Phase 1B Trial on Escalating Doses of Memantine in Down Syndrome

Based on preclinical evidence from mouse models of DS collected by our research team and others, we hypothesized over a decade ago that NMDA receptor dysfunction may play significant pathogenic roles in both the neurodevelopmental and the neurodegenerative components of DS. Four years ago, our research team published in the results of a two-site, randomized phase 2 trial of the AD drug memantine to investigate the safety, efficacy, and tolerability of this drug on cognitive and adaptive outcome measures in adolescents and young adults with DS. In this study, we found no evidence of cognitive-enhancing effects of standard doses of memantine treatment in the primary analysis. Memantine was well tolerated, with infrequent mild-to-moderate adverse events observed. Notably, however, measured plasma memantine levels in more than 90% of study participants were lower than those considered therapeutic in patients with AD (0.5 -1 μmol/l), and much lower than the doses used in preclinical behavioral studies in mouse models of DS (1.7 μmol/l). In this same clinical study, an exploratory analysis of data from 23 participants with memantine plasma levels >0.4 μmol/l (representing the top quartile of quantified memantine plasma levels) revealed significant improvement in scores on two neuropsychological measures in the memantine arm compared to the placebo arm. One of these measures (the California Verbal Learning Test short form second version, or CVLT-II sf) assessed episodic memory, whereas the other (the Recall of Digits Forward from the Differential Ability Scales Second Edition, or DAS-II) measured short-term memory. These findings led us to hypothesize that higher-than-standard doses of memantine should produce significant cognitive improvements in most individuals with DS, with minimal adverse events.

The exploratory analysis performed in that study pointed to possibility that higher-than-standard therapeutic memantine doses might not only produce statistically significant efficacy in a larger proportion of individuals with DS but also yield effect sizes significantly higher than those observed in that study. Although there are several examples in the literature where memantine was used at doses as high as 60 mg/day in the treatment of various neurological disorders, the key question is whether the majority of individuals with DS would tolerate such doses.

Here we describe an open-label phase 1b clinical trial, in which 25 participants with DS will receive escalating doses of memantine (20 mg/day, 40 mg/day and 60 mg/day; for 9 weeks at each of these dosing stages). Safety and tolerability will be the primary outcome measures for this phase of the project. However, this initial study will also provide a unique chance for us to fine tune the neuropsychological test battery to better understand the psychometric properties of each test, including test-retest reliability across multiple, closely spaced retest sessions. Assessments of plasma levels of memantine at each dose level will allow us to confirm the expected linear relationship between oral dose and steady state levels of this drug. Additionally, the assessment of plasma levels of various AD plasma biomarkers should provide preliminary objective information on whether memantine can affect such biomarkers at Stage 0 DSAD. The inclusion of a washout visit will allow us to evaluate the reversibility of any observed drug effect. After the washout phase, a single oral dose (20 mg) will be used to evaluate the absorption, distribution, and excretion of memantine in young individuals with DS (through PK properties, such as time to peak, peak concentration, and half-life), which are expected to approximate first order kinetics.