A randomized, double-blind, placebo-controlled phase II trial to explore the effects of a GABAA-α5 NAM (basmisanil) on intellectual disability associated with Down syndrome

Celia Goeldner, Priya S Kishnani, Brian G Skotko, Julian Lirio Casero, Joerg F Hipp, Michael Derks, Maria-Clemencia Hernandez, Omar Khwaja, Sian Lennon-Chrimes, Jana Noeldeke, Sabine Pellicer, Lisa Squassante, Jeannie Visootsak, Christoph Wandel, Paulo Fontoura, Xavier Liogier d'Ardhuy, Clematis Study Group, Rafael De La Torre Fornell, Paul Glue, Julie Hoover-Fong, Sonja Uhlmann, Jorge Malagón Valdez, Andrew Marshall, Federico Martinón-Torres, Lorenzo Redondo-Collazo, Carmen Rodriguez-Tenreiro, Valeria Marquez Chin, Adriana G Michel Reynoso, Ed A Mitchell, Rebecca F Slykerman, Trecia Wouldes, Sarah Loveday, Fernando Moldenhauer, Ramon Novell, Cesar Ochoa, Michael S Rafii, Anne-Sophie Rebillat, Damien Sanlaville, Pierre Sarda, Rohit Shankar, Margaret Pulsifer, Casey L Evans, Alexandra M Silva, Mary Ellen McDonough, Maria Stanley, Lindsay M McCary, Stefano Vicari, William Wilcox, Giuseppe Zampino, Alessandro Zuddas, Celia Goeldner, Priya S Kishnani, Brian G Skotko, Julian Lirio Casero, Joerg F Hipp, Michael Derks, Maria-Clemencia Hernandez, Omar Khwaja, Sian Lennon-Chrimes, Jana Noeldeke, Sabine Pellicer, Lisa Squassante, Jeannie Visootsak, Christoph Wandel, Paulo Fontoura, Xavier Liogier d'Ardhuy, Clematis Study Group, Rafael De La Torre Fornell, Paul Glue, Julie Hoover-Fong, Sonja Uhlmann, Jorge Malagón Valdez, Andrew Marshall, Federico Martinón-Torres, Lorenzo Redondo-Collazo, Carmen Rodriguez-Tenreiro, Valeria Marquez Chin, Adriana G Michel Reynoso, Ed A Mitchell, Rebecca F Slykerman, Trecia Wouldes, Sarah Loveday, Fernando Moldenhauer, Ramon Novell, Cesar Ochoa, Michael S Rafii, Anne-Sophie Rebillat, Damien Sanlaville, Pierre Sarda, Rohit Shankar, Margaret Pulsifer, Casey L Evans, Alexandra M Silva, Mary Ellen McDonough, Maria Stanley, Lindsay M McCary, Stefano Vicari, William Wilcox, Giuseppe Zampino, Alessandro Zuddas

Abstract

Background: There are currently no pharmacological therapies to address the intellectual disability associated with Down syndrome. Excitatory/inhibitory imbalance has been hypothesized to contribute to impairments in cognitive functioning in Down syndrome. Negative modulation of the GABAA-α5 receptor is proposed as a mechanism to attenuate GABAergic function and restore the excitatory/inhibitory balance.

Methods: Basmisanil, a selective GABAA-α5 negative allosteric modulator, was evaluated at 120 mg or 240 mg BID (80 or 160 mg for 12-13 years) in a 6-month, randomized, double-blind, placebo-controlled phase II trial (Clematis) for efficacy and safety in adolescents and young adults with Down syndrome. The primary endpoint was based on a composite analysis of working memory (Repeatable Battery for the Assessment of Neuropsychological Scale [RBANS]) and independent functioning and adaptive behavior (Vineland Adaptive Behavior Scales [VABS-II] or the Clinical Global Impression-Improvement [CGI-I]). Secondary measures included the Behavior Rating Inventory of Executive Functioning-Preschool (BRIEF-P), Clinical Evaluation of Language Fundamentals (CELF-4), and Pediatric Quality of Life Inventory (Peds-QL). EEG was conducted for safety monitoring and quantitatively analyzed in adolescents.

Results: Basmisanil was safe and well-tolerated; the frequency and nature of adverse events were similar in basmisanil and placebo arms. EEG revealed treatment-related changes in spectral power (increase in low ~ 4-Hz and decrease in high ~ 20-Hz frequencies) providing evidence of functional target engagement. All treatment arms had a similar proportion of participants showing above-threshold improvement on the primary composite endpoint, evaluating concomitant responses in cognition and independent functioning (29% in placebo, 20% in low dose, and 25% in high dose). Further analysis of the individual measures contributing to the primary endpoint revealed no difference between placebo and basmisanil-treated groups in either adolescents or adults. There were also no differences across the secondary endpoints assessing changes in executive function, language, or quality of life.

Conclusions: Basmisanil did not meet the primary efficacy objective of concomitant improvement on cognition and adaptive functioning after 6 months of treatment, despite evidence for target engagement. This study provides key learnings for future clinical trials in Down syndrome.

Trial registration: The study was registered on December 31, 2013, at clinicaltrials.gov as NCT02024789.

Keywords: Adaptive behavior; Cognition; Down syndrome; EEG; GABAA-α5.

Conflict of interest statement

At the time of the study, P Fontoura, C Goeldner, MC Hernandez, JF Hipp, O Khwaja, X Liogier d’Ardhuy, J Noeldeke, S Pellicer, L Squassante, C Wandel were employees of F.Hoffmann-La Roche AG Switzerland; M Derks and S Lennon-Chrimes were employees of Roche Products Ltd. UK; J Visootsak was an employee of Roche New York. All employees (former and current) may be eligible for stock and stock options. P S Kishnani has no disclosures for Down syndrome-related research. J Lirio Casero has no disclosures. B G Skotko occasionally consults on the topic of Down syndrome through the Gerson Lehrman Group. He receives remuneration from Down syndrome non-profit organizations for speaking engagements and associated travel expenses. Dr. Skotko receives annual royalties from Woodbine House, Inc., for the publication of his book, Fasten Your Seatbelt: A Crash Course on Down Syndrome for Brothers and Sisters. Within the past 2 years, he has also received research funding from AC Immune and LuMind Research Down Syndrome Foundation to conduct clinical trials for people with Down syndrome. Dr. Skotko is occasionally asked to serve as an expert witness for legal cases where Down syndrome is discussed. Dr. Skotko serves in a non-paid capacity on the Honorary Board of Directors for the Massachusetts Down Syndrome Congress and the Professional Advisory Committee for the National Center for Prenatal and Postnatal Down Syndrome Resources. Dr. Skotko has a sister with Down syndrome.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Participant disposition (CONSORT diagram)
Fig. 2
Fig. 2
Percent of participants with above-threshold improvement on the composite endpoint. A Primary efficacy endpoint after 6 months of treatment. Percent of participants with above-threshold improvement: B by age group (adolescents, adults) after 6 months of treatment; C combined age group after 3 months of treatment; D by age group (adolescents, adults) after 3 months of treatment. Above-threshold improvement on the composite endpoint was defined as having (1) a relevant increase in raw scores from baseline in at least two out of three tasks from the Repeatable Battery for the Assessment of Neuropsychological Status ([RBANS]; ≥ 2 points for list learning, ≥ 1 point for list recognition, ≥ 1 point for list recall); and (2) either an increase from baseline in the Vineland Adaptive Behavior Scales-II (VABS II) composite score of ≥ 7 or a Down syndrome-specific Clinical Global Impression-Improvement (DS-CGI-I) ≤ 3 (minimally improved). Efficacy assessments were performed at baseline and after 3 and 6 months of treatment. Statistics: *p < 0.05 vs. placebo-treated group
Fig. 3
Fig. 3
Quantitative EEG. A Change in EEG spectral power (average across week 2 and week 20 visits relative to baseline) for dosed (red) and the placebo (gray) groups. B, C Effects of assessment time-point (week 2 vs. week 20) and dose (low dose vs. high dose) for signal power extracted from the centers of the clusters identified in 1.2.3 (theta cluster, frequency range [3 bins]: ~ 3.5–4.5 Hz, electrodes: F3, Fz, F4, T7, T8, P7, P8, O1, O2; beta cluster, frequency range [3 bins]: ~ 19–22.5 Hz, electrodes: Fz, Cz). The top plots indicate the electrodes used for each extraction of signal power. The numbers at the base of the bars indicate the number of participants entering the analyses

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