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Cited by 48Down syndrome and intellectual disability researchAlzheimer's disease research and treatmentsGenetics and Neurodevelopmental Disorders

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

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Goeldner, Celia, Kishnani, Priya S., Skotko, Brian G., Casero, Julian Lirio, Hipp, Joerg F., Derks, Michael, Hernandez, Maria-Clemencia, Khwaja, Omar +42 more·2022·Journal of Neurodevelopmental Disorders
DOI 10.1186/s11689-022-09418-0PMC PMC8903644
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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 GABA A -α5 receptor is proposed as a mechanism to attenuate GABAergic function and restore the excitatory/inhibitory balance. Methods: Basmisanil, a selective GABA A -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.

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  • Although therapeutic targeting of the altered excitation-inhibition ratio proved successful in treating cognitive deficits in mice, similar strategies did not prove efficacious for the treatment of intellectual disability in individuals with Down syndrome.

    “Although therapeutic targeting of this altered excitation–inhibition ratio proved successful in treating cognitive deficits in mice, similar strategies did not prove efficacious for the treatment of intellectual disability in individuals with DS130.”

    From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [130]

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Authors
Goeldner, C., Kishnani, P. S., Skotko, B. G., Casero, J. L., Hipp, J. F., Derks, M., Hernandez, M.-C., Khwaja, O., Lennon-Chrimes, S., Noeldeke, J., Pellicer, S., Squassante, L., Visootsak, J., Wandel, C., Fontoura, P., d’Ardhuy, X. L., Clematis Study Group, De La Torre Fornell, R., Glue, P., Hoover-Fong, J., Uhlmann, S., Malagón Valdez, J., Marshall, A., Martinón-Torres, F., Redondo-Collazo, L., Rodriguez-Tenreiro, C., Marquez Chin, V., Michel Reynoso, A. G., Mitchell, E. A., Slykerman, R. F., Wouldes, T., Loveday, S., Moldenhauer, F., Novell, R., Ochoa, C., Rafii, M. S., Rebillat, A.-S., Sanlaville, D., Sarda, P., Shankar, R., Pulsifer, M., Evans, C. L., Silva, A. M., McDonough, M. E., Stanley, M., McCary, L. M., Vicari, S., Wilcox, W., Zampino, G., & Zuddas, A.
Affiliations
  • F. Hoffmann-La Roche AG (CH)
  • Duke Clinical Research Institute (US)
  • Harvard University (US)
  • Roche (United Kingdom) (GB)
Corresponding author
Goeldner, Celia
ORCID
Venue
Journal of Neurodevelopmental Disorders
Publisher
Springer Science and Business Media LLC
Published
2022-02-05
Volume
14
Issue
1
Pages
10-10
ISSN
  • 1866-1947 (ISSN-L)
  • 1866-1955
DOI
10.1186/s11689-022-09418-0
PMC
PMC8903644
OpenAlex
W4210703968
Cited by
48
References
44
Citations by year
2026: 11 · 2025: 14 · 2024: 10 · 2023: 9 · 2022: 4
FWCI
8.16
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neurodevelopmental Disorders (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PEARL (University of Plymouth) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
  • PEARL (University of Plymouth) (submittedVersion)
  • PubliCatt (Università Cattolica del Sacro Cuore) (submittedVersion, other-oa)
  • Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, cc-by)
  • ResearchSpace (University of Auckland) (submittedVersion, cc-by)
Funders
F. Hoffmann-La Roche
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
negative allosteric modulators, Down syndrome, intellectual disability, working memory, adaptive behavior, functional independence, EEG spectral power, target engagement, executive function, language, quality of life, adolescents and young adults
MeSH terms
Adolescent, Child, Child, Preschool, Down Syndrome, gamma-Aminobutyric Acid, Humans, Intellectual Disability, Morpholines, Oxazoles, Pyridines, Quality of Life, Treatment Outcome, Young Adult

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