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Comment on the Roche clinical trial targeting GABAA receptor for improving cognitive deficits in Down syndrome


Roger Reeves, President of T21RS

Marie-Claude Potier, Secretary of T21RS

Jean-Maurice Delabar, former President of T21RS

Andre Strydom, Chair of the Committee for Clinical Research

Yann Hérault, Chair of the Committee for Preclinical Research

Peter Paul De Deyn, Chair of the Committee for Science & Society


Recently, Roche pharmaceutical company has published a statement about a phase II clinical trial investigating the efficacy of Basmisanil in adults and adolescents with Down syndrome. It was a 26 week, multi-center, randomized, double-blind, three arm, parallel-group, placebo-controlled study designed to FDA approved criteria. This phase II study did not meet its primary and secondary endpoints on improvement in cognition and function. There was no statistically significant difference observed between individuals who took the drug and those who took the placebo. The same negative result was obtained both for the adult group (18-30 years old) and adolescent group (12-17 years old).

The rationale for this study was based on preclinical results obtained with two molecules belonging to the pharmacological class of α5 GABAA inverse agonists (α5IA, Braudeau et al. 2011) and (RO4938581, Martinez-Cue et al. 2013) in a mouse model of Down syndrome. The two studies showed a rescue of cognitive deficits on various behavioral memory tests. Neurons that use the GABAA-α5IA receptor are concentrated in a region of the brain, the hippocampus, that is affected by trisomy such that transmission of signals between neurons (synaptic transmission) is affected (Hanson et al., 2007). This is correlated with learning and memory deficits in mice and analogous problems in people who have Down syndrome (Reeves et al., 1995; Thomas et al., 2001). The drugs were shown to normalize important aspects of synaptic transmission in the mouse brain.

Basmisanil, the molecule used in the phase II clinical trial by Roche is the third member of a family of GABAA-α5IA inverse agonists (also known as RO5186582 or RG1662) with a different chemical structure. It will be extremely important to determine whether these molecules differ in their ability to correct behavioral deficits in mouse models of Down syndrome.

At this time, Roche is discussing the future of their Down syndrome research effort with the clinical trial participants. It is expected that all relevant data from the trials will be analyzed and made available at a scientific meeting(s) and in the literature in the fall of 2016.

Although the initial results of Basmisanil are disappointing, these phase II trials are an important milestone and have confirmed that clinical trials can be successfully and safely conducted in adults and children with Down syndrome. It is also likely that this effort will deliver important data on health profiles and clinical measures once the data is analyzed in more detail.