Saniona announced the selection of its proprietary GABAA a5 Negative Allosteric Modulator (NAM) lead compound, SAN2465, as a clinical candidate for major depressive disorder. This decision follows encouraging results obtained from a rodent model, specifically the chronic mild stress model of depression. SAN2465 demonstrated rapid and sustained reversal of chronic stress-induced depressive-like symptoms, including anhedonia, anxiety, and cognitive impairment.

This positions SAN2465 as an innovative and rapid-acting approach to treating major depressive disorder and its associated comorbidities. Originally discovered through collaboration with Boehringer Ingelheim for schizophrenia, SAN2465 is a highly potent and selective negative allosteric modulator of GABAA a5. Saniona holds exclusive global rights to the program following the termination of the collaboration with BoehringerIngelheim in November 2020.

SAN2465 is now poised for pre-clinical development as a rapid-acting antidepressant for collaboration with a partner. SAN2465 was rigorously tested in the chronic mild stress model of Depression in the laboratory of Professor Mariusz Papp, Maj Institute of Pharmacology, Polish Academy of sciences, Krakow, Poland. The chronic mild stress model is widely acknowledged as the most valid animal model of depression with translational potential to human disease.

Results indicate that a single oral treatment of SAN2465, administered 24 and 48 hours before testing, effectively reversed depressive-like symptoms, as assessed by stress-induced reduction of sucrose intake. Furthermore, SAN2465 reversed the anxiogenic-like behaviors and cognitive impairments induced by stress after a single oral treatment administered 48 hours and 72 hours before testing, respectively. Importantly, the onset and robustness of the effect are comparable to the NMDA antagonist ketamine, suggesting a potential new mechanism of action with a differentiated side effect profile.

The rapid antidepressant effect of esketamine is believed to stem from fast onset neuroplastic changes in molecular signaling cascades in relevant brain regions. Similar changes have been observed through pharmacological negative allosteric modulation of the GABAA a5 receptors in rodent studies suggesting that this mechanism could have a comparable rapid antidepressant effect in humans. Importantly, unlike NMDA receptor blockade with esketamine, negative modulation of GABAA a5 receptors is not anticipated to lead to significant adverse effects, as the expression of these receptors is more localized and mainly restricted to limbic areas.

Use of esketamine is restricted by a Risk Evaluation and Mitigation Strategy (REMS) Program.