Marinus Pharmaceuticals, Inc. provided a business overview to outline the clinical status of its CNS-selective GABAA modulator, ganaxolone, and an overview of near-term value-creating milestones expected in 2017. Near-term Clinical Value Catalysts: Initiate Phase 2 study in women with postpartum depression (PPD) in the first half of 2017; Initiate Phase 2 study in patients with refractory status epilepticus (RSE) in the first half of 2017; Report top-line data from patients with orphan, genetic disorders in mid-2017; Report data from PPD patients in the second half of 2017; and Report data from RSE patients in the second half of 2017. Clinical Development Overview: Marinus is developing ganaxolone to treat adults and children suffering from acute and chronic neuropsychiatric conditions where there is a mechanistic rationale for ganaxolone to provide a benefit. Ganaxolone is a one-carbon analog of a naturally occurring neurosteroid, allopregnanolone (allo), and based on pre-clinical and clinical studies conducted to date, has exhibited anxiolytic, anti-seizure and anesthetic activity by virtue of its GABAA receptor modulating properties.  Postpartum Depression (PPD): Marinus is preparing to initiate a Phase 2 double-blind, placebo-controlled, multi-center, dose-finding study to evaluate the safety, efficacy and pharmacokinetics of ganaxolone in women with PPD.  Marinus plans to evaluate dosing regimens utilizing its intravenous (IV) and oral dose forms, which will inform dosing for the pivotal studies in PPD. PPD is a mood disorder that affects about 15% of women within the first year of childbirth. Common symptoms include feelings of extreme sadness, hopelessness, suicidal ideation, anxiety, and fatigue. PPD is thought to be linked to the rapid fluctuations in the levels of reproductive hormones and allo after childbirth. Treatment with ganaxolone may provide benefit to women suffering from PPD. Marinus plans to initiate this Phase 2 clinical trial in women with PPD in the first half of 2017 and expects to announce data from the initial patient cohort(s) in the second half of 2017. Refractory Status Epilepticus (RSE): Marinus is preparing to commence a Phase 2 open-label, multi-center study to evaluate the safety, tolerability, efficacy, and pharmacokinetics of ganaxolone IV as adjunctive therapy in patients with various stages of status epilepticus (SE) who have failed first-line benzodiazepine treatment.  SE is a life-threatening occurrence within the spectrum of epileptic disorders and is characterized by the manifestation of continuous or intermittent seizures lasting more than five minutes in duration without full recovery. If SE is not treated immediately, prolonged seizure activity can result in permanent neuronal damage and contributes to the high rates of morbidity and mortality.  In RSE, certain synaptic GABAA receptors are internalized, thereby making them unavailable and limiting the effectiveness of drugs that target these receptors, such as benzodiazepines. Ganaxolone modulates both synaptic and extrasynaptic GABAA receptors, allowing a therapeutic pathway for situations where synaptic GABAA receptors are unavailable. Marinus plans to initiate this Phase 2 clinical trial in patients with RSE in the first half of 2017 and expects to announce data in the second half of 2017.  The study results will be used to inform dosing for the pivotal program in RSE. Orphan, Genetic Disorders: Ganaxolone is currently being evaluated in an ongoing Phase 2 open-label exploratory study as a treatment for orphan, genetic epilepsies.  In addition to seizures, children with genetic epilepsies typically suffer from cognitive impairment and behavioral disorders. In clinical studies, ganaxolone has shown both anti-seizure as well as anti-anxiety activity.  This dual benefit has the potential to address both the seizures and behavioral co-morbidities associated with a variety of orphan, genetic disorders. The ongoing multi-cohort study is designed to enroll up to 10 patients each with CDKL5 disorder, Lennox Gastaut Syndrome (LGS) and PCDH19 pediatric epilepsy. Marinus completed the PCDH19 cohort in the study and previously announced that ganaxolone reduced seizure frequency from baseline in the majority of patients enrolled in the study and was generally safe and well tolerated.  The study is actively recruiting CDKL5 and LGS patients. Marinus expects to complete enrollment and report top-line data from these cohorts in mid-2017. The results from the CDKL5 and LGS cohorts will be evaluated alongside the completed PCDH19 cohort and Fragile X Syndrome (FXS) Phase 2 study. Based on clinical data, anticipated regulatory pathway, program risk assessments and commercial considerations, Marinus plans to prioritize one or more indications for advancement to later-stage clinical trials. Marinus anticipates announcing its strategy for orphan, genetic disorders in the second half of 2017. Expanded Profiling of Ganaxolone: Through continued pre-clinical and clinical development, Marinus has identified additional key properties in the profile of ganaxolone. Synergistic Activity with Benzodiazepines: In a preclinical benzodiazepine refractory rat model of SE, the combination of ganaxolone and diazepam administered intravenously produced a synergistic effect in blocking pilocarpine-induced seizures in rats.  Ganaxolone and diazepam plasma levels were identical when measured both alone and in combination, indicating that neither drug affected the pharmacokinetic disposition of the other.  These data may have clinical implications on the treatment and dosing of ganaxolone in patients with SE who are or have been treated with benzodiazepines. Sedative and Anesthetic Activity of Ganaxolone IV: In a Phase 1 clinical study evaluating the safety, pharmacokinetics, and pharmacodynamics activity of ganaxolone IV, a Bispectral Index Score (BIS) was used to measure the level of consciousness by algorithmic analysis of the patient’s electroencephalogram.  The data showed that healthy volunteers who received a high bolus dose of ganaxolone IV achieved a sedative and anesthetic BIS range of 40-60.  These additional properties of ganaxolone IV may be further explored clinically in patients with SE. Anxiolytic Activity of Ganaxolone: The anxiolytic effects of ganaxolone were seen in a Phase 2 placebo-controlled study in children with FXS who had high anxiety at baseline.  In the study, anxious FXS patients (identified as those patients with a Pediatric Anxiety Rating Score =13) treated with ganaxolone showed improvements in anxiety and hyperactivity across multiple measurement scales. These anxiety benefits could be instrumental, not only in the continued development of ganaxolone for FXS patients, but for other indications that Marinus is pursuing where anxiety is a common feature of the disease, such as PPD and orphan, genetic epilepsies.