Innovative Strategies To Demonstrate “Immunological Proof-of-Mechanism” And To Explore Early Outcome Measures In Immunotherapy Trials

PURPOSE

JDRF is committed to addressing key hurdles in accelerating the clinical path towards approval of effective immunotherapies for the prevention and treatment of T1D. To that end, JDRF is soliciting letters of intent (LOIs) for the development of revised outcomes for clinical trials of immunotherapiesthat will allow faster and more efficient studies to establish proof-of-mechanism and proof-of-concept. Efforts are urgently needed in the T1D community to define measures that will allow evaluation of the therapeutic effects of candidate immune therapies in a shorter time frame and utilizing fewer subjects to evaluate therapeutic benefit.

BACKGROUND

In all T1D immunotherapy trials to date, efficacy has been defined as preservation of beta cell function measured in a mixed meal tolerance test (MMTT). However, the high burden and high variability in MMTTs, and the need for a long observation period (typically twelve months) results in overly burdensome trials that require large numbers of patients and take a long time to execute, significantly slowing progress for evaluating candidate therapies. Retrospective mechanistic analyses of samples from several T1D trials, are providing compelling evidence for enhanced regulatory T (Treg) cell numbers and function and reduced or disabled memory T effector (Teff) cell subsets in responders to immunotherapies, suggesting that immune regulation might be achieved with the right type of therapy(ies) in the right subjects with the right treatment regimen. This rationale underscores the potential to identify robust early markers or predictors of immune efficacy and to link such to early markers of beta cell health, early metabolic measures, and possibly relevant patient reported outcomes.

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