Future Directions and Clinical Trial Considerations for Novel Islet β-Cell Replacement Therapies for Type 1 Diabetes

Abstract

Type 1 diabetes results from the immune-mediated loss of insulin-producing pancreatic islet β-cells, rendering those affected dependent on exogenous insulin to survive. Despite the array of choices available for insulin delivery, treatment to maintain near-normal glucose metabolism while avoiding hypo- and hyperglycemia remains a challenge. After two decades of clinical trials across four continents, the transplantation of islets isolated from deceased donor pancreases has been shown to be both safe and efficacious in patients experiencing severe hypoglycemia (level 3) or already requiring immunosuppression to support a kidney transplant, offering a distinct set of advantages to appropriate candidates. We are entering a phase of clinical development where islet β-cell replacement approaches should be recognized and studied as more than just a rescue therapy for those with severe hypoglycemia and could be expanded to all individuals with type 1 diabetes. Our aim is to expedite translation of cellular therapy for all individuals living with type 1 diabetes by focusing on new emerging islet β-cell replacement approaches and proposing clinical trial designs that accelerate their development. As we support expansion of the population to be included in the investigation of novel therapies, this perspective presents a road map and clinical trial considerations to guide the development of the next generations of islet β-cell replacement therapies that address the unmet needs of the broader type 1 diabetes community. ARTICLE HIGHLIGHTS Current research and development are ushering in a new era of novel islet β-cell replacement therapies that can no longer be considered solely a rescue treatment for those with unstable glucose management. Clinical trial design must ensure that the application of islet β-cell replacement is broadened beyond the indication of severe hypoglycemia given the potential for establishing insulin-independent normoglycemia. It is imperative that people with type 1 diabetes and their clinicians are at the center of the risk-benefit equipoise as evidence for the safety of cellular products, transplant sites, and immune protection strategies accumulates and an increasing number of options for intervention become available.