Innovative Designs and Logistical Considerations for Expedited Clinical Development of Combination Disease-Modifying Treatments for Type 1 Diabetes

Abstract

It has been 100 years since the life-saving discovery of insulin, yet daily management of type 1 diabetes (T1D) remains challenging. Even with closed-loop systems, the prevailing need for persons with T1D to attempt to match the kinetics of insulin activity with the kinetics of carbohydrate metabolism, alongside dynamic life factors affecting insulin requirements, results in the need for frequent interventions to adjust insulin dosages or consume carbohydrates to correct mismatches. Moreover, peripheral insulin dosing leaves the liver underinsulinized and hyperglucagonemic and peripheral tissues overinsulinized relative to their normal physiologic roles in glucose homeostasis. Disease-modifying therapies (DMT) to preserve and/or restore functional β-cell mass with controlled or corrected autoimmunity would simplify exogenous insulin need, thereby reducing disease mortality, morbidity, and management burdens. However, identifying effective DMTs for T1D has proven complex. There is some consensus that combination DMTs are needed for more meaningful clinical benefit. Other complexities are addressable with more innovative trial designs and logistics. While no DMT has yet been approved for marketing, existing regulatory guidance provides opportunities to further “de-risk” development. The T1D development ecosystem can accelerate progress by using more innovative ways for testing DMTs for T1D. This perspective outlines suggestions for accelerating evaluation of candidate T1D DMTs, including combination therapies, by use of innovative trial designs, enhanced logistical coordination of efforts, and regulatory guidance for expedited development, combination therapies, and adaptive designs.

The National Clinical Care Commission Report to Congress: Leveraging Federal Policies and Programs to Prevent Diabetes in People With Prediabetes

“…Scientifically, it is still not well understood why people develop type 1 diabetes or how it can be best prevented ( 78 ). Approximately 30% of patients with new-onset type 1 diabetes present with diabetic ketoacidosis (DKA) ( 79 , 80 ), a serious yet avoidable acute metabolic complication.…”

Advances in the Use of Biologics and Biomaterials toward the Improvement of Pancreatic Islet Graft Survival in Type 1 Diabetes

“…Future scientific developments would likely target a combination therapy approach whereby islets derived from renewable sources such as iPSCs are housed in an immunoprotective encapsulation allowing for vascularization using growth factors or patient‐derived cells with local delivery of compounds to improve islet cell function. As most promising T1D cell therapies are a combination of cells, biomaterials, and/or pharmaceutics, the regulatory approval process for combination therapies presents significant hurdles that can be optimized with innovations in clinical trial design and approval process as described in depth by Anderson et al [ 157 ]…”

What does the licensing of teplizumab mean for diabetes care?

“…A cure for T1D remains elusive but the last decade has witnessed an expansion of immunoprevention trials in children and adults, including the repurposing of agents successfully used in other diseases to modulate the autoimmune process and preserve beta cells 2 . It is anticipated that long‐term delay will most probably be identified with combination therapy tested through adaptive and platform trials 3 . This commentary will provide the background to the licensing of teplizumab and the implications.…”

“…The complex autoimmune processes that result in T1D may benefit from combination therapies targeting different aspects of the immune system to preserve pancreatic beta cells. Adaptive trials offer an approach to test multiple agents without undermining validity or integrity, 3 an approach that is used in other multifactorial diseases, such as oncology. The future of early stage T1D management will probably incorporate a personalized medicine approach with combination therapies.…”