11 December 2019 - - US-based biopharmaceutical company Sage Therapeutics (NASDAQ: SAGE) plans to advance SAGE-718, a novel, first-in-class, oxysterol-based positive allosteric modulator of N-methyl-D-aspartate receptors, to a Phase 2 placebo-controlled clinical trial in patients with Huntington's disease, the company said.

The planned progression of SAGE-718 is based on results from Phase 1 studies evaluating the safety and tolerability of SAGE-718, including an open-label cohort of patients with HD.

In the 14-day open-label study of patients with HD, the safety, tolerability, and pharmacokinetic profile of daily SAGE-718 oral solution were evaluated in six patients with early HD. In the study, SAGE-718 was well tolerated, with no serious adverse events or adverse events leading to treatment discontinuation.

In addition, patients demonstrated improved performance, compared to baseline, on assessments of executive functioning, with measures relevant to the core cognitive decline seen in people with HD. These results are comparable to improvements in measures of executive function observed in an earlier Phase 1 cohort of individuals without HD.

Additional data from the Phase 1 open-label cohort study on the safety and tolerability of SAGE-718 in patients with early HD will be presented at a future congress in 2020.

In addition, the company is presenting data from three other non-clinical and Phase 1 studies with SAGE-718 at the 58th annual meeting of the American College of Neuropsychopharmacology.

The poster presentations provide supportive evidence for the role of NMDA receptor dysfunction in Huntington's Disease-related cognitive impairment, as well as functional target engagement of SAGE-718, including positive cognitive effects in healthy volunteers.

Data presentations at ACNP focus on additional studies in HD, including SAGE-718 data:
Poster [M-147]: Cognitive Deficits in Huntington's Disease and Altered 24(S)-hydroxycholesterol
24(S)-hydroxycholesterol -HC) is an endogenous, brain-specific, cholesterol metabolite that acts as a PAM of the NMDA receptor.

Previous work has established that levels of 24(S)-HC are decreased in the plasma and brain in people with HD.

In this study, plasma samples from the TRACK-HD study, a longitudinal observational study of biological and clinical manifestations of HD, were analyzed.

Results demonstrated levels of 24(S)-HC declined during the transition from pre-manifest to manifest HD, and that levels correlated with performance on tests of executive dysfunction and emotional processing.

These data support a role for 24(S)-HC in cognitive changes in HD and suggest that NMDA hypofunction may contribute to cognitive impairment in HD.

Poster [M-144]: Using a Multimodal Biomarker Approach to Identify Functional Target Engagement of the Novel NMDA Positive Allosteric Modulator SAGE-718.

A suite of three clinical studies was designed to evaluate CNS-target engagement of SAGE-718 by electrophysiology and magnetic resonance imaging, using a low-dose ketamine challenge paradigm in healthy adults in a placebo controlled cross-over design.

In these studies, SAGE-718 was generally well tolerated with no serious adverse events or adverse events leading to treatment discontinuation.

A single dose administration of SAGE-718 (3 mg oral solution) attenuated ketamine-induced changes in functional MRI-derived alterations of blood oxygenation levels, including attenuation of ketamine-induced increases of BOLD observed in posterior brain regions and decreases observed in anterior brain regions.

In a single-click, auditory evoked potential paradigm, the N100-P200 potential waveform was significantly reduced by ketamine under placebo conditions, but not after administration of SAGE-718.

Results from these studies demonstrate that SAGE-718 had effects on functional imaging in healthy volunteers. SAGE-718 also modulated the effects of ketamine on regional and global measures of resting brain activity.

These effects are in line with the presumed mechanism of action of SAGE-718 as an NMDA PAM, which supports the hypothesis of functional engagement of the NMDA receptor.