Complex Disposition of Methylthioninium Redox Forms Determines Efficacy in Tau Aggregation Inhibitor Therapy for Alzheimer's Disease

Methylthioninium (MT) is a tau aggregation inhibitor with therapeutic potential in Alzheimer's disease (AD). MT exists in equilibrium between reduced (leuco-methylthioninium, LMT) and oxidized (MT+) forms; as the chloride salt (MTC, "methylene blue"), it is stabilized in its MT+ form. While the results of a phase 2 study of MTC in 321 mild/moderate AD subjects identified a 138 mg MT/day dose as the minimum effective dose on cognitive and imaging endpoints, further clinical development of MT was delayed pending resolution of the unexpected lack of efficacy of the 228 mg MT/day dose. We hypothesized that the failure of dose-response may depend on differences in dissolution in simulated gastric and intestinal fluids of the 100 mg MTC capsules used in the trial to deliver the 228 mg dose. Furthermore, such differences may reflect previously unsuspected differences in redox processing of MT at different levels in the gut. The synthesis of a novel chemical entity, LMTX® (providing LMT in a stable anhydrous crystalline form), has enabled a systematic comparison of the pharmacokinetic properties of MTC and LMTX® in preclinical and clinical studies. The quantity of MT released in water or gastric fluid within 60 minutes proved in retrospect to be an important determinant of clinical efficacy. A further factor was a dose-dependent limitation in the ability to absorb MT in the presence of food when delivered, as MTC, in the MT+ form. A model is presented to account for the complexity of MT absorption and which may have relevance to other similar redox molecules.