Regulatory approval of islet transplantation for treatment of type 1 diabetes: Implications and what is on the horizon

For the first time, the US Food and Drug Administration (FDA) approved the use of a cell therapy for the treatment of type 1 diabetes. These cells, allogeneic pancreatic islets sourced from cadaveric organ donors, are implanted into the liver microvasculature via portal vein infusion. To suppress graft rejection of the foreign cells, transplant recipients are required to receive daily, systemic immune suppression. Indications for use are for the treatment of type 1 diabetes in people with high glycemic liability indicators (i.e., repeated episodes of severe hypoglycemia and off-target hemoglobin A1C [HbA1c]) despite aggressive disease management. This approval, coordinated by the Center for Biologics Evaluation and Research arm of the FDA, is specific to the biological product donislecel, designated as the tradename “Lantidra” by the company CellTrans.

As the first cell therapy approved for the treatment of type 1 diabetes in the United States, this is an exciting milestone. Previous results of extensive experimental clinical trials clearly support the efficacy of allogeneic islets for the mitigation of hyperglycemic events and for improving glycemic targets in a highly glycemic liable patient cohort.^1,2 Of interest, clinical islet transplantation (CIT) has already been accessible for patients in other countries (e.g., Canada and European Union), whereas unique regulatory hurdles in the United States delayed access until now. Most industrialized countries have designated pancreatic islets as a non-advanced therapy medicinal product, resulting in regulatory oversight similar to whole organ transplantation; however, the United States designated allogeneic islet transplantation, but not autologous islet transplantation, as a biological drug, which created unique and arduous regulatory challenges.^3,4,5,6 CellTrans, a company initiated by Jose Oberholzer, MD, took on this challenge and not only conducted two non-randomized single-arm, open-label CIT trials enrolling a total of 30 patients with longstanding type 1 diabetes (of whom 21 [70%] stayed insulin independent for at least 1 year) but also optimized regulatory compliance of cell processing protocols and navigated additional regulatory hurdles. Their journey from first biological license application (BLA) in 2017, to its resubmission in 2020, and final BLA approval in 2023 is a considerable feat that should be commended. As such, this approval finally provides an avenue for the limited cohort of people with type 1 diabetes living in the United States who meet eligibility requirements to receive this impactful cellular approach.

This regulatory approval, however, is one that is not without controversy in the islet transplant community. As outlined in several published papers on the topic,^4,7,8 many in the field are concerned with the commercialization of cadaveric pancreatic islets. Beyond the general restrictions of BLA approval to a single company, the designation of the product as an orphan drug potentially further limits competition by providing 7 years of market exclusivity. While it is understandable that this durable and limited market access was necessary to justify the risks, costs, and time required for pioneering this product through regulatory approval, it is also reasonable to express concerns on granting exclusive rights to a cell source procured from cadaveric organ donation. Finally, a BLA approval alters regulatory oversight and monitoring from that outlined for organ transplantations via Organ Procurement and Transplantation Network/United Network for Organ Sharing to BLA requirements, which may reduce reporting of clinical impacts. Overall, while this is an exciting advancement for people living with type 1 diabetes in the United States, there are emerging concerns about how this nationally impacts CIT accessibility and costs.

With the approval of islet transplantation for the treatment of type 1 diabetes, there is a motivation to look on the horizon for alternative cell sources, as cadaveric procurement will always be limited in access and consistency. Led by considerable advances in optimized, cost-effective, and large-scale generation of functional pluripotent stem cell-derived beta-like cells (sBCs),^9,10 this approach provides a feasible path for broader clinical impact compared with CIT. Vertex Pharmaceuticals is currently conducting clinical trials using sBCs, following the acquisition of two leading companies in the field, Semma Therapeutics in 2019 and Viacyte in 2022. A recent company press release on Vertex`s ongoing clinical trials using allogeneic sBCs in conjugation with systemic immune suppression indicates promising results, with six treated patients demonstrating indicators of considerable beta-cell function post-transplantation.¹¹ While early, these results illustrate the potential of stem cell-derived sources as an attractive and viable alternative to primary pancreatic islets.

While cell sourcing options are expanding, critical challenges remain regarding durable cell function in the face of immunological allo-rejection and recurring autoreactivity toward the foreign, insulin-producing beta-cell graft. Current beta-cell replacement strategies rely on systemic immune suppression, which due to considerable adverse effects, excludes a wide patient population. To broaden access, there is a significant need to develop alternative approaches. These approaches may serve to either mask the implanted cells and/or reinstruct the immune system to accept the graft. One rapidly emerging option involves gene editing to modify key immunological genes that are required for immune recognition and/or provision of localized immune tolerance. Tools such as CRISPR have enabled this approach, with promising results in small and large pre-clinical models.^12,13 Alternatively, local immunomodulatory materials are also under development, whereby constituents capable of instructing immune responses or masking the graft can be co-transplanted with cells to not only suppress immune activation but potentially direct them toward more regulatory or tolerogenic pathways.¹⁴

Overall, the approval of Lantidra provides a key enabling treatment for US individuals with type 1 diabetes in need of alternative options. The focused efforts toward this BLA approval can also provide guideposts for advancing additional safe and effective beta-cell replacement treatment options that may expand access to a wider patient population.