CellTrans’ Lantidra™ (donislecel) approaches a decision from the FDA
The cell therapy would treat brittle type 1 diabetes, a rare form of diabetes.June 15, 2021
Lantidra (donislecel): a purified allogeneic deceased donorpancreas-derived islets of Langerhans for brittle type 1 diabetes.
Background: Type 1 diabetes (T1D) is a disease of glucose metabolism characterized by persistently elevated blood glucose levels caused by reduced endogenous insulin production. A recent meta-analysis estimated the prevalence of T1D to be 12.2 per 10,000 people. Brittle T1D is a rare, difficult-to-control form of diabetes characterized by the autoimmune-mediated loss of insulin-producing ?-cells within the islets of Langerhans in the pancreas. This results in the complete deficiency of insulin, causing frequent and unpredictable episodes of hypoglycemia, often requiring hospitalization and other complications. Brittle T1D is estimated to affect fewer than 80,000 people in the United States.
Other Medications: For most T1D patients, insulin therapy can manage blood glucose levels. For brittle T1D, insulin delivered by manual subcutaneous injection or via pump may be insufficient. Beyond intensive insulin therapy, whole pancreas or islet cell transplants are options. Both carry surgical and post-procedural risk and are not appropriate for all brittle T1D patients.
Product Description: Donislecel comes as a suspension of allogeneic pancreatic islets in one 1000 mL infusion bag filled with a supplied volume of 400 mL, containing not more than 10 cc of estimated packed islet tissue.
Anticipated cost: Prime anticipates an average annual cost of over $300,000 for donislecel. While this will be a high cost drug, the assumption is there will be too few utilizers of the drug for it to contribute to significant net new spend.
Mechanism of Action: Purified pancreatic cells from a deceased donor are transplanted into recipients with brittle T1D to supplement endogenous insulin and glucagon production, improving pancreas-mediated control of blood glucose and potentially eliminating the need for exogenous insulin administration.
Dosage and Administration: Donislecel is infused into the hepatic portal vein via percutaneous or transvenous transhepatic access, or if these are not feasible, then via laparoscopic or open surgical access. Following transplant, the patient is monitored for graft function, immunosuppression levels, and safety. Patients enrolled in donislecel clinical trials could receive up to three transplants, but no maximum number of transplants has been defined.
Site of care: If approved, the product would be available at launch only through a single transplant center, University of Illinois Hospital. This was the site used for the two pivotal trials.
Continuous Immunosuppression: Maintenance immunosuppression must be continued permanently to prevent islet graft rejection. The immunosuppression regimen typically includes a combination of a calcineurin inhibitor and an mTOR inhibitor or appropriate alternatives.
Efficacy: The efficacy of donislecel was examined in two pivotal studies (UIH-001-Phase 1/2 and UIH-002-Phase 3; pooled population, N=30 participants who received 56 transplants). The composite efficacy endpoint consisted of A1C <6.5% and absence of severe hypoglycemic events through one year after a patient’s last transplant.
- Nineteen patients (63%) met the composite efficacy endpoint and 20 (67%) were insulin independent at one year after last transplant.
- Eight of 12 (67%) evaluable patients met requirements for success on the composite efficacy endpoint as well as insulin independence at six-years post-last transplant.
- The FDA believes the efficacy analysis is difficult to interpret due to the combination of substantial missing data and inclusion of a significant proportion of patients who had already met or nearly met the primary endpoint at baseline.
Safety: The safety of donislecel was examined in the same two pooled studies with a follow-up period from initial transplant through one year after last transplant. The most reported (?60% of patients) treatment-emergent adverse events (TEAEs) in the pooled population were acne (87%), anemia (83%), nausea (83%), fatigue (80%), abnormal loss of weight (73%), diarrhea (73%), headache (63%), increased transaminases (63%), and vomiting (60%); only anemia accounted for >5% of all TEAEs reported. The most common ? Grade 3 TEAEs (?20% of patients) were diarrhea (23%), anemia (20%), and nausea (20%).
- Of the 1,319 adverse events reported during the first year after transplantation, eight were life-threatening and 75 were severe.
- One patient died due to multiorgan failure from an infection after initial transplant with donislecel which the sponsor deemed probably related to immunosuppression/study drug.
- Donislecel safety outcomes were comparable to those of similar islet products from other islet transplant centers and may support the safety of islet transplantation as a less invasive alternative to whole pancreas transplantation. Most risks appear to mirror those observed for patients on immunosuppression.
FDA Advisory Committee: The Cellular, Tissue, and Gene Therapies Advisory Committee voted 12 yes-4 no (one abstention) that donislecel delivered by intraportal administration has an overall favorable benefit-risk profile for some patients with type 1 diabetes.
- The four panelists who voted ‘no’ cited concerns about the side effects of long-term immunosuppression and the design and patient selection for the pivotal trials, including the lack of control group. There were also issues surrounding the studies because they were started before glucose monitoring and insulin dosing systems became the standard of care.
- One panelist noted the patients who could be candidates for donislecel should be those who are not candidates for pancreas transplants and noted there are only about 100 pancreas transplants performed in the United States every year.
Utilization Management (UM): Prime’s UM department will create medical drug criteria for donislecel.
Mobasseri M et al. Prevalence and incidence of type 1 diabetes in the world: a systematic review and meta-analysis. Health Promot Perspect. 2020;10(2):98-115.
Cellular, tissue, and gene therapies advisory committee briefing document. Lantidra (donsilecel) for the treatment of brittle type 1 diabetes mellitus. 15 April 2021. Available at: https://www.fda.gov/media/147529/download
Phase 3 Trial of Islet Transplantation in Type 1 Diabetic Patients Using the University of Illinois at Chicago (UIC) Protocol (NCT00679042). Available at: https://clinicaltrials.gov/ct2/show/results/NCT00679042?term=islet+of+langerhan&draw=2&rank=1
Expanded Access for Islet Transplantation in Type 1 Diabetic Patients Using the University of Illinois at Chicago (UIC) Protocol (NCT03791567). Available at: https://clinicaltrials.gov/ct2/show/NCT03791567?term=donislecel&draw=2&rank=
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