Preclinical Pharmacology of Alogabat: A Novel GABAA-α5 Positive Allosteric Modulator Targeting Neurodevelopmental Disorders with Impaired GABAA Signaling

Giuseppe Cecere¹Theresa M Ballard¹Frederic Knoflach¹Michael Honer¹Joerg F Hipp¹Pilar Garcés¹Thomas Mueggler¹Basil Künnecke¹Andreas Bruns¹Eric P. Prinssen¹Philipp Schoenenberger¹Philipp Janz¹Roger Redondo¹Barbara Biemans¹Henner Knust¹Andrés Olivares-Morales¹Alessandro Brigo¹Jan Michael Schulz¹Daniel BERTRAND²Michael Saxe¹Eoin C O'Connor¹Maria-Clemencia Hernandez^1*

• ¹Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland
• ²HiQScreen (Switzerland), Geneva, Geneva, Switzerland

Background: Alterations of the GABAergic system contribute to the pathophysiology of neurodevelopmental disorders, including autism spectrum disorder and Angelman syndrome carrying large deletions in the 15q11-13 region. Positive modulation of GABAA-α5 receptors may provide a novel therapeutic approach without the typical side effects of non-selective GABAA positive allosteric modulators such as diazepam. Methods: Alogabat was assessed for binding and functional activity at GABAA-α5β3γ2 receptors in vitro, and in electrophysiological studies in hippocampal slices. In vivo studies in rodents included receptor occupancy using a selective GABAA-α5 tracer (autoradiography), pharmacological MRI and EEG. Alogabat was assessed on the repetitive behavior phenotype of BTBR and contactin-associated protein-like 2 knockout (Cntnap2-/-) mice, on seizure models and cognitive performance in rats, and on rotarod performance following combination treatment with diazepam. Results: Alogabat is a potent positive allosteric modulator of GABAA-α5 receptors with binding and functional selectivity. Receptor occupancy studies provided direct proof of dose-dependent target occupancy. Functional circuit modulation was demonstrated by dose-dependent regional perfusion changes in pharmacological MRI and changes in EEG theta and beta band power in rats. Alogabat at >50% GABAA-α5 receptor occupancy normalized elevated self-grooming in both Cntnap2-/- and BTBR mice and exhibited antiepileptic activity in rats. Alogabat did not impair cognition in wildtype rats at GABAA-α5 receptor occupancy up to 75%, although impairment occurred at higher doses probably due to increased activity at other receptor subtypes and/or saturation of α5 receptors. Alogabat did not worsen diazepam-induced rotarod impairment. Conclusions: Alogabat showed beneficial effects in mouse models relevant for neurodevelopmental disorders, as well as anti-seizure activity, at doses without cognitive, sedative, and motoric side effects.