SGE-516 / Sage Therapeutics - LARVOL DELTA

Witnessed trauma exposure induces fear in mice through a reduction in endogenous neurosteroid synthesis. (PubMed, J Neuroendocrinol) - "We demonstrated that genetic knockdown or pharmacological inhibition of 5α-reductase type 2 exaggerates the behavioral expression of fear in response to witnessed trauma, whereas oral treatment with an exogenous, synthetic neuroactive steroid gamma-aminobutyric acid-A receptor positive allosteric modulator with molecular pharmacology similar to allopregnanolone (SGE-516 [tool compound]) decreased the behavioral response to observational fear. These data implicate impaired endogenous neurosteroidogenesis in the pathophysiology of threat exposure, both direct and witnessed. Further, these data suggest that treatment with exogenous 5α-reduced neurosteroids or targeting endogenous neurosteroidogenesis may be beneficial for the treatment of individuals with PTSD, whether resulting from direct or witnessed trauma."

Journal • Preclinical • CNS Disorders • Mood Disorders • Post-traumatic Stress Disorder

Influence of Neurosteroids on Network Activity that Govern Affective States (ACNP 2023) - "We utilized in vivo local field potential recording and in vivo calcium imaging to examine the impact of CUS on network activity in the BLA and the ability of allopregnanolone and SGE-516 to modulate BLA network states...Treatment with NAS GABAA receptor PAMs alters the activity of specific subsets of BLA neurons and network states within and between the BLA, which may contribute to the antidepressant effects of these compounds. These findings may explain the persistent therapeutic effects of NAS GABAA receptor PAMs for the treatment of both postpartum depression and major depressive disorder."

CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Zuranolone, a positive allosteric modulator of the GABAA receptor and a neuroactive steroid: hypothesized mechanism of action in depression (ECNP 2023) - "While both benzodiazepines and neuroactive steroid GABAAR PAMs, including zuranolone, led to increased beta-band power in rat EEG studies, they modulated theta-band EEG power differentially.[4,5] A benzodiazepine (diazepam), a non-benzodiazepine (alpidem), and a benzodiazepine receptor partial agonist (imepitoin) exhibited minimal theta-band modulation, whereas neuroactive steroid GABAAR PAMs (zuranolone, SGE-516 and SGE-872) robustly increased theta-band power in rats.[4,5] These distinct effects of zuranolone and benzodiazepines reflect the differential pharmacological modulation of GABAAR subpopulations and potentially their differential effects on depressive symptoms. In conclusion, zuranolone is hypothesized to increase neuroplasticity and restore excitatory-inhibitory balance via upregulation of GABAAR expression and increased phasic and tonic inhibitory GABAergic signaling, thus allowing the brain to respond appropriately to internal and external stimuli. Via..."

CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Impaired endogenous neurosteroid signaling contributes to behavioral deficits associated with chronic stress. (PubMed, Biol Psychiatry) - "Our findings demonstrate that chronic stress impairs endogenous neurosteroid signaling in the BLA which is sufficient to induce behavioral deficits. Further, these studies suggest allopregnanolone-based treatments may directly target the underlying pathophysiology of mood disorders suggesting that targeting endogenous neurosteroidogenesis may offer a novel therapeutic strategy."

Journal • CNS Disorders • Depression • Mental Retardation • Mood Disorders • Psychiatry

Differential network activity of benzodiazepines and neuroactive steroids observed with cortical EEG in rat. (Neuroscience 2022) - "Recent FDA approval of NAS GABAAR PAMs brexanolone and ganaxolone for postpartum depression and CDKL5 deficiency disorder, respectively, indicate the broad therapeutic potential of this compound class...At exposures that elicit a 100% increase in β-band power, NAS GABAAR PAMs zuranolone and SGE-516 increase θ-band power, while the benzodiazepine diazepam reduces θ-band power (Antonoudiou 2022). Increased θ-band power was observed clinically with zuranolone (Antonoudiou 2022), whereas reduced θ-band power was reported in humans with lorazepam (Gilles 2002)...All compounds increased β-band power. The differential effects on θ-band power in rat EEG recordings between NAS GABAAR PAMs and the other GABAergic compounds tested may reflect the differential modulation of GABAAR subpopulations, since only the NAS GABAAR PAMs in this study modulate both γ and δ subunit-containing GABAARs."

Preclinical • CNS Disorders • Depression • Epilepsy • Psychiatry

Observational stress impairs neurosteroid signaling in the BLA (Neuroscience 2022) - "We then administered a synthetic neurosteroid analog (SGE-516) which significantly decreases freezing upon recall compared to vehicle mice. Conversely, we administered Finasteride, a 5α-reductase inhibitor, which significantly increased freezing in mice during the recall session. Taken together, this data demonstrates a role for endogenous neurosteroidogenesis in the BLA in the behavioral outcomes of observational fear and suggests that targeting endogenous neurosteroidogenesis may be a useful therapeutic intervention for PTSD, including cases resulting from witnessing a trauma."

CNS Disorders • Mood Disorders • Post-traumatic Stress Disorder • SRD5A1 • SRD5A2

Inhibition of human macrophage activation via pregnane neurosteroid interactions with toll-like receptors: Sex differences and structural requirements. (PubMed, Front Immunol) - "TLR4 and TLR7 were activated by lipopolysaccharide (LPS) or imiquimod in the presence/absence of allopregnanolone or related neurosteroids and pro-inflammatory markers were detected by ELISA or western blotting. 3α,5α-THDOC and SGE-516 inhibited TLR4 and TLR7 pathways only in females. These studies demonstrate anti-inflammatory effects of allopregnanolone in human macrophages for the first time and suggest that inhibition of pro-inflammatory cytokines/chemokines may contribute to its therapeutic actions."

IO biomarker • Journal • IL6 • IRF7 • TNFA

Allopregnanolone Mediates Affective Switching Through Modulation of Oscillatory States in the Basolateral Amygdala. (PubMed, Biol Psychiatry) - "Our findings demonstrate a novel molecular and cellular mechanism mediating the well-established anxiolytic and antidepressant effects of neuroactive steroids."

Journal • CNS Disorders • Depression • Postpartum Depression • Psychiatry • MRI

[VIRTUAL] Neuroactive Steroids Influence Affective Switching Through Parvalbumin Interneuron-Driven Modulation of Oscillatory States in the Basolateral Amygdala (ACNP 2020) - "Here we examine the ability of neuroactive steroids, allopregnanolone and SGE-516, to facilitate transitions between network and behavioral states...Correlations between changes in network and behavioral states were analyzed using a regression analysis. Exploratory No"

Alzheimer's Disease • CNS Disorders • Depression • Mood Disorders • Psychiatry

[VIRTUAL] Using the Novel Synthetic Neurosteroid SGE-516 to Modulate the Escalation of Binge Drinking and its Consequences in Male and Female Mice (ACNP 2020) - "These findings suggest that synthetic neurosteroids may indeed be a successful treatment strategy to temper binge drinking and is a successful treatment strategy to block the expression of withdrawal behaviors associated with chronic alcohol exposure. Future work will establish whether this compound can block stress-escalated drinking in our mouse model for comorbid PSTD/AUD."

Preclinical • Addiction (Opioid and Alcohol) • Alzheimer's Disease • CNS Disorders • Mood Disorders • Post-traumatic Stress Disorder • Psychiatry

Sustained Effects of SGE-516 in Combatting Network and Behavioral Consequences of Chronic Unpredictable Stress (SOBP 2020) - "These findings demonstrate that chronic stress is capable of perturbing the mPFC-BLA network and neuroactive steroids are capable of restoring a healthy network and behavioral state. The persistent effects of SGE-516 on network states may contribute to the sustainable antidepressant effects that were observed in clinical trials with brexanolone. Funding Source: Sponsored Research Agreement with SAGE Therapeutics"

CNS Disorders • Depression • Mood Disorders • Psychiatry

GABAergic approach of postpartum depression: A translational review of literature (PubMed, Encephale) - "Disability to modulate GABA-A-r expression during pregnancy and restore its previous state after parturition appears to trigger PPD. The GABAergic system is a promising pharmacotherapy target. From preclinical to clinical studies for about twenty years the GABAergic system has been incriminated and targeted in this challenging mental disease."

Journal

Health-Related Quality of Life in a Phase 3, Randomized, Placebo-Controlled Trial of the Neuroactive Steroid GABAA Receptor Positive Allosteric Modulator SAGE-217 in Postpartum Depression (ACNP 2019) - P3; "In the GABA-A-R δ subunit deficient mouse model of PPD, administration of a synthetic neuroactive steroid GABA-A-R PAM (SGE-516) reduced depression-like behaviors, supporting the potential relevance of positive allosteric modulation GABA-A-Rs as a novel PPD therapy. Brexanolone injection, an intravenous formulation of the neuroactive steroid GABA-A-R PAM allopregnanolone, was recently approved for the treatment of adult women with PPD... SAGE-217 administration was associated with rapid (by Day 3), statistically significant, and sustained (through Day 45) reductions in depressive symptoms in women with PPD in this double-blind, randomized, placebo-controlled Phase trial. This improvement in clinician-rated depression was followed by statistically significant improvements across multiple domains of patient-reported HRQoL at Day 45. These results support the further study of SAGE-217 in PPD."

Clinical • HEOR • P3 data

Time to Antidepressant Response in Double-Blind, Randomized, Placebo-Controlled Trials of Brexanolone Injection in Postpartum Depression (ACNP 2019) - P2, P3; "Treatment of a mouse model of PPD with the synthetic NAS GABA-A-R PAM SGE-516 resulted in a decrease in depression-like behaviors. NAS GABA-A-R PAMs, such as allopregnanolone, have a pharmacology distinct from benzodiazepines, including targeting of both synaptic and extrasynaptic GABAARs and upregulation of GABA-A-R surface expression... BRX achieved rapid (by Hour 60), sustained (through Day 30), clinically and statistically significant reductions in depressive symptoms versus placebo as assessed by HAM-D total score change from baseline. Using categorical assessments of HAM-D or CGI-I response, BRX90 was associated with significantly faster median time to onset versus placebo. BRX was generally well tolerated in the all BRX population."

Clinical

Evaluation of Depression and Anxiety in a Phase 3, Double-Blind, Placebo-Controlled Trial of the Neuroactive Steroid GABAA Receptor Positive Allosteric Modulator SAGE-217 in Postpartum Depression (ACNP 2019) - P3; "In the GABA-A-R δ subunit deficient mouse model of PPD, SGE-516, a synthetic neuroactive steroid GABA-A-R PAM, decreased depression-like behaviors. Brexanolone injection, an intravenous formulation of the neuroactive steroid GABA-A-R PAM allopregnanolone, was recently approved by the FDA for the treatment of adults with PPD, further supporting the relevance of the GABAergic mechanism in PPD... SAGE-217 achieved the primary endpoint of a reduction in depressive symptoms versus placebo as assessed by HAM-D total score change from baseline at Day 15. SAGE-217 treatment resulted in rapid (by Day 3), clinically meaningful, statistically significant, and sustained (beyond study drug dosing through Day 45) reductions in depressive symptoms as assessed by HAM-D total score in this Phase 3, double-blind, randomized, placebo-controlled trial in women with PPD. SAGE-217 was well tolerated, and the HAM-D results were supported by secondary assessments of depression and anxiety..."

Clinical • P3 data

Activity of Neurosteroid GABAA Positive Allosteric Modulators in Preclinical Harmaline Model for Essential Tremor (MDS Congress 2019) - "NAS SGE-516, is a positive modulator of both synaptic and extrasynaptic GABAARs and is effective in a preclinical model of tremor. By modulating network excitability in a manner distinct from historical GABAergic treatments (e.g. benzodiazepines) it is hypothesized that neurosteroid GABAA receptor modulators may also have a therapeutic potential beyond seizure disorders."

Preclinical

The synthetic neuroactive steroid SGE-516 reduces seizure burden and improves survival in a Dravet syndrome mouse model. (PubMed, Sci Rep) - "Treatment with standard benzodiazepines like clobazam, in combination with valproate and stiripentol, provides only modest seizure control. SGE-516 treatment protected against hyperthermia-induced seizures, reduced spontaneous seizure frequency and prolonged survival in the Scn1a (+/-) mice. This provides the first evidence of SGE-516 activity in a mouse model of Dravet syndrome, and supports further investigation of neuroactive steroids as potential anticonvulsant compounds for refractory epilepsies."

Journal