.5%), 20 of the participants from a pooled population from UIH-001 and UIH-002 were insulin-independent at 1 year after last transplant. One patient previously enrolled in UIH-001 was reenrolled in UIH-002 and was counted as a single patient in the pooled population study (6). A report on these combined studies indicate that, of the 30 total participants, 19 achieved a target A1C <6.5% and were free of severe hypoglycemic events (7).

Increased access to donislecel fulfills the unmet need for treatment of brittle type 1 diabetes, a rare subset of type 1 diabetes resulting in unpredictable and debilitating hypoglycemia, which may require hospitalization, and further complications, which may result in decreased quality of life. For individuals in whom insulin therapy poses a significant and substantial risk for severe hypoglycemia, donislecel provides a minimally invasive approach to glycemic control, bypassing further risks and complications associated with whole-pancreas transplantation. The use of this cellular therapy is also an opportunity for individuals in whom whole-pancreas transplantation is not an option.

Clinical benefits of donislecel include, but are not limited to, improved A1C, reduction in or absence of the consequences of severe hypoglycemic events, insulin independence or lower insulin requirements, and improvements in overall glycemic control as measured by various parameters. Donislecel provides clinically meaningful improvements in glycemic control that last for several years beyond administration and can prevent or slow the progression of secondary complications of diabetes and thereby improve overall quality of life (7).

The use of donislecel poses procedural risks from its portal vein delivery and the potential for an acute infusion reaction. Donislecel is to be used alongside long-term immunosuppression to maintain islet cell viability, resulting in an increased risk of common community-acquired infections and opportunistic infections, malignancies, and potentially severe anemia (6). The side effect profiles of immunosuppressant agents are consistent and well known from their use in transplant recipients regardless of procedure type. The risks associated with hepatic portal vein delivery can include complications of bleeding, portal vein hypertension, and elevated liver enzymes (6). Such procedural risks can be managed with the oversight of well-trained health care providers during the course of treatment.

Direct adverse effects of donislecel are dependent on the number of infusions an individual receives. The most common side effects include fatigue, anemia, nausea, diarrhea, and abdominal pain. The use of this therapy requires ongoing diabetes management, not all patients who receive donislecel will be able to achieve independence from exogenous insulin, and there is no guarantee that any insulin independence achieved will be sustained. The primary safety risk of donislecel is potential sensitization of the recipient to donor antigen, which may result in graft loss or difficulties in obtaining future transplants (6). However, the safety profile and efficacy of donislecel is reflected in more than two decades of success relating to islet transplants in patients with brittle type 1 diabetes.

The cost of donislecel is not yet unavailable, but it is anticipated that it will be in a range similar to the cost of a whole-pancreas transplant, which is currently covered by Medicare and private payers. Because it is an FDA-approved cellular therapy to treat type 1 diabetes, donislecel may qualify for medical insurance coverage and reimbursement.

Deceased pancreatic cell donors for donislecel were carefully selected by the United Network for Organ Sharing/Organ Procurement Organizations to reduce further complications associated with disease and malignancy transmission to recipients through eligibility screening and infectious disease testing per FDA Code of Federal Regulations, Title 21, Part 1271, requirements (7). Donors must meet specified criteria and are rejected if any of these characteristics are present at time of death: A1C >6.0%, age <18 or >70 years, BMI <19 kg/m², or estimated cold ischemia time >16 hours or warm ischemia time >30 minutes (for donation after cardiac death). These characteristics are predictive of poor islet yield or quality (7).

The safety and efficacy of donislecel have been examined in two core studies under the CellTrans investigational new drug research program. The composite efficacy end point was A1C <6.5% and absence of severe hypoglycemic events through 1 year after the last transplant. Insulin independence and other markers of glycemic control were also assessed to provide comprehension to the value of donislecel administration in brittle type 1 diabetes. Among the total 30 patients in these two studies, 19 (63%) met the composite efficacy end point and 20 (67%) were insulin-independent 1 year after the last transplant (7). Dose efficacy relating to the composite end point and insulin independence was observed with increased islet dosing. The two core studies reflect a minimum cumulative dose of 10,000 EIN/kg (across one or more transplants) to ensure ≥500,000 total EIN are transplanted for successful engraftment and achievement of insulin independence; however, the minimum dose of donislecel is 5,000 EIN/kg for initial transplant and 4,500 EIN/kg for subsequent transplants in the same recipient. Regarding safety, no treatment-emergent adverse events led to early discontinuation or death (7). Although quality of life was not formally assessed in the study population, >20 years of safe and effective islet transplantation have demonstrated improved health quality of life in patients with brittle type 1 diabetes.

Supporting data for the use of islet cell transplantation in the United States have been available for more than two decades. Offering expanded access to donislecel, the first donor-derived pancreatic islet cell therapy, provides individuals with brittle type 1 diabetes a less invasive approach to traditional whole-pancreas transplantation. The recent approval of donislecel marked a significant turning point for the first official treatment of brittle type 1 diabetes.

Donislecel is projected to become available in the United States in early 2024. This opportunity may slow or reverse debilitating comorbidities and complications of type 1 diabetes, reduce or eliminate the need for exogenous insulin, and potentially restore quality of life to individuals with brittle type 1 diabetes.

The information in this article was reviewed by the scientific and medical team at CellTrans, Inc., which manufactures donislecel.