Ganaxolone for use in treatment of status epilepticus

Abstract

To provide ganaxolone for use in treatment of status epilepticus.SOLUTION: The invention relates to a method for treating status epilepticus comprising administering to a subject in need thereof an intravenous bolus of ganaxolone and a continuous intravenous infusion of a neurosteroid. The disclosure relates to a method for effectively treating SE that provides rapid suppression of SE, sustained efficacy (i.e., prevents SE-relapse and provides for continued suppression of SE), and improved safety. The method disclosed herein comprises administering to a subject in need thereof a therapeutically effective amount of a neurosteroid, preferably ganaxolone as an intravenous bolus and a continuous intravenous infusion.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 882,648, filed August 5, 2019, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] 1. Background Status epilepticus ("SE") is a fatal neurological emergency with significant morbidity and mortality (Betjemann and Lowenstein, (2015) The Lancet Neurology, 14(6):615-624). In fact, it is the second most common neurological emergency in the United States with approximately 150,000 cases and 55,000 associated deaths per year (Moghasddasi et al., (2015) J. Epilepsy Res., 5(1):13-16).

[0003] SE is characterized by sustained seizure activity, usually lasting more than 5 minutes, or recurrent seizures without recovery of consciousness between seizures. (Ibid.) SE requires aggressive treatment to terminate the seizures and prevent neuronal damage, including neuronal cell death. The longer SE lasts, the more difficult it becomes to control, and prolonged SE and refractoriness to treatment are associated with poor prognosis (Cherian & Thomas (2009), Ann. Indian. Acad. Neurol., 12(3):140-153). The goals of treatment are rapid seizure cessation, maintenance of seizure control, avoidance of transition to anesthetic drugs, and avoidance of further medical complications. (Ibid.)

[0004] Current treatment protocols for SE follow a three-tiered approach (Shorvon and Ferlisi (2011), Brain, 134(10)-2802-2818). First-line treatment is usually with benzodiazepines (e.g., diazepam, lorazepam, and midazolam) (Trinka and Kalviainen (2017), Seizure, 44:65-73; Glauser et al., (2016), Epilepsy Curr. 26(1):48-61). However, benzodiazepines are ineffective in approximately 35%-45% of cases and are associated with cardiovascular and respiratory side effects. (Ibid.). If SE persists despite benzodiazepine treatment, other antiseizure medications (e.g., fosphenytoin, levetiracetam, and valproic acid) are administered intravenously (IV) as second-line treatment. (Ibid.). When SE continues despite first-line and second-line treatments (also called refractory SE), intravenous anesthetics (e.g., thiopental, propofol, and midazolam) are used as tertiary treatments. (ibid.). Approximately 31%-41% of patients with SE develop refractory SE. Use of tertiary agents can result in iatrogenic coma, necessitating airway management with intubation and mechanical ventilation. Furthermore, use of anesthetics is associated with high morbidity and a mortality rate of approximately 35%. When SE continues despite induction of iatrogenic coma, this is called ultra-refractory SE. An overview of available therapies for SE, including side effects, is provided in Table 1. [Table 1] At best, current treatments effectively control only about 50% of patients with mild to severe SE. In severe SE, the response rate drops even further (Shorvon and Ferlisi, (2011), Brain, 134(1): 2802-2818). Furthermore, several recent attempts to develop novel therapeutics have failed. For example, brexanolone (SAGE-547), a synthetic form of endogenous allopregnanolone, failed to demonstrate efficacy over placebo in a randomized, double-blind, placebo-controlled trial for the treatment of highly refractory SE (Sage Pharmaceuticals press release published September 12, 2017, www.businesswire.com / news / home / 20170912005509 / en / Sage-Therapeutics-Reports-Top-Line-Results-Phase-3). Thus, there is a significant unmet need for effective therapies to treat SE. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Betjemann and Lowenstein,(2015)The Lancet Neurology,14(6):615-624 [Non-Patent Document 2] Moghasddasi et al.,(2015)J.Epilepsy Res.,5(1):13-16 [Non-Patent Document 3] Cherian & Thomas(2009),Ann.Indian.Acad.Neurol.,12(3):140-153 [Non-Patent Document 4] Shorvon and Ferlisi(2011),Brain,134(10)-2802-2818 [Non-Patent Document 5] Trinka and Kalviainen(2017),Seizure,44:65-73 [Non-Patent Document 6] Glauser et al.,(2016),Epilepsy Curr.26(1):48-61 [Non-Patent Document 7] Sage Pharmaceuticals press release published September 12, 2017, www.businesswire.com / news / home / 20170912005509 / en / Sage-Therapeutics-Reports-Top-Line-Results-Phase-3 Summary of the Invention

[0006] 2. Overview The present disclosure relates to a method for treating SE. SE is a highly complex condition to treat, and the development of new therapeutic agents for SE is extremely challenging and largely unsuccessful. As noted above, conventional therapies are ineffective in over 50% of patients. Attempts to develop new therapeutic agents for SE have largely failed. For example, brexanolone (i.e., allopregnanolone) failed to demonstrate efficacy over placebo in a double-blind, placebo-controlled Phase 3 study in highly refractory SE patients.

[0007] As further described and exemplified herein, the inventors believed that ganaxolone could provide an effective therapy for SE. However, given the complexity and difficulty of SE treatment and the lack of efficacy in previous studies, the inventors predicted that effective treatment of SE would require at least 4 days of high drug exposure followed by at least about 1 day of maintenance doses. Contrary to such predictions, the inventors unexpectedly discovered that administering ganaxolone as a bolus, plus continuous infusion to maintain ganaxolone plasma concentrations much lower than expected serum levels for at least about 8 hours (or in some subjects, at least about 4 hours), resulted in rapid and sustained suppression of SE. As further described and exemplified herein, sustained suppression of SE was achieved in the patients tested when continuous infusion maintained ganaxolone plasma concentrations of about 500 ng / ml or greater for a target concentration period of at least about 8 hours or at least about 12 hours (although 4 hours may be sufficient for some patients).

[0008] Thus, the present disclosure relates to an effective method of treating SE that provides rapid suppression of SE, sustained efficacy (i.e., preventing recurrence of SE and providing ongoing suppression of SE), and improved safety.

[0009] The methods disclosed herein include administering to a subject in need thereof a therapeutically effective amount of a neurosteroid, preferably ganaxolone, as an intravenous bolus and a continuous intravenous infusion. The intravenous bolus is administered in an amount that suppresses SE. Suppression of SE reduces seizure burden. Typically, a ganaxolone plasma concentration of about 500ng / ml to about 1000ng / ml is sufficient to suppress SE. For example, to achieve a ganaxolone plasma concentration level of 500ng / ml to about 1000ng / ml, about 5mg to about 40mg of ganaxolone infusion may be injected into the subject at the start of the intravenous bolus. Preferably, about 30mg of ganaxolone is injected into the subject at the start of or during the intravenous bolus. The intravenous bolus may be administered (i.e., infused) into the subject for about 1 minute to about 5 minutes.

[0010] A continuous intravenous infusion of ganaxolone is administered for the target concentration period in an amount sufficient to provide continuous suppression of SE, which in clinical terms is a reduction in seizure burden.

[0011] A continuous intravenous infusion of ganaxolone is initiated perioperatively using an intravenous bolus. The continuous intravenous infusion is generally administered simultaneously with the administration of the intravenous bolus. In some cases, the continuous intravenous infusion can be initiated before or after the intravenous bolus.

[0012] Continuous infusion achieves continuous suppression of SE when it maintains ganaxolone plasma concentration of about 500ng / ml or more throughout the target concentration period. Continuous infusion is administered throughout the treatment period, including the target concentration period, during which the subject's ganaxolone plasma concentration is maintained above the target concentration, such as about 425ng / ml, about 45ng / ml, about 475ng / ml, or preferably about 500ng / ml. However, it is recognized that a plasma concentration of about 425ng / ml, at least about 450ng / ml, or at least about 475ng / ml, or preferably at least about 500ng / ml, is sufficient to maintain continuous suppression of SE. In general, it is desirable for the ganaxolone plasma concentration not to exceed about 1000ng / ml. This is because ganaxolone plasma concentration exceeding 1000ng / ml may induce loss of consciousness, which is not a desired effect of treatment. The target concentration period is usually at least about 8 hours or at least 12 hours. In some cases, it is possible that the target concentration may be at least about 4 hours. Typically, the amount of ganaxolone administered to a subject per hour by continuous intravenous infusion during the target concentration period can be increased or decreased to maintain continued suppression of SE, but maintaining a ganaxolone plasma concentration of at least about 500 ng / ml is sufficient.

[0013] The amount of ganaxolone administered to the subject per hour by continuous intravenous infusion can be decreased over a period of about 24 hours from the start of the continuous intravenous infusion. The amount of ganaxolone administered to the subject per hour by continuous intravenous infusion can be decreased about 2 hours and / or about 10 to about 14 hours after the start of the continuous intravenous infusion. Preferably, the amount of ganaxolone administered to the subject per hour by continuous intravenous infusion is decreased about 2 hours after the start of the continuous intravenous infusion and further about 10 to about 14 hours after the start of the continuous intravenous infusion. The amount of ganaxolone administered to the subject per hour by continuous intravenous infusion can be reduced by about 50% about 2 hours after the start of the continuous intravenous infusion, compared to the hourly dose at the start of the continuous intravenous infusion. The amount of ganaxolone administered to the subject per hour by continuous intravenous infusion can be reduced by about 75% about 10 to about 14 hours after the start of the continuous intravenous infusion, compared to the hourly dose at the start of the continuous intravenous infusion. The amount of ganaxolone administered to the subject per hour by continuous intravenous infusion can be reduced by about 50% about 2 hours after the start of the continuous intravenous infusion, compared to the hourly dose at the start of the continuous intravenous infusion, and further reduced by about 75% about 10 to about 14 hours after the start of the continuous intravenous infusion, compared to the hourly dose at the start of the continuous intravenous infusion.

[0014] The amount of ganaxolone administered to a subject per hour by continuous intravenous infusion can be reduced by about 50% 2 to 12 hours after initiation of the infusion, compared to the rate achieved during the target concentration period. For an additional 12 to 24 hours after initiation of the continuous intravenous infusion, the continuous intravenous infusion can again be reduced by half, or 75%, of the infusion rate during the target concentration period.

[0015] About 20 mg of ganaxolone per hour to about 80 mg of ganaxolone per hour can be infused to the subject during the continuous infusion treatment period. Generally, at the start of the continuous intravenous infusion, about 80 mg of ganaxolone per hour can be infused to the subject. After about another 2 hours, during the treatment period, the amount of ganaxolone can be reduced to about 40 mg of ganaxolone per hour and then to about 20 mg of ganaxolone per hour. In some cases, about 80 mg of ganaxolone can be administered to the subject by continuous intravenous infusion from the start and for about 2 hours thereafter, and about 40 mg of ganaxolone can be administered to the subject by continuous intravenous infusion from about 2 hours after the start for about 2 hours to about 10 hours thereafter, and about 20 mg of ganaxolone can be administered to the subject by continuous intravenous infusion from about 12 hours after the start for about 12 hours to about 24 hours thereafter.

[0016] The amount of ganaxolone administered to a subject by continuous intravenous infusion can be increased about 24 hours after the start of intravenous infusion.Generally, the amount of ganaxolone administered per hour by continuous intravenous infusion can be increased by up to about 45% compared to the hourly dose starting about 24 hours after the start of continuous intravenous infusion.For example, the amount of ganaxolone infused to a subject by continuous intravenous infusion can be increased up to about 45 mg of ganaxolone per hour, but preferably does not exceed 45 mg starting about 24 hours after the start and for about 12 hours thereafter.The amount of ganaxolone can be increased up to 12 hours.

[0017] The treatment period of the continuous intravenous infusion can be for a period of about 36 hours, about 48 hours, about 72 hours, or about 96 hours after the start of the intravenous infusion. Preferably, the treatment period is for a period of at least about 8 hours to about 36 hours after the start of the continuous intravenous infusion.

[0018] The continuous intravenous infusion is usually followed by a tapering period, which generally begins about 36 hours after the start of the continuous intravenous infusion. During the tapering period, the continuous intravenous infusion of ganaxolone is systematically reduced, usually by decreasing the amount of ganaxolone administered to the subject by about one-third every four hours until the subject no longer requires ganaxolone. The methods disclosed herein are suitable for treating any form of SE, such as generalized convulsive SE, non-convulsive SE, refractory SE, and highly refractory SE. The methods are particularly useful for treating refractory SE. The methods can also be used to treat subjects who have failed first-line (e.g., benzodiazepines), second-line (e.g., fosphenytoin, valproic acid, or levetiracetam), and / or third-line (thiopental, midazolam, pentobarbital, or propofol) treatments. During treatment, the subject's ganaxolone plasma concentration can be monitored, and EEG can be used to monitor seizure activity.

[0019] The ganaxolone formulations used in the methods disclosed herein preferably contain sulfobutylether-β-cyclodextrin.

[0020] In summary, an exemplary method of treating SE includes administering an intravenous bolus dose of about 5 to about 40 mg, preferably about 30 mg, of ganaxolone to a subject over about 1 to about 5 minutes, usually about 3 minutes, to achieve an increase in ganaxolone plasma concentration to about 800 ng / ml to about 1000 ng / ml over a short period of time. The intravenous bolus suppresses SE. A continuous intravenous infusion is administered to the subject either simultaneously with the intravenous bolus or after the intravenous bolus. The continuous intravenous infusion provides continued suppression of SE. Continued suppression of SE is achieved when the continuous intravenous infusion maintains a ganaxolone plasma concentration of about 500 ng / ml or greater over the target concentration period. The target concentration period is typically at least about 8 hours or at least about 12 hours in duration. However, in some cases, at least about 4 hours may be a sufficient target concentration period. During the target concentration period, the infusion rate of ganaxolone can be increased and / or decreased to maintain the desired plasma ganaxolone concentration. The amount of ganaxolone administered to the subject per hour can typically be reduced by about 50% about 2 hours after the start of the continuous intravenous infusion, compared to the hourly dose at the start of the continuous infusion. Additionally, the amount of ganaxolone administered to the subject per hour can be reduced by 75% compared to the dose at the start of the continuous intravenous infusion. Typically, the continuous intravenous infusion is followed by a tapering period.

[0021] Methods disclosed herein include administering a therapeutically effective amount of ganaxolone to reduce or eliminate seizure activity and / or reduce or eliminate convulsions and / or completely suppress status epilepticus (i.e., suppress EEG seizure activity and convulsions) in a subject. In certain embodiments, a therapeutically effective amount of ganaxolone to reduce or eliminate seizure activity and / or completely suppress status epilepticus in a subject is an amount that produces and maintains a ganaxolone plasma concentration of about 50 ng / ml to about 3500 ng / ml in the subject for a period of time sufficient to reduce or eliminate seizure activity and / or reduce or eliminate convulsions and / or completely suppress status epilepticus. In certain embodiments, (i) a bolus of ganaxolone (e.g., about 5 mg to about 100 mg, about 25 mg to about 60 mg, or about 25 mg to about 30 mg) is administered intravenously over about 1 to about 5 minutes; (ii) a continuous intravenous infusion of ganaxolone at a rate of about 5 mg / hour to about 130 mg / hour (e.g., about 5 mg / hour to about 85 mg / hour) for about 8 hours to about 120 hours (e.g., about 10 hours to about 96 hours), which continuous intravenous infusion begins simultaneously with or shortly (e.g., within about 30 minutes) after the bolus injection; and (iii) the intravenous infusion rate is reduced for about 12 hours to about 24 hours (e.g., over 12 hours, about 10 hours, about 14 hours, about 16 hours, about 18 hours, or about 20 hours) before the continuous infusion is stopped, resulting in a plasma concentration of about 50 mg / ml to about 3500 ng / ml.In certain embodiments, (i) a bolus of ganaxolone (e.g., about 5 mg to about 100 mg, about 25 mg to about 60 mg, or about 25 mg to about 30 mg) is administered intravenously over about 1 to about 5 minutes; (ii) a continuous intravenous infusion of ganaxolone at a rate of about 5 mg / hour to about 130 mg / hour (e.g., about 5 mg / hour to about 85 mg / hour) for about 24 hours to about 120 hours (e.g., about 48 hours to about 96 hours), which continuous intravenous infusion begins simultaneously with or shortly (e.g., within about 30 minutes) after the bolus injection; and (iii) the intravenous infusion rate is reduced over about 10 hours to about 24 hours (e.g., over 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, or about 20 hours) before the continuous infusion is stopped, resulting in a plasma concentration of about 50 mg / ml to about 3500 ng / ml. In some embodiments, a portion of the therapeutically effective dose (e.g., about 5 mg to about 100 mg, about 10 mg to about 90 mg, about 15 mg to about 80 mg, about 20 mg to about 70 mg, about 25 mg to about 60 mg, etc.) is administered by bolus intravenous injection, and the remainder of the therapeutically effective dose is administered by continuous intravenous infusion. In some embodiments, for a subject weighing 40 kg or more, about 5 mg to about 100 mg (e.g., about 10 mg to about 90 mg, about 15 mg to about 80 mg, about 20 mg to about 70 mg, about 25 mg to about 60 mg, etc.) of ganaxolone is administered by bolus intravenous injection, and the remainder of the dose may be administered by intravenous infusion at a rate of about 10 mg / hour, 15 mg / hour, 20 mg / hour, or greater than 25 mg / hour for about 1 hour to about 120 hours. In some embodiments, the continuous intravenous infusion is for about 1 hour to about 120 hours at a rate of about 5 mg / hour to about 130 mg / hour, about 5 mg / hour to about 120 mg / hour, about 5 mg / hour to about 110 mg / hour, about 5 mg / hour to about 100 mg / hour, about 5 mg / hour to about 90 mg / hour, or about 5 mg / hour to about 85 mg / hour. In some embodiments, the continuous intravenous infusion is for at least 1 hour at a rate of about 50 mg / hour to about 130 mg / hour.In some embodiments, a therapeutically effective dose, or a portion thereof, is administered intravenously at a rate of about 40 mg / hr to about 140 mg / hr for about 1 hour to about 4 hours, then at a rate of about 20 mg / hr to about 70 mg / hr for about 1 hour to about 4 hours, then at a rate of about 10 mg / hr to about 35 mg / hr for about 1 hour to about 4 hours, then at a rate of about 10 mg / hr to about 30 mg / hr for about 1 hour to about 96 hours, and then at a rate of about 15 mg / hr to about 35 mg / hr for about 1 hour to about 96 hours. In some embodiments, after about 1 hour to about 96 hours of administration at a rate of about 15 mg / hr to about 35 mg / hr, the rate is decreased by about 10% to about 50% every 1 hour to about 12 hours (e.g., the rate can be decreased by about 15% to about 30% every 4 hours to about 8 hours). In some of these embodiments, ganaxolone is administered at about 18 mg / hour, about 20 mg / hour, about 22 mg / hour, about 25 mg / hour, about 28 mg / hour, about 30 mg / hour, about 35 mg / hour, about 40 mg / hour, about 45 mg / hour, about 50 mg / hour, about 60 mg / hour, about 65 mg / hour, or about 70 mg / hour for at least about 1 hour of administration. For subjects weighing less than 40 kg, in some embodiments, a bolus dose of about 0.07 mg / kg to about 1.43 mg / kg (e.g., about 0.125 mg / kg to about 0.4 mg / kg) is administered (over 1-5 minutes), followed by continuous infusion at a rate of about 0.8 mg / kg / hr to about 2 mg / kg / hr for about 1-3 hours, followed by continuous infusion at a rate of about 0.6 mg / kg / hr to about 1 mg / hr for about 4-8 hours, followed by continuous infusion at a rate of about 0.15 mg / kg / hr to about 0.4 mg / kg / hr for 13-19 hours. At the end of the 24 hour continuous infusion, the infusion rate may be increased to a rate of about 0.2 mg / kg / hr to about 0.6 mg / kg / hr for, e.g., 24-48 hours or 24-96 hours.

[0022] The disclosure also relates to a method of treating status epilepticus (e.g., generalized convulsive status epilepticus, nonconvulsive status epilepticus, early status epilepticus, confirmed status epilepticus, refractory status epilepticus, or super refractory status epilepticus) comprising administering a therapeutic dose of ganaxolone to a subject experiencing status epilepticus in a manner that produces a ganaxolone plasma concentration of about 50 ng / ml to about 3500 ng / ml over a period of about 24 hours to about 120 hours, with about 2 to 5 peaks in the ganaxolone plasma concentration during said 24 hours to about 120 hours. In certain embodiments, a portion of the therapeutic dose is administered by intravenous infusion at a rate of about 20 mg / hr to about 140 mg / hr for about 4 hours to about 120 hours, maintaining a ganaxolone plasma level of about 800 ng / ml to about 1600 ng / ml for about 1 hour to about 96 hours, and a portion of the dose is administered by bolus injection. For subjects weighing 40 kg or more, the bolus injection may contain, for example, about 5 mg to about 100 mg of ganaxolone, and the amount of ganaxolone delivered by intravenous infusion may be, for example, about 450 mg to about 3000 mg. In some embodiments, about 450 mg to about 1000 mg of ganaxolone is administered every 24 hours for the above 24 hours to about 120 hours. For subjects weighing less than 40 kg, a bolus injection may contain, for example, from about 0.25 mg to about 16 mg, or from about 100 mg to about 600 mg of ganaxolone may be administered by intravenous infusion every 24 hours.

[0023] The present disclosure also provides a method of treating status epilepticus (e.g., generalized convulsive status epilepticus, nonconvulsive status epilepticus, early status epilepticus, confirmed status epilepticus, refractory status epilepticus, or very refractory status epilepticus) comprising administering a therapeutically effective dose of ganaxolone, or a portion thereof, to the subject for a period of about 1 hour to about 120 hours, about 2 hours to about 100 hours, about 3 hours to about 100 hours, about 4 hours to about 100 hours, about 4 hours to about 96 hours, or intravenously (e.g., by continuous intravenous infusion) to reduce or eliminate seizure activity and / or reduce or eliminate convulsions and / or completely suppress status epilepticus in a subject experiencing status epilepticus, the intravenous infusion being at a dose of about 5 mg to about 100 mg (e.g., about 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 30 mg, 35 mg, 36 mg, 37 mg, 38 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 100 mg, 100 mg, 100 mg, 100 mg, 100 mg, 100 mg, , 32mg, 34mg, 36mg, 38mg, 40mg, 42mg, 44mg, 46mg, 48mg, 50mg, 52mg, 54mg, 56mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64 mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, In some embodiments, the bolus dose is about 5 mg to about 90 mg, about 5 mg to about 80 mg, about 5 mg to about 70 mg, about 5 mg to about 60 mg, about 5 mg to about 50 mg, about 5 mg to about 40 mg, or about 5 mg to about 30 mg.

[0024] The disclosure further relates to a method of treating a subject experiencing status epilepticus (e.g., generalized convulsive status epilepticus, nonconvulsive status epilepticus, early status epilepticus, confirmed status epilepticus, refractory status epilepticus, or super refractory status epilepticus) comprising intravenously administering about 450 mg to about 3000 mg of ganaxolone over a period of about 4 hours to about 120 hours at a rate sufficient to reduce or eliminate seizure activity and / or reduce or eliminate convulsions and / or completely suppress status epilepticus in the subject. In certain embodiments, the rate is greater than about 10 mg / hr, 15 mg / hr, 20 mg / hr, 25 mg / hr, or 30 mg / hr. In some embodiments, about 5 mg to about 100 mg of ganaxolone is administered by bolus intravenous injection and the remainder of the dose is administered by continuous intravenous infusion at a rate of greater than about 25 mg / hour over a period of about 1 hour to about 120 hours.

[0025] The present disclosure also relates to a method of treating status epilepticus in a subject (e.g., generalized convulsive status epilepticus, nonconvulsive status epilepticus, incipient status epilepticus, confirmed status epilepticus, refractory status epilepticus, or super refractory status epilepticus), comprising administering to the subject about 1 gram to about 100 grams (e.g., about 20 grams to about 70 grams, about 25 grams to about 65 grams, about 30 grams to about 60 grams, about 35 grams to about 55 grams, etc.) of sulfobutylether-β-cyclodextrin per day in a ganaxolone-containing formulation.

[0026] The disclosure further relates to a method of treating a subject experiencing status epilepticus (e.g., generalized convulsive status epilepticus, nonconvulsive status epilepticus, early status epilepticus, confirmed status epilepticus, refractory status epilepticus, or super refractory status epilepticus) comprising intravenously administering to the subject a formulation containing ganaxolone and sulfobutylether-β-cyclodextrin in a weight ratio of about 1:50 to about 1:75, administering about 450 mg to about 1000 mg of ganaxolone and about 1 gram to about 100 grams of sulfobutylether-β-cyclodextrin per day. In some embodiments, the weight ratio is about 1:60, about 1:65, or about 1:70.

[0027] The disclosure further relates to a method of treating a subject experiencing status epilepticus (e.g., generalized convulsive status epilepticus, nonconvulsive status epilepticus, incipient status epilepticus, confirmed status epilepticus, refractory status epilepticus, or super refractory status epilepticus) comprising intravenously administering to the subject a formulation containing ganaxolone and sulfobutylether-β-cyclodextrin in a weight ratio of about 1:50 to about 1:75 at a rate and duration sufficient to produce a ganaxolone plasma concentration of about 50 ng / ml to about 3500 ng / ml over a period of about 24 hours to about 120 hours. In some of these embodiments, the weight ratio of ganaxolone to sulfobutylether-β-cyclodextrin is about 1:51, about 1:52, about 1:53, about 1:54, about 1:55, about 1:56, about 1:57, about 1:58, about 1:59, about 1:60, about 1:61, about 1:62, about 1:63, about 1:64, about 1:65, about 1:66, about 1:67, about 1:68, about 1:69, about 1:70, about 1:71, or about 1:72.

[0028] In an additional aspect, a method of treating status epilepticus (e.g., generalized convulsive status epilepticus, nonconvulsive status epilepticus, incipient status epilepticus, confirmed status epilepticus, refractory status epilepticus, or super refractory status epilepticus) comprises administering ganaxolone by intravenous infusion at a rate that varies from about 10 mg / hour to about 150 mg / hour, from about 15 mg / hour to about 150 mg / hour, or from about 20 mg / hour to about 150 mg / hour during administration. In some embodiments, a therapeutically effective dose, or a portion thereof, is parenterally administered at a rate of about 40 mg / hr to about 140 mg / hr for about 1 hour to about 4 hours, then at a rate of about 20 mg / hr to about 70 mg / hr for about 1 hour to about 4 hours, then at a rate of about 10 mg / hr to about 35 mg / hr for about 1 hour to about 4 hours, then at a rate of about 10 mg / hr to about 30 mg / hr for about 1 hour to about 96 hours, and then at a rate of about 15 mg / hr to about 35 mg / hr for about 1 hour to about 96 hours. In some embodiments, after about 1 hour to about 96 hours of administration at a rate of about 15 mg / hr to about 35 mg / hr, the rate is decreased by about 10% to about 50% every 1 hour to about 12 hours (e.g., the rate can be decreased by about 15% to about 30% every 4 hours to about 8 hours). In some of these embodiments, ganaxolone may be administered at a rate of at least about 18 mg / hr, about 20 mg / hr, about 22 mg / hr, about 25 mg / hr, about 28 mg / hr, about 30 mg / hr, about 35 mg / hr, about 40 mg / hr, about 45 mg / hr, about 50 mg / hr, about 60 mg / hr, about 65 mg / hr, or about 70 mg / hr for at least about 1 hour of administration. In certain embodiments, a bolus dose of ganaxolone is administered intravenously before the start of the intravenous infusion. The bolus dose of ganaxolone may comprise, for example, about 5 mg to about 100 mg of ganaxolone. In certain embodiments, one or more additional bolus doses of ganaxolone are administered intravenously before, during, or after the intravenous infusion. The additional bolus dose may comprise, for example, about 5 mg to about 100 mg of ganaxolone.

[0029] In part, the disclosure also provides a method of treating status epilepticus (e.g., generalized convulsive status epilepticus, nonconvulsive status epilepticus, early status epilepticus, confirmed status epilepticus, refractory status epilepticus, or super refractory status epilepticus), comprising administering to a subject experiencing status epilepticus a medicament for a period of about 30 minutes to about 120 hours (e.g., about 1 hour, 3 hours, 5 hours, 7 hours, 9 hours, 11 hours, 13 hours, 15 hours, 17 hours, 19 hours, 21 hours, 23 hours, 25 hours, 27 hours, 29 hours, 31 hours, 33 hours, 35 hours, 37 hours, 39 hours, 40 hours, 42 hours, 44 hours, 46 hours, 48 ​​hours, 49 hours, 50 hours, 51 hours, 52 hours, 53 hours, 54 hours, 55 hours, 56 hours, 57 hours, 58 hours, 59 hours, 60 hours, 61 hours, 62 hours, 63 hours, 64 hours, 65 hours, 66 hours, 67 hours, 68 hours, 69 hours, 70 hours, 71 hours, 72 hours, 73 hours, 74 hours, 75 hours, 76 hours, 77 hours, 78 hours, 79 hours, 80 hours, 81 hours, 82 hours, 83 hours, 84 hours, 85 hours, 86 hours, 87 hours, 88 hours, 89 hours, 90 hours, 91 hours, 92 hours, 93 hours, 94 hours, 95 hours, 96 hours, 97 hours, 98 hours, 99 hours, 100 hours, 101 hours, 10 , 41 hours, 43 hours, 45 hours, 47 hours, 49 hours, 51 hours, 53 hours, 55 hours, 57 hours, 59 hours, 61 hours, 63 hours, 65 hours, 67 hours, 69 hours, 71 hours, 73 hours, 75 hours, 77 hours, 79 hours, 81 hours, 83 hours, 85 hours, 87 hours, 89 hours, 91 hours, 93 hours, or 95 hours), 0ng / ml, about 175ng / ml to about 2250ng / ml, about 200ng / ml to about 2200ng / ml, about 250ng / ml to about 2150ng / ml, about 300ng / ml to about 2100ng / ml, about 350ng / ml to about 2100ng / ml, about 400ng / ml to about 2100ng / ml, or about 450ng / ml to about 2100ng / ml, about 500ng / ml to about 2000ng / ml, about 500ng / ml to about 1800ng / ml, about 500ng / ml to about 1600ng / ml, about 500ng / ml to about 1500ng / ml, about 600ng / ml and for about 2 hours to about 120 hours, about 2 hours to about 100 hours, about 3 hours to about 100 hours, about 4 hours to about 100 hours, about 4 hours to about 96 hours, about 5 hours to about 96 hours, about 6 hours to about 96 hours, about 6 hours to about 90 hours, or about 6 hours to about 88 hours in an amount and at a rate sufficient to produce a ganaxolone plasma concentration of about 600 ng / ml to about 1300 ng / ml, about 650 ng / ml to about 1200 ng / ml, about 700 ng / ml to about 1200 ng / ml, about 750 ng / ml to about 1100 ng / ml, or about 800 ng / ml to about 1100 ng / ml.or for a period of about 10 hours to about 72 hours.

[0030] In part, the disclosure also provides a method of treating status epilepticus (e.g., generalized convulsive status epilepticus, non-convulsive status epilepticus, early status epilepticus, confirmed status epilepticus, refractory status epilepticus, or super refractory status epilepticus) in a subject, comprising administering to the subject a concentration of from about 50 ng / ml to about 3500 ng / ml, from about 75 ng / ml to about 3250 ng / ml, from about 100 ng / ml to about 3000 ng / ml, from about 125 ng / ml to about 2750 ng / ml, from about 150 ng / ml to about 2500 ng / ml, from about 175 ng / ml to about 2250 ng / ml, or from about 260 ng / ml to about 3000 ng / ml within 5 minutes of administration. administering intravenously a bolus dose of ganaxolone in an amount sufficient to achieve a maximum plasma ganaxolone concentration (Cmax) of about 200 ng / ml, about 250 ng / ml to about 2150 ng / ml, about 300 ng / ml to about 2100 ng / ml, about 350 ng / ml to about 2100 ng / ml, about 400 ng / ml to about 2100 ng / ml, about 450 ng / ml to about 2100 ng / ml, or about 500 ng / ml to about 2000 ng / ml, and administering a bolus dose of ganaxolone in an amount sufficient to achieve a maximum plasma ganaxolone concentration (Cmax) of about 200 ng / ml to about 2200 ng / ml, about 250 ng / ml to about 2150 ng / ml, about 300 ng / ml to about 2100 ng / ml, about 350 ng / ml to about 2100 ng / ml, about 400 ng / ml to about 2100 ng / ml, about 450 ng / ml to about 2100 ng / ml, or about 500 ng / ml to about 2000 ng / ml, and about 45 minutes, about 1 second to about 30 minutes, about 1 second to about 15 minutes, about 1 second to about 10 minutes, about 1 second to about 5 minutes, or about 2 seconds to about 3 minutes), about 1 hour to about 96 hours, about 50ng / ml to about 3500ng / ml, about 75ng / ml to about 3250ng / ml, about 100ng / ml to about 3000ng / ml, about 125ng / ml to about 2750ng / ml, about 150ng / ml to about 2500ng / ml, about 175ng / ml to about 2250ng / ml, about 200ng / ml to about 2200ng / ml, about 250ng / ml to about 2150ng / ml, about 300ng / ml to about 21 2 to 120 hours, about 2 to 100 hours, in an amount and at a rate sufficient to maintain a ganaxolone plasma concentration of about 00 ng / ml, about 350 ng / ml to about 2100 ng / ml, about 400 ng / ml to about 2100 ng / ml, about 450 ng / ml to about 2100 ng / ml, about 500 ng / ml to about 1800 ng / ml, about 600 ng / ml to about 1700 ng / ml, about 650 ng / ml to about 1600 ng / ml, about 700 ng / ml to about 1500 ng / ml, about 750 ng / ml to about 1400 ng / ml, or about 800 ng / ml to about 1300 ng / ml for about 2 hours to about 120 hours, about 2 hours to about 100 hours,and administering ganaxolone by continuous intravenous infusion for a period of about 3 hours to about 100 hours, about 4 hours to about 100 hours, or about 4 hours to about 96 hours (e.g., about 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 26 hours, 28 hours, 30 hours, 32 hours, 34 hours, 36 hours, 38 hours, 40 hours, 42 hours, 44 hours, 46 hours, 48 ​​hours, 50 hours, 52 hours, 54 hours, 56 hours, 58 hours, 60 hours, 62 hours, 64 hours, 66 hours, 68 hours, 70 hours, 72 hours, 74 hours, 76 hours, 78 hours, 80 hours, 82 hours, 84 hours, 86 hours, 88 hours, 90 hours, 92 hours, or 94 hours). For a subject weighing 40 kg or more, the total daily dose of ganaxolone can be, for example, about 450 mg to about 2000 mg, about 500 mg to about 1900 mg, about 500 mg to about 1800 mg, about 550 mg to about 1600 mg, about 550 mg to about 1400 mg, about 550 mg to about 1200 mg, or about 600 mg to about 1100 mg, and a bolus dose can include, for example, about 5 mg to about 100 mg.

[0031] In part, the disclosure further provides a method of treating status epilepticus in a subject (e.g., generalized convulsive status epilepticus, non-convulsive status epilepticus, early status epilepticus, confirmed status epilepticus, refractory status epilepticus, or ultra-refractory status epilepticus), comprising administering to the subject a concentration of from about 50 ng / ml to about 3500 ng / ml, from about 75 ng / ml to about 3250 ng / ml, from about 100 ng / ml to about 3000 ng / ml, from about 125 ng / ml to about 2750 ng / ml, from about 150 ng / ml to about 2500 ng / ml, from about 17 ng / ml to about 3000 ng / ml, from about 20 ng / ml to about 3500 ng / ml, from about 25 ng / ml to about 3000 ng / ml, from about 25 ng / ml to about 3500 ng / ml, from about 20 ng / ml to about 3000 ng / ml, from about 25 ng / ml to about 3500 ng / ml, from about 25 ... administering intravenously a bolus dose of ganaxolone in an amount sufficient to achieve a maximum plasma ganaxolone concentration (Cmax) of 5 ng / ml to about 2250 ng / ml, about 200 ng / ml to about 2200 ng / ml, about 250 ng / ml to about 2150 ng / ml, about 300 ng / ml to about 2100 ng / ml, about 350 ng / ml to about 2100 ng / ml, about 400 ng / ml to about 2100 ng / ml, about 450 ng / ml to about 2100 ng / ml, or about 500 ng / ml to about 1500 ng / ml; and about 1 second to about 1 hour, about 1 second to about 45 minutes, about 1 second to about 30 minutes, about 1 second to about 15 minutes, about 1 second to about 10 minutes, about 1 second to about 5 minutes, or about 2 seconds to about 3 minutes after the administration), more than 1 hour (e.g., about 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 26 hours, 28 hours, 30 hours, 32 hours, 34 hours, 36 hours, 38 hours, 40 hours, 42 hours, 44 hours, 46 hours, 48 ​​hours, 50 hours, 52 hours, 54 hours, 56 hours, 58 hours, 60 hours, 62 hours, 64 hours, 2 hours to about 120 hours, about 2 hours to about 100 hours, about 3 hours to about 100 hours, about 4 hours to about 100 hours, about 4 hours to about 96 hours, about 5 hours to about 96 hours, about 6 hours to about 96 hours, about 6 hours to about 90 hours, about 6 hours to about 88 hours, etc.or administering ganaxolone intravenously by intravenous infusion for a period of about 10 to 72 hours.

[0032] In part, the disclosure also relates to a method of treating status epilepticus in a subject (e.g., generalized convulsive status epilepticus, nonconvulsive status epilepticus, incipient status epilepticus, confirmed status epilepticus, refractory status epilepticus, or super refractory status epilepticus), comprising parenterally administering (e.g., by intravenous (IV) infusion) about 400 mg to about 1500 mg of ganaxolone for at least one day to a subject experiencing status epilepticus. In certain embodiments, a portion of the daily dose is administered by bolus injection and the remainder of the dose is administered by continuous infusion.

[0033] Additionally, the disclosure provides a method of treating status epilepticus (e.g., generalized convulsive status epilepticus, nonconvulsive status epilepticus, early status epilepticus, confirmed status epilepticus, refractory status epilepticus, or super refractory status epilepticus) in a subject, comprising intravenously administering about 700 mg to about 1200 mg of ganaxolone, wherein the administration provides a period of at least 1 hour (e.g., 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, 48 ​​hours, 49 hours, 50 hours, 51 hours, 52 hours, 53 hours, 54 hours, 55 hours, 56 hours, 57 hours, 58 hours, 59 hours, 60 hours, 61 hours, 62 hours, 63 hours, 64 hours, 65 hours, 66 hours, 67 hours, 68 hours, 69 hours, 70 hours, 71 hours, 72 hours, 73 hours, 74 hours, 75 hours, 76 hours, 77 hours, 78 hours, 79 hours, for about 50ng / ml to about 3500ng / ml, about 75ng / ml to about 3250ng / ml, about 100ng / ml to about 3000ng / ml, about 125ng / ml to about 2750ng / ml, about 150ng / ml to about 2500ng / ml, about 175ng / ml to about 2250ng / ml, about 200ng / ml to about 2200ng / ml, about 250ng / ml to about 2150ng / ml, about 300ng / ml to about 2100ng / ml, about 350ng / ml to about 2100ng / ml, about 400 ng / ml~about 2100ng / ml, about 450ng / ml~about 2100ng / ml, about 500ng / ml~about 1400ng / ml, about 500ng / ml~about 1300ng / ml, about 500ng / ml~about 1200ng / ml the method of administering a portion of the daily dose by bolus intravenous injection and the remaining dose by continuous intravenous infusion, wherein the plasma levels of ganaxolone are about 600 ng / ml to about 1200 ng / ml, about 600 ng / ml to about 1100 ng / ml, about 650 ng / ml to about 1100 ng / ml, about 700 ng / ml to about 1100 ng / ml, about 750 ng / ml to about 1100 ng / ml, or about 800 ng / ml to about 1100 ng / ml,

[0034] The disclosure also relates to a method of treating status epilepticus in a subject (e.g., generalized convulsive status epilepticus, nonconvulsive status epilepticus, early status epilepticus, confirmed status epilepticus, refractory status epilepticus, or super refractory status epilepticus) comprising administering about 500 mg to about 1200 mg of ganaxolone parenterally (e.g., intravenously) for a period of about 1 hour to about 8 hours (e.g., 2, 4, 5, or 6 hours) at a rate varying from about 10 mg / hour to about 150 mg / hour, from about 15 mg / hour to about 140 mg / hour, or from about 15 mg / hour to about 120 mg / hour, whereby administration terminates EEG seizure activity (e.g., ongoing paroxysmal discharges). In some embodiments, ganaxolone is administered at a rate of about 50 mg / hour to about 130 mg / hour.

[0035] In part, the disclosure further relates to a method of treating a subject experiencing a non-convulsive EEG seizure, comprising administering a therapeutically effective amount of ganaxolone to stop or reduce the frequency of the non-convulsive EEG seizures in the subject. In certain embodiments, the therapeutically effective amount of ganaxolone is administered in a subject at about 50 ng / ml to about 3500 ng / ml, about 75 ng / ml to about 3250 ng / ml, about 100 ng / ml to about 3000 ng / ml, about 125 ng / ml to about 2750 ng / ml, about 150 ng / ml to about 2500 ng / ml, about 175 ng / ml to about 2250 ng / ml, about 200 ng / ml to about 3000 ng / ml, or about 300 ng / ml to about 3500 ng / ml. ng / ml to about 2200 ng / ml, about 250 ng / ml to about 2150 ng / ml, about 300 ng / ml to about 2100 ng / ml, about 350 ng / ml to about 2100 ng / ml, about 400 ng / ml to about 2100 ng / ml, about 450 ng / ml to about 2100 ng / ml, or about 500 ng / ml to about 1900 ng / ml. In some embodiments, a portion of the therapeutically effective amount is administered by bolus intravenous injection and the remainder of the therapeutically effective amount is administered by continuous intravenous infusion. For example, for a subject weighing 40 kg or more, in some embodiments, about 5 mg to about 100 mg of ganaxolone is administered by bolus intravenous injection and the remainder of the dose is administered by intravenous infusion at a rate of greater than 10 mg / hr, 15 mg / hr, 20 mg / hr, 25 mg / hr, 30 mg / hr, 35 mg / hr, 40 mg / hr, 45 mg / hr, 50 mg / hr, 55 mg / hr, 60 mg / hr, 65 mg / hr, 70 mg / hr, 75 mg / hr, 80 mg / hr, or 85 mg / hr over a period of about 1 hour to about 120 hours (e.g., 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, etc.).

[0036] The disclosure also provides a method of treating non-convulsive EEG seizures, comprising administering a therapeutically effective dose of ganaxolone or ganaxolone-containing agonist to a subject by continuous intravenous infusion for a period of about 2 hours to about 120 hours, about 2 hours to about 100 hours, about 3 hours to about 100 hours, about 4 hours to about 100 hours, about 4 hours to about 96 hours, about 5 hours to about 96 hours, about 6 hours to about 96 hours, about 6 hours to about 90 hours, about 6 hours to about 88 hours, or about 10 hours to about 72 hours. the method comprises administering a portion thereof intravenously to a subject, and terminating or reducing the frequency of non-convulsive EEG seizures in the subject, wherein the intravenous infusion is initiated after a bolus dose of about 5 mg to about 100 mg is administered intravenously to the subject (e.g., about 1 second to about 1 hour, about 1 second to about 45 minutes, about 1 second to about 30 minutes, about 1 second to about 15 minutes, about 1 second to about 10 minutes, about 1 second to about 5 minutes, or about 2 seconds to about 3 minutes after the bolus administration).

[0037] The disclosure further relates to a method of treating a subject experiencing a non-convulsive EEG seizure comprising intravenously administering about 450 mg to about 3000 mg of ganaxolone at a rate of greater than about 10 mg / hour, 15 mg / hour, 20 mg / hour, 25 mg / hour, or 30 mg / hour for a period of about 4 hours to about 120 hours. In some embodiments, about 2 mg to about 100 mg of ganaxolone is administered by bolus intravenous injection and the remainder of the dose is administered by continuous intravenous infusion at a rate of greater than about 10 mg / hour, 15 mg / hour, 20 mg / hour, 25 mg / hour, or 30 mg / hour for a period of about 1 hour to about 120 hours.

[0038] The present disclosure also relates to a method of treating status epilepticus (e.g., generalized convulsive status epilepticus, nonconvulsive status epilepticus, early status epilepticus, confirmed status epilepticus, refractory status epilepticus, or super refractory status epilepticus), comprising intravenously administering about 450 mg to about 1000 mg of ganaxolone to a subject in need thereof for about 24 hours to about 120 hours, and administering an additional dose of an antiepileptic drug during said 24 hours to about 120 hours. The additional antiepileptic drug can be selected from the group consisting of benzodiazepines, phenytoin, fosphenytoin, valproic acid, phenobarbital, and / or levetiracetam. In certain embodiments, the antiepileptic drug is a benzodiazepine (e.g., diazepam, lorazepam, etc.). In some of these embodiments, administration of ganaxolone and an additional antiepileptic drug provides a synergistic effect.

[0039] The present disclosure also relates to a method of treating acute recurrent seizures (ARS), comprising intravenously administering a therapeutically effective amount of ganaxolone to a subject in need thereof. The therapeutically effective amount may include, for example, about 1 mg to about 1000 mg of ganaxolone, administered as one or more bolus doses, each bolus dose containing about 1 mg to about 50 mg, about 1 mg to about 45 mg, about 1 mg to about 40 mg, about 2 mg to about 35 mg, about 3 mg to about 30 mg, or about 5 mg to about 30 mg, and may be administered over a period of about 1 to about 5 minutes. In some embodiments, the method further includes administering ganaxolone by continuous intravenous infusion at a rate of about 5 mg / hour to about 130 mg / hour (e.g., about 5 mg / hour to about 85 mg / hour) for about 24 hours to about 120 hours (e.g., about 48 hours to about 96 hours) after one or more bolus doses of ganaxolone, the continuous intravenous infusion beginning simultaneously with or shortly after (e.g., within about 30 minutes) the bolus injection; and reducing the intravenous infusion rate for about 10 hours to about 24 hours (e.g., over 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, or about 20 hours) before stopping the continuous infusion.

[0040] In certain embodiments, the methods of the invention further comprise administering one or more rescue bolus dose(s) of ganaxolone of about 1 mg to about 50 mg, about 1 mg to about 45 mg, about 1 mg to about 40 mg, about 2 mg to about 35 mg, about 3 mg to about 30 mg, or about 5 mg to about 30 mg, which can be administered intravenously over about 1 to about 5 minutes during the intravenous infusion. One or more rescue dose(s) may be administered, for example, if there is a recurrence of seizure(s) (i.e., abnormal EEG activity) and / or convulsion(s). In some embodiments, one, two, three, four, or five rescue doses are administered during the intravenous infusion.

[0041] In certain embodiments, the methods of the present invention involve administering some or all of the ganaxolone dose in the form of nanoparticles.

[0042] 3. Brief description of the drawings The drawings are not necessarily to scale or exhaustive. Instead, emphasis has been placed on illustrating the principles of the invention generally described herein. The accompanying drawings, which form a part of the specification, illustrate several embodiments consistent with the present disclosure and, together with the description, serve to explain the principles of the disclosure. The description of the drawings is as follows: [Brief description of the drawings]

[0043] [Figure 1] 1 depicts EEG and BIS changes from a Phase 1 clinical trial in Example 1. Changes are consistent with the sedative / anesthetic effects of ganaxolone. [Diagram 2] 1 is a graph showing predicted ganaxolone plasma concentrations versus time. [Diagram 3] 1 is a graph showing predicted and observed ganaxolone plasma concentrations versus time for subject 004-101. The vertical lines represent time to seizure recurrence. [Figure 4] Snapshot of an EEG recording from Subject 004-101. [Diagram 5]1 is a graph showing predicted and observed ganaxolone plasma concentrations versus time for subject 004-102. The vertical line represents the onset of return of abnormal EEG activity that subsequently required additional intervention. [Figure 6] Snapshot of an EEG recording from Subject 004-102. [Figure 7] 1 is a graph showing predicted and observed ganaxolone plasma concentrations versus time for subject 006-101. The vertical lines represent time to seizure recurrence. [Figure 8] Photograph of EEG tracings from subjects 106-102. The vertical line indicates the start of ganaxolone treatment. [Figure 9] 1 is a graph showing predicted and observed ganaxolone plasma concentrations versus time for subject 006-102. The vertical line represents time to seizure recurrence. [Figure 10] 1 is a graph showing predicted and observed ganaxolone plasma concentrations versus time for subject 015-101. [Figure 11] Snapshot of EEG recording of subject from eIND No. 131,642. Seizures appear as dense areas, as noted in the comments in the top margin. [Figure 12] 1 is a graph showing time to termination of SE in the low, medium, and high dose groups. The graph shows that the median termination of SE was 5 minutes for all dose groups. [Figure 13A] 1 is a graph showing the PK / PD relationship and rationale for target dose. [Figure 13B] 1 is an exemplary electroencephalogram (EEG) showing that acute treatment with ganaxolone plasma concentrations of 500 ng / mL or greater resulted in improved seizure control on the EEG. [Figure 13C] 1 is an exemplary electroencephalogram (EEG) showing that acute treatment with ganaxolone plasma concentrations of 500 ng / mL or greater resulted in improved seizure control on the EEG. [Figure 13D] 1 is an exemplary electroencephalogram (EEG) showing that acute treatment with ganaxolone plasma concentrations of 500 ng / mL or greater resulted in improved seizure control on the EEG. [Figure 14]Graph showing modeled PK curves for low, medium, and high dose cohorts. [Figure 15] FIG. 13 is a graph depicting percent change in EEG seizure burden in refractory SE patients receiving IV ganaxolone in low, medium, and high dose cohorts. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0044] 4. Detailed Description Effective treatment of SE is challenging, and current treatment protocols are ineffective for many patients. Approximately 50% of subjects do not respond to first-line drug therapy, and approximately 50% of these subjects also do not respond to second-line drug therapy, resulting in refractory SE. Approximately one-third of refractory subjects die, and another third recover but with neurological or other disabilities. Clearly, improved approaches to the treatment of SE are needed.

[0045] The present disclosure relates to a new method for treating SE. As exemplified and described herein, treatment according to the method results in rapid suppression of SE and also results in sustained suppression of SE. The method can be used to treat any form of SE, including generalized convulsive SE, non-convulsive SE, refractory SE, and highly refractory SE. The method is particularly useful for treating refractory SE. The method can also be used to treat subjects who have failed first-line, second-line, and / or third-line treatments.

[0046] SE manifests as prolonged seizures lasting at least 5 minutes or longer, or seizures without recovery of consciousness between seizures. Suppression of SE usually interrupts the seizures (i.e., suppresses or reduces seizure activity). Clinically, suppression of SE can be a reduction in seizure burden (i.e., the percentage of time that seizure activity is present on the EEG). For example, a clinician may consider suppression of SE as a seizure burden of less than 20% and / or at least 50% less than the seizure burden in the 30 minutes prior to the start of treatment (i.e., intravenous bolus and continuous intravenous infusion).

[0047] The methods described herein include administering a therapeutically effective amount of a neurosteroid (e.g., ganaxolone) to a subject as an intravenous bolus and a continuous intravenous infusion. The intravenous bolus of ganaxolone is administered in an amount sufficient to suppress SE. Typically, a neurosteroid (e.g., ganaxolone) plasma concentration of about 500 ng / ml to about 1000 ng / ml is sufficient to suppress SE. For example, a bolus of about 30 mg of ganaxolone may be administered to achieve a ganaxolone plasma concentration of about 500 ng / ml to about 1000 ng / ml. Treatment according to the methods continues for a treatment period that includes a period during which the continuous intravenous infusion is administered to maintain the subject's neurosteroid (e.g., ganaxolone) serum concentration at or near the target level (i.e., the target concentration period), a period during which the subject's neurosteroid (e.g., ganaxolone) plasma concentration is allowed or caused to fall below the target concentration, and a tapering period during which the patient is weaned off the neurosteroid.

[0048] The continuous intravenous infusion of neurosteroid (e.g., ganaxolone) is administered in an amount sufficient to continuously suppress SE for a target concentration period. Continuous suppression of SE is achieved when the continuous infusion maintains a plasma concentration of neurosteroid (e.g., ganaxolone) of about 500 ng / ml or more throughout the target concentration period. The target concentration period is usually at least about 8 hours or at least 12 hours, although it is possible that the target concentration period may be at least about 4 hours for some subjects. During the target concentration period, the amount of neurosteroid (e.g., ganaxolone) administered to the subject (i.e., by continuous intravenous infusion) may be increased and / or decreased to maintain continuous suppression of SE, but it is sufficient to maintain a plasma concentration of ganaxolone of at least about 500 ng / ml in the subject for at least 4 hours, or preferably about 8 hours, after intravenous bolus administration, and optionally throughout the treatment period. Typically, the amount of ganaxolone administered by continuous intravenous infusion may be decreased over a period of about 24 hours from the start of intravenous infusion. For example, the amount of ganaxolone administered to the subject can be decreased about 2 hours after the start of the continuous intravenous infusion, and then about 10 to about 14 hours after the infusion. Surprisingly, SE continues to be suppressed by the continuous intravenous infusion, even if the amount of neurosteroid (e.g., ganaxolone) administered during the continuous intravenous infusion is decreased during the treatment period. As a result, the method results in less exposure to ganaxolone than expected, and safety and efficacy are enhanced. During treatment, the subject's neurosteroid (e.g., ganaxolone) plasma concentration can be monitored, and seizure activity can be monitored using EEG. If the subject appears to be exhibiting signs of recurrent SE, the dosage of ganaxolone can be adjusted accordingly. For example, an additional intravenous bolus can be delivered or the infusion rate of ganaxolone can be increased. The amount of neurosteroid (e.g., ganaxolone) administered during the infusion is typically adjusted by increasing or decreasing the infusion rate.

[0049] The continuous intravenous infusion is generally administered simultaneously with the administration of the intravenous bolus, although in some cases the continuous intravenous infusion can be started before or after the intravenous bolus.

[0050] The continuous intravenous infusion is typically followed by a tapering period during which the subject is weaned off ganaxolone. During the tapering period, the continuous intravenous infusion of ganaxolone is typically systematically reduced by decreasing the amount of ganaxolone administered to the subject (e.g., by continuous intravenous infusion) by about one-third every four hours until the subject no longer requires ganaxolone.

[0051] Further description of the method and guidance for carrying out the method are provided herein. For ease of explanation, further details and guidance are provided with respect to a preferred embodiment using ganaxolone. The further details and guidance are also intended to be relevant to treatment with other neurosteroids.

[0052] A bolus injection Methods for treating SE include administering to a subject in need thereof an intravenous bolus of ganaxolone in an amount sufficient to suppress SE, typically sufficient to produce a ganaxolone plasma concentration of at least about 500 ng / ml to about 1000 ng / ml. Typically, the intravenous bolus results in a ganaxolone plasma concentration of about 750 ng / ml to about 1000 ng / ml, more typically about 1000 ng / ml.

[0053] For example, an intravenous bolus of ganaxolone can contain an amount of ganaxolone sufficient to achieve a ganaxolone plasma concentration of at least about 500 ng / ml, about 525 ng / ml, about 550 ng / ml, about 575 ng / ml, about 600 ng / ml, about 625 ng / ml, about 650 ng / ml, about 675 ng / ml, about 700 ng / ml, about 725 ng / ml, about 750 ng / ml, about 775 ng / ml, about 800 ng / ml, about 825 ng / ml, about 850 ng / ml, about 875 ng / ml, about 900 ng / ml, about 925 ng / ml, about 950 ng / ml, about 975 ng / ml, about 1000 ng / ml, about 1025 ng / ml, about 1050 ng / ml, about 1075 ng / ml, or about 1100 ng / ml. Preferably, the intravenous bolus achieves a ganaxolone plasma concentration of at least about 500 ng / ml to about 1000 ng / ml.

[0054] To suppress SE, a ganaxolone plasma concentration of at least about 500ng / ml to about 1000ng / ml is preferred, although some variation may exist based on, for example, differences in subject weight, metabolism, age, duration of SE, and / or severity of SE. Thus, a skilled clinician will appreciate that some SE patients may be able to suppress SE with low exposure to ganaxolone, such as plasma concentrations of at least about 425ng / ml, at least about 450ng / ml, at least about 475ng / ml. However, it is preferred to deliver an amount of ganaxolone by bolus that is sufficient to achieve a ganaxolone plasma concentration of about 1000ng / ml. Plasma concentrations of ganaxolone above about 1000ng / ml may induce loss of consciousness in the subject, which is generally not an intended effect or desired outcome of the methods described herein. Preferably, an intravenous bolus of ganaxolone results in minimal or no anesthetic effect. For example, preferably, the dosage of ganaxolone does not result in loss of consciousness, does not result in paralysis, and / or does not cause deep sedation. Preferably, treatment in accordance with the methods described herein does not require the subject to undergo controlled ventilation and / or endotracheal intubation.

[0055] In some cases, suppression of SE without loss of consciousness can be achieved at plasma concentrations of about 1005 ng / ml, about 1010 ng / ml, 1020 ng / ml, 1030 ng / ml, 1040 ng / ml, 1050 ng / ml, 1060 ng / ml, 1070 ng / ml, 1080 ng / ml. In other cases, ganaxolone plasma concentrations about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15% greater than 1000 ng / ml can be sufficient to suppress SE without loss of consciousness.

[0056] About 1mg, about 2mg, about 3mg, about 4mg / hour, about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16m g, about 17mg, about 18mg, about 19mg, about 20mg, about 21mg, about 22mg, about 23mg, about 24mg, about 25mg, about 26mg, about 27mg, about 28mg, about 29mg, about 30mg, about 3 An intravenous bolus of ganaxolone can be administered (i.e., infused) to a subject in an amount of 1 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg. Preferably, about 30 mg of ganaxolone is infused to a subject in an intravenous bolus.

[0057] For subjects weighing less than about 40 kg, about 0.10 mg / kg, about 0.11 mg / kg, about 0.12 mg / kg, about 0.13 mg / kg, about 0.14 mg / kg, about 0.15 mg / kg, about 0.16 mg / kg, about 0.17 mg / kg, about 0.18 mg / kg, about 0.19 mg / kg, about 0.20 mg / kg, about 0.21 mg / kg, about 0.22 mg / kg, about 0.23 mg / kgr, about 0.24 mg / kg, about 0.25 mg / kg , about 0.26mg / kg, about 0.27mg / kg, about 0.28mg / kg, about 0.29mg / kg, about 0.30mg / kg, about 0.31mg / kg, about 0.32mg / kg, about 0.33mg / kg, about 0.34mg / kg, about 0.35mg / kg, about 0.36mg / kg, about 0.37mg / kg, about 0.38mg / kg, about 0.39mg / kg, about 0.40mg / kg, about 0.41mg / kg, about 0.42mg / kg, about 0.43 mg / kg, about 0.44 mg / kg, about 0.45 mg / kg, about 0.46 mg / kg, about 0.47 mg / kg, about 0.48 mg / kg, about 0.49 mg / kg, about 0.5 mg / kg, about 0.51 mg / kg, about 0. 52mg / kg, about 0.53mg / kg, about 0.54mg / kg, about 0.55mg / kg, about 0.56mg / kg, about 0.57mg / kg, about 0.58mg / kg, about 0.59mg / kg, about 0.60mg / kg, about The subject may be infused with 0.61 mg / kg, about 0.62 mg / kg, about 0.63 mg / kg, about 0.64 mg / kg, about 0.65 mg / kg, about 0.66 mg / kg, about 0.67 mg / kg, about 0.68 mg / kg, about 0.69 mg / kg, about 0.7 mg / kg, about 0.75 mg / kg, about 0.80 mg / kg, about 0.85 mg / kg, about 0.90 mg / kg, or about 0.95 mg / kg of ganaxolone in an intravenous bolus. Preferably, the subject is infused with about 0.43 mg / kg of ganaxolone in an intravenous bolus.

[0058] The intravenous bolus can be administered to the subject for any desired period of time, typically for about 1 minute to about 10 minutes, e.g., about 1 minute to about 5 minutes, about 1 minute to about 4 minutes, about 1 minute to about 3 minutes, about 1 minute to about 2 minutes, about 2 minutes to about 5 minutes, about 2 minutes to about 4 minutes, about 2 minutes to about 3 minutes, about 3 minutes to about 5 minutes, or about 3 minutes to about 4 minutes. The intravenous bolus can be administered to the subject preferably for about 1 minute, about 2 minutes, about 3 minutes, or about 5 minutes. More preferably, the intravenous bolus is administered to the subject for about 3 minutes.

[0059] If a ganaxolone plasma concentration of at least about 500 ng / ml is not reached after the intravenous bolus of ganaxolone, an additional intravenous bolus of ganaxolone may be administered to the subject until a ganaxolone plasma concentration of at least about 500 ng / ml, preferably about 1000 ng / ml, is reached.

[0060] B continuous intravenous infusion Continuous intravenous infusion of ganaxolone is administered perioperatively using an intravenous bolus. For example, the continuous intravenous infusion can be started simultaneously with administration of the intravenous bolus. Alternatively, the continuous intravenous infusion can be started before or after administration of the intravenous bolus. Typically, the intravenous infusion and the continuous intravenous infusion are administered from the same ganaxolone source (e.g., an IV bag is connected to an IV line) and are started at the same time. The continuous intravenous infusion of ganaxolone is administered in an amount that continues to suppress SE throughout the treatment period and beyond. The continuous intravenous infusion of ganaxolone provides durable suppression of SE that preferably persists throughout the treatment period, preferably throughout the tapering period, preferably after the tapering period, and preferably after treatment.

[0061] In embodiments, continuous intravenous infusion of ganaxolone achieves suppression of SE for at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours, at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, or more after treatment. In embodiments, continuous intravenous infusion of ganaxolone achieves suppression of SE for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, or more after treatment. In embodiments, continuous intravenous infusion of ganaxolone achieves suppression of SE for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, or longer, following treatment.

[0062] Continuous suppression of SE is achieved by administering to the subject a continuous intravenous infusion in an amount sufficient to produce a ganaxolone plasma concentration of at least about 500ng / ml for the target concentration period, i.e., usually at least 4 hours after intravenous bolus administration, or preferably at least about 8 hours or at least about 12 hours, and optionally throughout the treatment period.In practice, the patient's plasma concentration of ganaxolone can be monitored, and the amount of ganaxolone infused can be adjusted or titrated to maintain a plasma concentration of at least about 500ng / ml throughout the treatment period.For example, continuous suppression of SE can be achieved if the ganaxolone plasma concentration is at least about 500ng / ml for about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, or more.

[0063] A continuous intravenous infusion of ganaxolone can be administered to a subject in an amount to achieve a ganaxolone plasma concentration of about 500 ng / ml to about 1000 ng / ml for at least 4 hours, preferably at least about 8 hours or at least about 12 hours.

[0064] A plasma concentration of at least about 500 ng / ml is preferred for continued suppression of SE, although some variation may exist based on, for example, differences in subject weight, metabolism, age, duration of SE, and / or severity of SE. Thus, a skilled clinician will appreciate that in some SE subjects, a ganaxolone plasma concentration of, for example, at least about 425 ng / ml, at least about 450 ng / ml, at least about 475 ng / ml may be sufficient for continued suppression of SE. Ganaxolone plasma concentrations below 400 ng / ml or below 500 ng / mL are generally considered insufficient for continued suppression of SE. In some embodiments, continuous intravenous infusion of ganaxolone provides a therapeutic effect of about 425 ng / ml, about 450 ng / ml, about 475 ng / ml, about 500 ng / ml, about 525 ng / ml, about 550 ng / ml, about 575 ng / ml, about 600 ng / ml, about 625 ng / ml, about 650 ng / ml, about 675 ng / ml, about 700 ng / ml, about 725 ng / ml, about 750 ng / ml The method achieves a ganaxolone plasma concentration of about 775ng / ml, about 800ng / ml, about 825ng / ml, about 850ng / ml, about 875ng / ml, about 900ng / ml, about 925ng / ml, about 950ng / ml, about 975ng / ml, about 1000ng / ml, about 1025ng / ml, about 1050ng / ml, about 1075ng / ml, or about 1100ng / ml. Preferably, a ganaxolone plasma concentration of about 500ng / ml to about 1000ng / ml is desired.

[0065] Plasma concentrations of ganaxolone above about 1000ng / ml may induce loss of consciousness in the subject, which is generally not the intended effect or desired outcome of the methods described herein.Preferably, continuous intravenous infusion of ganaxolone results in minimal or no anesthetic effects.For example, preferably, the dose of ganaxolone does not cause loss of consciousness, does not cause paralysis, and / or does not cause deep sedation.Preferably, treatment according to the methods described herein does not require the subject to undergo controlled ventilation and / or endotracheal intubation.

[0066] In some cases, ganaxolone plasma concentrations of about 1005 ng / ml, about 1010 ng / ml, 1020 ng / ml, 1030 ng / ml, 1040 ng / ml, 1050 ng / ml, 1060 ng / ml, 1070 ng / ml, 1080 ng / ml can provide continued suppression of SE without loss of consciousness. In some cases, ganaxolone plasma concentrations of about 1% less, about 2% less, about 3% less, about 4% less, about 5% less, about 6% less, about 7% less, about 8% less, about 9% less, about 10% less, about 11% less, about 12% less, about 13% less, about 14% less, or about 15% less than 500 ng / ml can be sufficient to suppress SE. In other cases, ganaxolone plasma concentrations of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15% greater than 1000 ng / ml may be sufficient for continued suppression of SE without loss of consciousness.

[0067] The amount of ganaxolone administered to the subject per hour by continuous intravenous infusion can be reduced during the treatment period of continuous intravenous infusion.In some cases, continuous intravenous infusion can be reduced for a period of about 24 hours from the start of intravenous infusion.For example, the amount of ganaxolone administered to the subject per hour by continuous intravenous infusion can be reduced about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours after the start of continuous intravenous infusion.

[0068] The amount of ganaxolone administered to the subject per hour by continuous intravenous infusion can be decreased or further decreased for one or more periods during the treatment period of continuous intravenous infusion.For example, the amount of ganaxolone administered to the subject per hour by continuous intravenous infusion can be decreased for one interval, two intervals, three intervals, four intervals, five intervals or more during the treatment period of continuous intravenous infusion.In the method provided herein, the amount of ganaxolone administered to the subject per hour by continuous intravenous infusion is preferably decreased for two intervals over about 24 hours from the start of continuous intravenous infusion.

[0069] The amount of ganaxolone administered to a subject per hour by continuous intravenous infusion can be decreased or further decreased about 1 hour to about 5 hours, about 1 hour to about 4 hours, about 1 hour to about 3 hours, about 2 hours to about 3 hours, about 2 hours to about 4 hours, about 2 hours to about 4 hours, about 2 hours to about 5 hours, about 3 hours to about 4 hours, about 4 hours to about 5 hours after the start of the continuous intravenous infusion. The amount of ganaxolone administered to a subject per hour by continuous intravenous infusion is preferably decreased about 2 hours after the start of the continuous intravenous infusion.

[0070] The amount of ganaxolone administered to a subject per hour by continuous intravenous infusion can be decreased or further decreased by about 8 hours to about 16 hours, about 8 hours to about 15 hours, about 8 hours to about 14 hours, about 8 hours to about 13 hours, about 8 hours to about 12 hours, about 8 hours to about 11 hours, about 8 hours to about 10 hours, about 9 hours to about 16 hours, about 9 hours to about 15 hours, about 9 hours to about 14 hours, about 9 hours to about 13 hours, about 9 hours to about 12 hours, about 9 hours to about 11 hours, about 9 hours to about 10 hours, about 10 hours to 16 hours, about 10 hours to about 15 hours, about 10 hours to about 14 hours, about 10 hours to about 13 hours, about 10 hours to about 12 hours, or about 10 hours to about 11 hours after the start of the continuous intravenous infusion. The amount of ganaxolone administered to the subject per hour by continuous intravenous infusion is preferably decreased about 10 to about 14 hours after the start of the continuous intravenous infusion. More specifically, the amount of ganaxolone administered to the subject per hour by continuous intravenous infusion is decreased about 12 hours after the start of the continuous intravenous infusion.

[0071] The amount of ganaxolone administered to a subject per hour by continuous intravenous infusion is about 1 to about 5 hours, about 1 to about 4 hours, about 1 to about 3 hours, about 2 to about 3 hours, about 2 to about 4 hours, about 2 to about 4 hours, about 2 to about 5 hours, about 3 to about 4 hours, about 4 to about 5 hours, and further thereafter about 8 to about 16 hours, about 8 to about 15 hours, about 8 to about 14 hours, about 8 to about 18 hours, about 8 to about 20 hours, about 8 to about 22 hours, about 8 to about 26 hours, about 8 to about 28 hours, about 8 to about 29 hours, about 9 to about 32 hours, about 9 to about 36 hours, about 9 to about 38 hours, about 9 to about 39 hours, about 10 ... The reaction time can be reduced by 3 hours, about 8 hours to about 12 hours, about 8 hours to about 11 hours, about 8 hours to about 10 hours, about 9 hours to about 16 hours, about 9 hours to about 15 hours, about 9 hours to about 14 hours, about 9 hours to about 13 hours, about 9 hours to about 12 hours, about 9 hours to about 11 hours, about 9 hours to about 10 hours, about 10 hours to 16 hours, about 10 hours to about 15 hours, about 10 hours to about 14 hours, about 10 hours to about 13 hours, about 10 hours to about 12 hours, or about 10 hours to about 11 hours.

[0072] Preferably, the amount of ganaxolone administered to a subject per hour by continuous intravenous infusion is decreased about 2 hours after the start of the continuous intravenous infusion, and further decreased from about 10 hours to about 14 hours after the start of the continuous intravenous infusion.

[0073] The amount of ganaxolone administered to a subject per hour by continuous intravenous infusion can be reduced by about 40%, about 45%, about 50%, about 55%, about 65%, about 75%, about 80%, about 85%, or about 90% compared to the hourly dose at the start of the continuous intravenous infusion.

[0074] In embodiments, the amount of ganaxolone administered to a subject per hour by continuous intravenous infusion can be reduced by about 40%, about 45%, about 50%, about 55%, about 65%, about 75%, about 80%, about 85%, or about 90% at about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours after the start of the continuous intravenous infusion, compared to the hourly dose at the start of the continuous intravenous infusion.

[0075] The amount of ganaxolone administered to a subject per hour by continuous intravenous infusion can be reduced by about 40%, about 45%, about 50%, about 55%, or about 60% from about 1 hour to about 5 hours after the start of the continuous intravenous infusion, compared to the hourly dose at the start of the continuous intravenous infusion. The amount of ganaxolone administered to a subject per hour by continuous intravenous infusion can preferably be reduced by about 50% about 2 hours after the start of the continuous intravenous infusion, compared to the hourly dose at the start of the continuous intravenous infusion.

[0076] The amount of ganaxolone administered to a subject per hour by continuous intravenous infusion can be reduced by about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, or about 85% about 10 to about 14 hours after the start of the continuous intravenous infusion, compared to the hourly dose at the start of the continuous intravenous infusion. The amount of ganaxolone administered to a subject per hour by continuous intravenous infusion can preferably be reduced by about 75% about 10 hours after the start of the continuous intravenous infusion, compared to the hourly dose at the start of the continuous intravenous infusion.

[0077] Continuous intravenous infusion includes infusing about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 65 mg, about 70 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg of ganaxolone per hour to the subject during the continuous intravenous infusion. Preferably, the continuous intravenous infusion includes infusing about 20 mg of ganaxolone per hour to about 80 mg of ganaxolone per hour to the subject during the continuous infusion treatment period.

[0078] In some embodiments, at the beginning of the continuous intravenous infusion, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, or about 89 mg, about 90 mg of ganaxolone is infused to the subject.Preferably, at the beginning of the continuous intravenous infusion, about 80 mg of ganaxolone is infused to the subject per hour.The amount of ganaxolone can then be reduced to about 60 mg, about 55 mg, about 40 mg, about 35 mg, about 30 mg, about 25 mg, about 20 mg, about 15 mg, or about 10 mg. Preferably, during the treatment period, the amount of ganaxolone is reduced to about 40 mg of ganaxolone, and thereafter to about 20 mg of ganaxolone. In some embodiments, the subject is administered about 40 mg of ganaxolone per hour by continuous intravenous infusion beginning about 2 hours after the initiation of the continuous intravenous infusion and for about 6 to about 10 hours thereafter. In some embodiments, the subject is administered about 20 mg of ganaxolone per hour by continuous intravenous infusion beginning about 12 hours after the initiation of the continuous intravenous infusion and for about 12 to about 24 hours thereafter. If desired or medically indicated, the amount of ganaxolone infused to the subject by continuous intravenous infusion can be increased to up to about 45 mg of ganaxolone per hour beginning about 24 hours after the initiation and for up to about 12 hours thereafter. Generally, the amount of ganaxolone administered to the subject by continuous intravenous infusion does not exceed 45 mg of ganaxolone per hour.

[0079] The amount of ganaxolone administered to a subject per hour by continuous intravenous infusion can be decreased or increased by increasing or decreasing the infusion rate. The infusion rate generally varies between about 5 mg / hour of ganaxolone and about 130 mg / hour of ganaxolone, depending on clinical response and safety. In certain embodiments, the administration rate is from about 5 mg / hour to about 90 mg / hour.

[0080] The treatment period of the continuous intravenous infusion may be at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours, at least 13 hours, at least 14 hours, at least 15 hours, at least 16 hours, at least 17 hours, at least 18 hours, at least 19 hours, at least 20 hours, at least 21 hours, at least 22 hours, at least 23 hours, at least 24 hours, at least 25 hours, at least 26 hours, at least 27 hours, at least 28 hours, at least 29 hours, at least 30 hours, at least 31 hours, at least 32 hours, at least 33 hours, at least 34 hours, at least 35 hours, at least 36 hours, at least 37 hours, at least 38 hours, at least 39 hours, at least 40 hours after the start of the continuous intravenous infusion. A preferred continuous intravenous infusion period is a period of about 8 hours to about 36 hours after the start of the continuous intravenous infusion. Generally, the continuous intravenous infusion will be for a period of about 36 hours, but may be longer, such as about 48 hours, about 72 hours, or about 96 hours.

[0081] During the continuous intravenous infusion of ganaxolone, one or more additional intravenous boluses of ganaxolone can be administered to subjects who show signs of recurrence of SE or experience recurrence of SE.Electroencephalogram (EEG) can be used to detect signs of recurrence of SE.In place of or in combination with EEG, the plasma concentration of ganaxolone can be used to detect signs of recurrence of SE or subjects who experience recurrence of SE.For example, ganaxolone plasma concentration less than 400ng / ml can indicate that the subject is likely to recur.

[0082] For example, if there is a recurrence of seizure(s) (i.e., abnormal EEG activity) and / or convulsion(s), one or more additional intravenous boluses of about 1 mg to about 100 mg, about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 2 mg to about 75 mg, about 3 mg to about 70 mg, about 5 mg to about 60 mg, about 5 mg to about 50 mg, about 5 mg to about 45 mg, or about 5 mg to about 35 mg of ganaxolone may be administered intravenously over about 1 to about 5 minutes.

[0083] Before the recurrence of a seizure or when the recurrence of a seizure is detected, for a period of about 1 to about 5 minutes, administer the following: about 1 mg / hour, about 2 mg / hour, about 3 mg / hour, about 4 mg / hour, about 5 mg / hour, about 6 mg / hour, about 7 mg / hour, about 8 mg / hour, about 9 mg / hour, about 10 mg / hour, about 11 mg / hour, about 12 mg / hour, about 13 mg / hour, about 14 mg / hour, about 15 mg / hour, about 16 mg / hour, about 17 mg / hour, about 18 mg / hour, about 19 mg / hour, about 20 mg / hour, about 21 mg / hour, about 22 mg / hour, about 23 mg / hour, about 24 mg / hour, about 25 mg / hour, about 26 mg / hour, about 27 mg / hour, about 28 mg / hour, about 29 mg / hour, about 30 mg / hour, about 31 mg / hour, about 32 mg / hour, about 33 mg / hour, about 34 mg / hour, about 35 mg / hour, about 36 mg / hour, about 37 mg / hour, about 38 mg / hour, about 39 mg / hour, about 40 mg / hour, about 41 mg / hour, about 42 mg / hour, about 43 mg / hour, about 44 mg / hour, about 45 mg / hour, about 46 mg / hour, about 47 mg / hour, about 48 mg / hour, about 49 mg / hour, about 50 mg / hour, about 51 mg / hour, about 52 mg / hour, about 53 mg / hour, about 54 mg / hour, about 55 mg / hour, about 56 mg / hour, about 57 mg / hour, about 58 mg / hour, about 59 mg / hour, about 60 mg An additional intravenous bolus of ganaxolone can be infused into the subject at an hourly ganaxolone amount of about 29 mg / hour, about 30 mg / hour, about 31 mg / hour, about 32 mg / hour, about 33 mg / hour, about 34 mg / hour, about 35 mg / hour, about 36 mg / hour, about 37 mg / hour, about 38 mg / hour, about 39 mg / hour, about 40 mg / hour, about 45 mg / hour, about 50 mg / hour, about 55 mg / hour, about 60 mg / hour, about 65 mg / hour, about 70 mg / hour, about 75 mg / hour, about 80 mg / hour, about 85 mg / hour, about 90 mg / hour, about 95 mg / hour, or about 100 mg / hour.

[0084] c. Weight loss period The method of treating SE may further comprise administering to a subject in need thereof a continuous intravenous infusion for a tapering period. The tapering period follows the target concentration period. In general, the tapering period is performed immediately after the treatment period of the continuous intravenous infusion. However, in some cases, the tapering period may be immediately after the target concentration period. If the treatment period of the continuous intravenous infusion is about 36 hours or more (i.e., about 8 hours, about 72 hours, or about 96 hours), the tapering period begins immediately after the treatment period.

[0085] During the tapering period, the amount of ganaxolone administered to the subject per hour is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, or more every about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours until the subject is weaned from ganaxolone.

[0086] During the tapering period, the amount of ganaxolone administered to the subject per hour is reduced by about one-third every about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours. Preferably, during the tapering period, the amount of ganaxolone administered to the subject per hour is reduced by about one-third every about 4 hours.

[0087] The tapering period can be a period of at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, at least about 12 hours, at least about 13 hours, at least about 14 hours, at least about 15 hours, at least about 16 hours, at least about 17 hours, at least about 18 hours, at least about 19 hours, at least about 20 hours, at least about 21 hours, at least about 22 hours, at least about 23 hours, at least about 24 hours, at least about 25 hours, at least about 26 hours, at least about 27 hours, at least about 28 hours, at least about 29 hours, at least about 30 hours, at least about 32 hours, at least about 36 hours, at least about 48 hours, at least about 72 hours, at least about 96 hours, or more until the subject is weaned off ganaxolone.

[0088] Alternatively, the continuous intravenous infusion can be discontinued and oral ganaxolone can be administered to the subject. Oral ganaxolone can be used in lieu of a tapering period to maintain serum concentrations of ganaxolone at about 200 ng / ml to about 400 ng / ml.

[0089] In certain embodiments, the methods disclosed herein further comprise orally administering ganaxolone to the subject after discontinuing the continuous intravenous infusion of ganaxolone. The daily oral dose of ganaxolone can be, for example, about 200 mg to about 3000 mg, about 400 mg to about 2000 mg, about 600 mg to about 1900 mg, or about 900 mg to about 1800 mg, and can be administered in an oral capsule, oral suspension, or oral tablet. In certain embodiments, the daily oral dose of ganaxolone can be, for example, about 200 mg to about 2000 mg, about 400 mg to about 1500 mg, about 400 mg to about 1250 mg, or about 400 mg to about 1000 mg, and can be administered in an oral capsule, oral suspension, or oral tablet. Oral administration can continue, for example, for about 7 days, 14 days, 21 days, 28 days, or more.

[0090] In certain embodiments, one or more oral doses of ganaxolone are administered before or after continuous intravenous infusion or administration of ganaxolone. The daily oral dose of ganaxolone can be, for example, about 200 mg to about 3000 mg, about 400 mg to about 2000 mg, about 600 mg to about 1900 mg, or about 900 mg to about 1800 mg, and can be administered in oral capsules, oral suspensions, or oral tablets. In certain embodiments, the daily oral dose of ganaxolone can be, for example, about 200 mg to about 2000 mg, about 400 mg to about 1500 mg, about 400 mg to about 1250 mg, or about 400 mg to about 1000 mg, and can be administered in oral capsules, oral suspensions, or oral tablets. Oral administration can continue for, for example, about 7 days, 14 days, 21 days, 28 days, or more.

[0091] The methods of the invention include, for example, administering ganaxolone by one or more intravenous bolus doses followed by continuous intravenous infusion; administering ganaxolone by one or more intravenous bolus doses followed by continuous intravenous infusion followed by oral administration of ganaxolone, for example, in an oral capsule, oral tablet, oral suspension, or oral liquid; administering ganaxolone orally, for example, in an oral capsule, oral tablet, oral suspension, or oral liquid, followed by continuous intravenous infusion; administering ganaxolone orally, for example, in an oral capsule, oral tablet, oral suspension, or oral liquid, followed by continuous intravenous infusion. This includes administering one or more intravenous boluses of ganaxolone during the intravenous infusion; for example, administering ganaxolone orally in an oral capsule, oral tablet, oral suspension, or oral liquid, followed by administering one or more intravenous boluses of ganaxolone, followed by administering ganaxolone by continuous intravenous infusion; for example, administering ganaxolone orally in an oral capsule, oral tablet, oral suspension, or oral liquid, followed by administering one or more intravenous bolus injections of ganaxolone, followed by administering ganaxolone by continuous intravenous infusion, followed by administering ganaxolone orally in, for example, an oral capsule, oral tablet, oral suspension, or oral liquid.

[0092] c. Additional details and guidance for carrying out the method The amount of ganaxolone administered intravenously in the methods of the invention can vary, for example, from about 0.25 mg to about 3000 mg (e.g., about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, , 180mg, 190mg, 200mg, 220mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 725mg, 750mg, 775mg, 800mg, 850mg, 900mg, 950mg, 1000mg, etc.).

[0093] The total daily dose of ganaxolone administered in the methods of the invention can vary from about 450 mg to about 1000 mg. In certain embodiments, the total daily dose of ganaxolone is about 500 mg to about 900 mg, about 500 mg to about 875 mg, about 525 mg to about 875 mg, about 525 mg to about 850 mg, about 525 mg to about 825 mg, about 525 mg to about 800 mg, about 525 mg to about 775 mg, about 525 mg to about 750 mg, or about 525 mg to about 725 mg.

[0094] In certain embodiments, the amount of ganaxolone administered is based on the subject's body weight. A subject weighing less than 40 kg may be given a bolus dose (over 1-5 minutes) of about 0.07 mg / kg to about 1.43 mg / kg (e.g., about 0.125 mg / kg to about 0.4 mg / kg), followed by a continuous infusion at a rate of about 0.8 mg / kg / hr to about 2 mg / kg / hr for about 1-3 hours, followed by a continuous infusion at a rate of about 0.6 mg / kg / hr to about 1 mg / hr for about 4-8 hours, followed by a continuous infusion at a rate of about 0.15 mg / kg / hr to about 0.4 mg / kg / hr for 13-19 hours. At the end of the 24-hour continuous infusion, the infusion rate may be increased to a rate of about 0.2 mg / kg / hr to about 0.6 mg / kg / hr for, e.g., 24-48 hours or 24-96 hours. Additionally, the dose may be reduced by 10-25% every 6 hours, followed by discontinuation. In some embodiments, the dose is reduced by about 25% (75%, 50%, and 25%) every 6 hours, followed by discontinuation, hi some embodiments, the reductions are over a 12-24 hour period.

[0095] Subjects weighing 40 kg or more may be given a bolus dose of about 5 mg to about 100 mg (over about 1 to 5 minutes), followed by a continuous infusion at about 60 mg / hour to about 160 mg / hour for 1 to 4 hours, followed by a rate of about 20 mg / hour to about 140 mg / hour for 4 to 8 hours, followed by a rate of about 10 mg / hour to about 120 mg / hour for 12 to 19 hours. At the end of the first 24 hour continuous infusion, the infusion rate may be increased for 24 to 48 hours or 24 to 96 hours. Additionally, the dose may be decreased by 10 to 25% every 6 hours, followed by discontinuation. In some embodiments, the dose is decreased by about 25% (75%, 50%, and 25%) every 6 hours, followed by discontinuation. In some embodiments, the reduction is for 12 to 24 hours.

[0096] In certain embodiments, the methods of the invention involve administering some or all of the ganaxolone dose in the form of nanoparticles. Exemplary nanoparticle formulations and compositions are described in the "Formulations" section below.

[0097] In embodiments, if the subject is dosed for less than 2 hours or transitions to IV anesthetic (tertiary line therapy) for seizure control, no dose reduction is necessary and the methods of the invention do not include a reduction step.

[0098] In some methods of the invention, the ganaxolone dose, or a portion thereof, is administered via a dedicated (peripheral or central) IV line.

[0099] The duration of treatment can vary, for example, from about 30 minutes to about 120 hours. In certain embodiments, the duration of treatment is from about 1 to about 5 days (e.g., about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 96 hours, or about 120 hours). In certain embodiments, the treatment includes a taper period of about 10 hours to about 24 hours (e.g., an 18 hour taper). In certain embodiments, the treatment is continued until the subject's improvement in seizure burden reaches about 100.

[0100] Seizure burden will be defined as the number of seizures per total duration of the EEG obtained during the first 2 days of treatment, which will be compared to the seizure burden from the pre-treatment EEG (up to 24 hours before starting the study drug until just before administration of the study drug). If a pre-treatment EEG is not available, the calculation should be made from the start of EEG acquisition to the end of the first 2 days.

[0101] In one particular embodiment, seizure burden is assessed as the duration of electroencephalographic seizure activity per hour of acquired EEG recordings.

[0102] In certain embodiments, improvement in seizure burden is calculated from about 12 to about 60 hours after initiation of therapy.

[0103] If the seizure burden calculation indicates that the subject is unlikely to benefit from additional dosing (e.g., partial seizure burden improvement is near 100%), the dose may be reduced over a 12-24 hour (e.g., 18 hour) period. Conversely, if the seizure burden calculation indicates that the subject would be likely to benefit (e.g., partial seizure burden improvement is 33-50%), ganaxolone administration is continued for an additional period (e.g., 24-48 hours). At the end of the additional period, the subject may be re-evaluated and / or the dose of ganaxolone may be reduced over a 12-24 hour (e.g., 18 hour) period.

[0104] Dose reductions are not necessary for subjects who receive study drug for less than 2 hours and / or if the subject transitions to IV anesthetic agents for seizure control (tertiary therapy) at any time during study drug administration.

[0105] Treatment methods for A.SE The present disclosure relates to a method for treating SE, comprising administering an intravenous bolus of ganaxolone and a continuous intravenous infusion of ganaxolone to a subject in need thereof. A preferred method for treating SE comprises administering to a subject an intravenous bolus of ganaxolone in an amount sufficient to suppress SE, and a continuous intravenous infusion for continued suppression of SE. SE manifests as prolonged seizures over a period of at least 5 minutes, or seizures without recovery between seizures. Suppression of SE usually interrupts seizures (i.e., suppresses or reduces seizure activity). Clinically, suppression of SE can be a reduction in seizure burden (i.e., the proportion of time that seizure activity is present on the electroencephalogram). For example, a clinician may consider suppression of SE as a seizure burden of less than 20% and / or at least 50% less than the seizure burden in the 30 minutes before the start of treatment (i.e., intravenous bolus and continuous intravenous infusion).

[0106] The human subject may be male, female, adult, and child, elderly (65 years or older). The human subject may be, for example, about 1 year to about 120 years old, about 1 year to about 100 years old, about 2 years to about 95 years old, about 5 years to about 90 years old, about 7 years to about 85 years old, about 10 years to about 85 years old, about 12 years to about 85 years old, about 14 years to about 85 years old, about 16 years to about 85 years old, about 18 years to about 85 years old, or about 20 years to about 85 years old.

[0107] SE can be classified into three subtypes: generalized convulsive SE, non-convulsive SE, and refractory SE. Generalized convulsive status epilepticus is the most common form of SE and is characterized by tonic-clonic movements of the limbs and convulsions associated with impaired mental status. Non-convulsive SE is defined as EEG findings of SE activity without clinical symptoms. Refractory SE occurs in subjects who do not respond to standard SE treatment regimens, first-line and second-line agents. Each of these subtypes is suitable for treatment according to the methods described herein.

[0108] Subjects suitable for treatment according to the methods described herein have and / or are experiencing status epilepticus, such as, but not limited to, generalized convulsive status epilepticus, non-convulsive status epilepticus, early status epilepticus, confirmed status epilepticus, refractory status epilepticus, or super-refractory status epilepticus. Subjects with refractory SE are particularly suitable for treatment according to the methods described herein.

[0109] Treatment of SE is usually performed in multiple stages: primary, secondary, and tertiary. The primary standard case treatment is parenteral benzodiazepines. Exemplary benzodiazepines include, but are not limited to, clonazepam, lorazepam, midazolam, and diazepam. Benzodiazepines are ineffective in approximately 35%-45% of cases. If SE continues despite treatment with benzodiazepines, other antiseizure medications (e.g., fosphenytoin, levetiracetam, and valproic acid) are administered as second-line treatments. Approximately 50% of cases are resistant to second-line treatments. If SE continues despite first- and second-line treatments, general anesthetics (e.g., thiopental, propofol, and midazolam) are used as third-line treatments. Approximately 31%-41% of SE subjects develop refractory SE. Use of third-line medications usually results in iatrogenic coma, necessitating airway management with intubation and mechanical ventilation. Furthermore, the use of general anesthetics is associated with high morbidity and a mortality rate of approximately 35%.

[0110] In some embodiments, the subject with SE treated according to the methods provided herein has failed to respond to a first line, second line, or third line treatment. In other embodiments, the subject with SE treated has failed to respond to a first line and second line treatment. In other embodiments, the subject with SE treated has failed to respond to a first line, second line, or third line treatment. A subject with SE can be treated according to the methods provided herein before receiving other treatments, such as a standard of care first line or second line treatment. Alternatively, the subject can be treated according to the methods provided herein after a first line treatment (e.g., a benzodiazepine) has failed. In some cases, a subject will be treated according to the methods provided herein after a second line treatment (e.g., an anti-seizure drug) has failed. A subject treated according to the methods provided herein may have failed to respond to one or more anti-seizure drugs. In some cases, a subject treated according to the methods provided herein may have failed to respond to a third line treatment (e.g., an anesthetic). A subject treated according to the methods disclosed herein may have failed to respond to a first line treatment (e.g., a benzodiazepine) and two or more second line treatments. For example, a subject may have failed two or more anti-seizure medications. Exemplary anti-seizure medications may include, but are not limited to, fosphenytoin / phenytoin, valproic acid, levetiracetam, lacosamide, or brivaracetam.

[0111] Extremely refractory status epilepticus is characterized by persistent status epilepticus despite first-line therapy, second-line therapy, and treatment with general anesthetics for more than 24 hours. Such patients are critically ill and are likely to die without some further intervention. It is recognized that large doses of ganaxolone may be required to treat such patients. To successfully treat such subjects according to the methods described herein, an intravenous bolus of ganaxolone is administered to achieve a ganaxolone plasma concentration of about 800 mg / ml to about 1200 mg / ml, followed by a continuous intravenous infusion of ganaxolone in an amount to achieve a ganaxolone plasma concentration of about 800 mg / ml to about 1200 mg / ml.

[0112] In certain embodiments, the subject does not have a refractory genetic condition selected from the group consisting of PCDH19-associated epilepsy, CDKL5 deficiency (CDD), Dravet syndrome, Lennox-Gastaut syndrome (LGS), continuous spikes and waves during sleep (CSWS), status epilepticus during sleep (ESES), and other refractory and refractory genetic epilepsy conditions that are clinically similar to PCDH19-associated epilepsy, CDKL5 deficiency, Dravet syndrome, LGS, CSWS, and ESES. In certain embodiments, the subject does not have a CDKL5 genetic disorder. In certain embodiments, the subject does not have PCDH19-associated epilepsy.

[0113] B. Ganaxolone Ganaxolone (also known as 3α-hydroxy-3β-methyl-5α-pregnan-20-one, SPT3162, MD 9150000, CCD-1042, Mepalon, and 1042) is the subject of Investigational New Drug Application (IND) No. 129,433. The molecular formula for ganaxolone is C 22 H 36 O2 and its chemical structure is [ka] It is.

[0114] Ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one) is a 3β-methylated synthetic analog of the endogenous neurosteroid allopregnanolone with similar biological activity (Carter et al., (1997), The Journal of Pharmacology and Experimental Therapeutics, 280:1284-1295), but is designed not to activate the nuclear (classical) progesterone receptor. Also, in contrast to allopregnanolone, ganaxolone can be taken orally.

[0115] Ganaxolone inhibits gamma-aminobutyric acid type A (GABA) in the CNS. AGanaxolone acts as a positive allosteric modulator of the GABA receptor (Carter et al 1997). It inhibits other allosteric GABA receptors, such as benzodiazepines and barbiturates. A By interacting with a recognition site different from that of the receptor modulators, GABA A Ganaxolone binds to synaptic and extrasynaptic receptors, mediating both phasic and tonic modulation, respectively. The unique binding of ganaxolone to these two distinct receptor types does not result in tolerance as seen with benzodiazepines (Mares and Stehlikova (2010) Neurosci. Let. 469:396-399), allowing ganaxolone to act as a broad-spectrum GABAergic compound that shows promise in the treatment of a myriad of conditions related to pediatric genetic epilepsy, intractable seizures, cognitive and behavioral disorders, and sleep dysfunction.

[0116] Ganaxolone represents an alternative mechanism for seizure treatment and may serve as an effective therapy in the management of SE, including generalized convulsive status epilepticus, nonconvulsive status epilepticus, early status epilepticus, established status epilepticus, refractory status epilepticus, or super-refractory status epilepticus.

[0117] Ganaxolone does not activate the progesterone receptor either directly or indirectly through metabolic transformation, ensuring that ganaxolone lacks hormonal activity.

[0118] Ganaxolone has the advantage of controlling both convulsive and non-convulsive seizures: in experimental animals, ganaxolone produced immediate and long-term cessation of benzodiazepine-resistant SE as evidenced by cessation of seizures, reduction in EEG seizure activity, and increased survival.

[0119] Ganaxolone is insoluble in water. Its solubility in 95% alcohol, propylene glycol, and polyethylene glycol is 13 mg / mL, 3.5 mg / mL, and 3.1 mg / mL, respectively. The half-life of ganaxolone is relatively long, about 20 hours in human plasma after oral administration (Nohria, V. and Giller, E., Neurotherapeutics, (2007) 4(1):102-105). Furthermore, the T max The time is short, meaning that therapeutic blood levels are reached quickly.

[0120] Ganaxolone is metabolized by CYP3A4 / 5, and in vitro data and human PK data from subjects taking strong CYP inducers (carbamazepine and phenytoin) indicate that the clearance of ganaxolone is increased, resulting in an approximately 45% decrease in overall ganaxolone levels and exposure.

[0121] Across the ganaxolone development program, no clinically significant trends in electrocardiogram (ECG) intervals, vital signs, or physical or neurological examinations were noted, and no mean changes from baseline in clinical laboratory results were identified. In completed placebo-controlled Phase 1, 2, and 3 trials, 0.32% of subjects receiving ganaxolone and 0.46% of subjects receiving placebo had elevations in LFTs (>3-fold ULN AST and / or ALT) during the study. One subject in a pediatric epilepsy trial of ganaxolone developed hepatic failure, which was not believed to be related to ganaxolone. The subject was diagnosed with short bowel syndrome, fatty liver, and IgG cholangitis, which were believed to be causative factors in the subject's hepatic failure. There were no other cases of High's Law or hepatic failure in the ganaxolone development program. Ganaxolone and its metabolites are known to be excreted in breast milk. After cessation of dosing, plasma ganaxolone levels are expected to decline rapidly, although low subtherapeutic levels may persist for several days as ganaxolone is slowly released from tissues.

[0122] Previous toxicity studies in animals focusing on fetal and neonatal development have not demonstrated toxicity associated with ganaxolone. Ganaxolone has been administered to infants as early as 4 months of age with severe epilepsy. In clinical trials involving administration of ganaxolone over several weeks, the study drug was tapered over 1-2 weeks. No withdrawal symptoms were reported following discontinuation of ganaxolone.

[0123] D. Preparation Contemplated herein is a formulation containing a therapeutically effective amount of a neurosteroid for treating status epilepticus according to the methods disclosed herein.Preferably, the neurosteroid is ganaxolone.Other neurosteroids that can be used according to the methods disclosed herein include allopregnanolone, 3α-dihydroprogesterone, 5α-dihydroprogesterone, 5β-dihydroprogesterone, allopregnanediol, dihydrodeoxycorticosterone, pregnanediol, pregnanolone, tetrahydrodeoxycorticosterone, alphadolone, alphadolone acetate, EIDD-036, hydroxydione, minaxolone, 21-chloro-2β-morpholino- These include, but are not limited to, 4-yl-5β-pregnan-3α-ol-20-one, 2β-(2,2-dimethyl-4-morpholinyl)-3α-hydroxy-11,20-dioxo-5α-pregnan-21-yl methanesulfonate, or lennanolone, SGE-516, SGE-872, SAGE-217 (zuranolone: ​​3α-hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1′-yl)-19-nor-5β-pregnan-20-one).

[0124] The formulation is preferably an intravenous formulation of ganaxolone. Intravenous formulations of ganaxolone may include a cyclodextrin, such as sulfobutyl ether beta-cyclodextrin (Captisol®). The IV solution may include a sterile solution for immediate administration containing 1 mg / ml ganaxolone in Captisol® (Captisol®:GNX ratio of 60:1). The solution for immediate administration may contain 1 mg / ml ganaxolone in sulfobutyl ether beta-cyclodextrin (Captisol®), i.e., a Captisol to ganaxolone ratio of 60:1, and a buffer. A buffer solution (i.e., phosphoric acid and / or sodium chloride) may be included. In embodiments, the IV solution is a sterile solution containing 3 mg / ml ganaxolone in Captisol® (sulfobutylether-β-cyclodextrin) (Captisol®:GNX ratio of 70:1) or 5 mg / ml ganaxolone in Captisol, each of which may or may not be diluted with 0.9% saline (i.e., sodium chloride) solution prior to administration to make, for example, a 1 mg / ml ganaxolone solution for administration.

[0125] In certain embodiments, the formulation (e.g., intravenous formulation) comprises ganaxolone and sulfobutylether-β-cyclodextrin (e.g., Captisol®) in a weight ratio of about 1:50 to about 1:75. In some of these embodiments, the weight ratio of ganaxolone to Captisol® is about 1:51, about 1:52, about 1:53, about 1:54, about 1:55, about 1:56, about 1:57, about 1:58, about 1:59, about 1:60, about 1:61, about 1:62, about 1:63, about 1:64, about 1:65, about 1:66, about 1:67, about 1:68, about 1:69, about 1:70, about 1:71, or about 1:72. In some of these embodiments, the weight ratio of ganaxolone to Captisol® is about 1:60.

[0126] The intravenous formulation may be selected from the group consisting of, for example, liquid formulations containing nanocrystal formulations; emulsions; lyocell; solvents or surfactants; liposomes; microemulsions; and solid lipid nanoparticles.

[0127] In certain embodiments, the intravenous formulation is an IV solution. The intravenous formulation is preferably a sterile liquid (e.g., an aqueous liquid in the form of an emulsion, suspension, solution, etc.). In some of these embodiments, the IV solution comprises ganaxolone and a pharma- ceutically acceptable solvent(s) and / or oil(s) capable of dissolving ganaxolone.

[0128] In certain embodiments, the intravenous formulation is an oil-in-water emulsion.

[0129] In certain embodiments, the intravenous formulation is a liquid nanoparticle formulation (e.g., a liquid formulation containing nanoparticles of ganaxolone). In some of these embodiments, the nanoparticle formulation comprises ganaxolone and a polymeric stabilizer and / or an ionic stabilizer, but does not comprise a complexing agent. In certain embodiments, the polymeric stabilizer and the ionic stabilizer are selected from the group consisting of surfactants. In certain embodiments, the surfactant is selected from the group consisting of sorbitan esters, polyoxyethylene sorbitan fatty acid esters, poloxamers, cholesterol salts, and bile salts.

[0130] In certain embodiments, the intravenous infusion formulation may be a formulation described and prepared in U.S. Patent Publication No. 2017 / 0258812 or U.S. Patent Publication No. 2016 / 0228454. However, the intravenous infusion formulation may also be prepared according to other methods known to those skilled in the art.

[0131] As described in US Patent Publication No. 2016 / 0228454, an aqueous injectable ganaxolone formulation may include a) ganaxolone and sulfobutylether-β-cyclodextrin in an inclusion complex; and b) water. In some embodiments, the complex comprising ganaxolone and sulfobutylether-β-cyclodextrin comprises a 1:1 ganaxolone:sulfobutylether-β-cyclodextrin complex, with a w / w ratio of sulfobutylether-β-cyclodextrin to ganaxolone of about 52:1 or greater. In some embodiments, the formulation may further comprise a surfactant. In some embodiments, the surfactant is a sorbitan ester, a polyoxyethylene sorbitan fatty acid ester, a poloxamer, a cholesterol salt, or a bile salt. In some embodiments, the surfactant may comprise about 1 to about 15 weight percent of the formulation. In some embodiments, the surfactant is polysorbate 80. In some embodiments, the formulation further comprises a buffer and has a pH of about 6.0 to about 7.6. In some embodiments, the buffer is a phosphate buffer. In some embodiments, the buffer is a combination of a first phosphate buffer and a second phosphate buffer, each phosphate buffer having a concentration of 2 mM to 50 mM. In some embodiments, the buffer is a phosphate buffer. In some embodiments, the buffer is a combination of a first phosphate buffer and a second phosphate buffer, each phosphate buffer having a concentration of 2 mM to 50 mM. In some embodiments, the concentration of ganaxolone is 2 mg / ml to 8 mg / ml, the w / w ratio of sulfobutylether-β-cyclodextrin to ganaxolone is in the range of about 52:1 to about 90:1; the formulation contains a buffer, has a pH of 6.7 to 7.3 or a pH of 6.0 to 7.0, and the formulation contains 1 to 15 weight percent surfactant. In some embodiments, the concentration of ganaxolone is between 1 mg / ml and 5 mg / ml; the weight percent of sulfobutylether-β-cyclodextrin is between 25% and 35%; and the formulation contains 5% to 15% (weight percent) of at least one of the following: a surfactant, ethanol, glycerin, or propylene glycol. In some embodiments, the formulation further comprises a preservative.In some embodiments, the preservative is benzyl alcohol, chlorbutanol, 2-ethoxyethanol, parabens (including methyl, ethyl, propyl, butyl, and combinations), benzoic acid, sorbic acid, chlorhexidene, phenol, 3-cresol, thimerosal, or a phenylmercuric salt.

[0132] As further described in U.S. Patent Publication No. 2016 / 0228454, the formulation may be a lyophilized ganaxolone formulation comprising ganaxolone and sulfobutylether-β-cyclodextrin, the ganaxolone formulation being 1.0% to 1.5% ganaxolone. In some embodiments, the formulation may further comprise a bulking agent. In some embodiments, the bulking agent is mannitol, lactose, sucrose, trehalose, sorbitol, glucose, raffinose, glycine, histidine, polyethylene glycol (PEG), or polyvinylpyrrolidone (PVP).

[0133] Ganaxolone formulations suitable for parenteral administration in the methods of the present invention may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as propylene glycol, polyethylene glycol, glycerol, cremophor, etc.), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. In addition, ganaxolone can be dissolved at a concentration of greater than 1 mg / ml using water-soluble beta cyclodextrins (e.g., beta-sulfobutyl-cyclodextrin and 2-hydroxypropyl beta cyclodextrin). A particularly suitable cyclodextrin is Captisol®, a substituted beta-cyclodextrin. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size (for dispersions), and by the use of surfactants. Ganaxolone formulations suitable for subcutaneous injection may contain additives such as preservatives, wetting agents, emulsifiers, and dispersing agents. Prevention of microbial growth can be ensured by various antibacterial and antifungal agents, such as parabens, benzoic acid, benzyl alcohol, chlorobutanol, phenol, sorbic acid, etc. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, etc. The use of absorption delaying agents, such as aluminum monostearate and gelatin, can result in sustained drug absorption of injectable pharmaceutical forms. Ganaxolone suspension formulations designed for sustained release by subcutaneous or intramuscular injection can avoid first-pass metabolism and require only low doses of ganaxolone to maintain plasma levels of about 50 ng / ml. In such formulations, the particle size of the ganaxolone particles and the range of particle sizes of the ganaxolone particles can be used to control the release of the drug by controlling the rate of dissolution in fat or muscle.

[0134] In certain embodiments, the intravenous formulation is a solution containing a complexing agent(s). In some of these embodiments, the complexing agent is a molecule with a lipophilic core and a hydrophilic shell capable of solubilizing ganaxolone.

[0135] In certain embodiments, the formulation is an IV solution containing ganaxolone and sulfobutylether cyclodextrin (Captisol®), where the ganaxolone is dissolved in the sulfobutylether cyclodextrin (Captisol®). In some embodiments, the solution contains 3 mg of ganaxolone per ml of solution and is sterile. In certain embodiments, the solution is stable for at least 18 months and is stored refrigerated at a temperature of about 4° C. to about 8° C.

[0136] In certain embodiments, the liquid formulations of the invention may be those described and prepared in U.S. Patent No. 8,022,054, entitled "Liquid Ganaxolone Formulations and Methods for the Making and Use Thereof." However, oral liquid (e.g., suspension) formulations of ganaxolone may also be prepared according to other methods known to those of skill in the art.

[0137] As described in U.S. Patent No. 8,022,054, the liquid formulation may be an aqueous dispersion of stabilized particles, the particles containing ganaxolone, a hydrophilic polymer, a wetting agent, and an effective amount of a complexing agent to stabilize initial particle growth and particle growth after an end point is reached, the complexing agent being selected from the group of organic small molecules having a molecular weight less than 550 and containing a moiety selected from the group consisting of a phenolic moiety, an aromatic ester moiety, and an aromatic acid moiety, the stabilized particles having a volume weighted mean diameter (D50) of about 50 nm to about 500 nm, the complexing agent being present in an amount of about 0.05% to about 5% (w / w) based on the weight of the particles, and the particles being dispersed in an aqueous solution further containing at least two preservatives in an amount sufficient to inhibit microbial growth. The hydrophilic polymer may be in an amount of about 3% to about 50% (w / w) based on the weight of the solid particles. The wetting agent may be in an amount of about 0.01% to about 10% (w / w) based on the weight of the solid particles. Ganaxolone may be present in an amount of about 10% to about 80% (in certain embodiments, forming about 50% to about 80%) based on the weight of the stabilized particles. The stabilized particles, when dispersed in simulated gastric fluid (SGF) or simulated intestinal fluid (SIF) at a concentration of 0.5 to 1 mg ganaxolone / mL and placed in a heat bath at 36°C to 38°C for 1 hour, do not exhibit an increase in volume weighted mean diameter (D50) of more than about 150% compared to the volume weighted mean diameter (D50) of the stabilized particles when dispersed in distilled water under the same conditions. In this case, the volume weighted mean diameter (D50) of the stabilized particles dispersed in SGF or SIF is less than about 750 nm. The stabilized particles, when dispersed in 15 mL of SGF or SIF at a concentration of 0.5 to 1 mg ganaxolone / mL, do not exhibit an increase in D50 of more than about 150% compared to the volume weighted mean diameter (D50) of the stabilized particles when dispersed in distilled water under the same conditions. In this case, the volume weighted mean diameter (D50) of the stabilized particles dispersed in the SGF or SIF is less than about 750 nm.

[0138] The complexing agent may be any molecule with a lipophilic core and a hydrophilic shell capable of solubilizing ganaxolone, hi certain embodiments, the complexing agent may be a material containing a phenolic, aromatic ester, or aromatic acid moiety. In certain embodiments, the complexing agent is selected from the group consisting of parabens, organic acids, carboxylic acids, aromatic acids, aromatic esters, acid salts of amino acids, methyl anthranilate, sodium metabisulfite, ascorbic acid and its derivatives, malic acid, isoascorbic acid, citric acid, tartaric acid, sodium sulfite, sodium bisulfate, tocopherol, water-soluble and lipid-soluble derivatives of tocopherol, sulfites, bisulfites and hydrogen sulfites, para-aminobenzoic acid and esters, 2,6-di-t-butyl-alpha-dimethylamino-p-cresol, t-butylhydroquinone, di-t-amylhydroquinone, di-t-butylhydroquinone, butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), pyrocatechol, pyrogallol, propyl gallate, nordihydroguaiaretic acid, phosphoric acid, sorbic acid and benzoic acid, esters, ascorbyl palmitate, derivatives and isomeric compounds thereof, pharma-ceutically acceptable salts thereof, and mixtures thereof. In certain embodiments, the complexing agent is selected from the group consisting of parabens, benzoic acid, phenol, sodium benzoate, methyl anthranilate, and the like. The hydrophilic polymer can be a cellulosic polymer, a vinyl polymer, and mixtures thereof. The cellulosic polymer can be a cellulose ether, such as hydroxypropyl methylcellulose. The vinyl polymer can be a polyvinyl alcohol, such as vinylpyrrolidone / vinyl acetate copolymer (S630). The humectant can be sodium lauryl sulfate, a pharma- ceutically acceptable salt of docusate, and mixtures thereof. The aqueous dispersion can further include a sweetener, such as sucralose. In certain embodiments, the preservative is selected from the group consisting of potassium sorbate, methylparaben, propylparaben, benzoic acid, butylparaben, ethyl alcohol, benzyl alcohol, phenol, benzalkonium chloride, and mixtures of any of the foregoing.

[0139] In some embodiments, a liquid ganaxolone formulation is provided that includes ganaxolone particles as described herein and at least one dispersing or suspending agent for oral administration to a subject. The ganaxolone formulation may be a powder and / or granules for suspension that, when mixed with water, results in a substantially uniform suspension. As described herein, the aqueous dispersion may contain amorphous and non-amorphous ganaxolone particles of multiple effective particle sizes, such that ganaxolone particles with smaller effective particle sizes are absorbed quickly and ganaxolone particles with larger effective particle sizes are absorbed slowly. In certain embodiments, the aqueous dispersion or suspension is an immediate release formulation. In another embodiment, the aqueous dispersion containing amorphous ganaxolone particles is formulated such that about 50% of the ganaxolone particles are absorbed within about 3 hours after administration and about 90% of the ganaxolone particles are absorbed within about 10 hours after administration. In another embodiment, the addition of a complexing agent to the aqueous dispersion increases the distance between the ganaxolone-containing particles, prolonging the drug absorption phase such that 50-80% of the particles are absorbed in the first 3 hours and approximately 90% is absorbed by about 10 hours.

[0140] A suspension is "substantially uniform" if it is generally uniform, i.e., if the suspension is made up of approximately the same concentration of ganaxolone at any point in the suspension. Preferred embodiments are those that exhibit essentially the same concentration (within 15%) when measured at various points in the aqueous ganaxolone oral formulation after shaking. Particularly preferred are aqueous suspensions and dispersions that maintain uniformity (up to 15% variation) when measured 2 hours after shaking. For determining the uniformity of the entire composition, uniformity should be determined by a consistent sampling method. In one embodiment, the aqueous suspension can be resuspended into a uniform suspension by physical agitation lasting less than 1 minute. In another embodiment, the aqueous suspension can be resuspended into a uniform suspension by physical agitation lasting less than 45 seconds. In yet another embodiment, the aqueous suspension can be resuspended into a uniform suspension by physical agitation lasting less than 30 seconds. In yet another embodiment, no agitation is required to maintain a uniform aqueous dispersion.

[0141] In some embodiments, the ganaxolone formulation is a powder for aqueous dispersion and includes stable ganaxolone particles having an effective particle size of less than 500 nm by weight formulated with ganaxolone particles having an effective particle size of greater than 500 nm by weight. In such embodiments, the formulation has a particle size distribution in which about 10% to about 100% by weight of the ganaxolone particles are between about 75 nm and about 500 nm, about 0% to about 90% by weight of the ganaxolone particles are between about 150 nm and about 400 nm, and about 0% to about 30% by weight of the ganaxolone particles are greater than about 600 nm. The ganaxolone particles described herein can be amorphous, semi-amorphous, crystalline, semi-crystalline, or a mixture thereof.

[0142] In one embodiment, the aqueous suspensions or dispersions described herein contain ganaxolone particles or ganaxolone complexes at a concentration of about 20 mg / ml to about 150 mg / ml of suspension. In another embodiment, the aqueous oral dispersions described herein contain ganaxolone particles or ganaxolone complexes at a concentration of about 25 mg / ml to about 75 mg / ml of solution. In yet another embodiment, the aqueous oral dispersions described herein contain ganaxolone particles or ganaxolone complexes at a concentration of about 50 mg / ml of suspension. The aqueous dispersions described herein are particularly beneficial for administration of ganaxolone to infants (under 2 years of age), children under 10 years of age, and any patient population unable to swallow or ingest solid oral dosage forms.

[0143] The liquid ganaxolone formulation for oral administration may be an aqueous suspension selected from the group including, but not limited to, pharma- ceutically acceptable aqueous oral dispersions, emulsions, solutions, and syrups. See, for example, Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002). In addition to ganaxolone particles, the liquid dosage form may include additives such as (a) disintegrants, (b) dispersants, (c) wetting agents, (d) at least one preservative, (e) viscosity enhancers, (f) at least one sweetener, (g) at least one flavoring agent, (h) complexing agents, and (i) ionic dispersion modifiers. In some embodiments, the aqueous dispersion may further include a crystallization inhibitor.

[0144] Examples of disintegrants for use in aqueous suspensions and dispersions include starches, e.g. natural starches such as corn starch or potato starch, pregelatinized starches such as National 1551 or Amijele®, or sodium starch glycolate such as Promogel® or Explotab®; celluloses, e.g. wood products, microcrystalline cellulose (e.g. Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Examples of suitable crosslinking agents include, but are not limited to, crosslinked starches such as sodium starch glycolate; crosslinked polymers such as crospovidone; crosslinked polyvinylpyrrolidone; alginates such as alginic acid or salts of alginic acid such as sodium alginate; clays such as Veegum HV (magnesium aluminum silicate); gums such as agar, guar, carob, karaya, pectin, or tragacanth; sodium starch glycolate; bentonite; natural sponges; surfactants; resins such as cation exchange resins; citrus pulp; sodium lauryl sulfate; sodium lauryl sulfate in mixed starches.

[0145] In some embodiments, dispersing agents suitable for the aqueous suspensions and dispersions described herein are known in the art and include, for example, hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP; trade name Plasdone®), carbohydrate-based dispersing agents such as hydroxypropyl cellulose and hydroxypropyl cellulose ethers (e.g., HPC, HPC-SL, and HPC-L), hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ethers (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M), sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone / vinyl acetate copolymers (Plasdone®, e.g., S-630), ethylene oxide and formaldehyde-containing 4-(1,1,3,3-tetramethylbutyl)-phenol polymers (also known as tyloxapol), poloxamers (e.g., Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g., Tetronic 9080, also known as Poloxamine 9080, which is a tetrafunctional block copolymer derived by the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, NJ)).In other embodiments, the dispersing agent is selected from the group consisting of hydrophilic polymers; electrolytes; Tween® 60 or 80; PEG; polyvinylpyrrolidone (PVP); hydroxypropyl cellulose and hydroxypropyl cellulose ethers (e.g., HPC, HPC-SL, and HPC-L); hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ethers (e.g., HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M, and Pharmacoat® USP2910 (Shin-Etsu); sodium carboxymethylcellulose; methylcellulose; hydroxyethyl cellulose; hydroxypropyl methyl-cellulose phthalate; hydroxypropyl methyl-cellulose acetate stearate; amorphous cellulose; magnesium aluminum silicate; triethanolamine; polyvinyl alcohol (PVA); ethylene oxide and formaldehyde-containing 4-(1,1,3,3-tetramethylbutyl)-phenol polymers; poloxamers (e.g., Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide; or poloxamine (e.g., Tetronic 908®, also known as poloxamine 908%).

[0146] Wetting agents (including surfactants) suitable for the aqueous suspensions and dispersions described herein are known in the art and include, but are not limited to, acetyl alcohol, glycerol monostearate, polyoxyethylene sorbitan fatty acid esters (e.g., those sold under the trade name Tweens, such as Tween 20 and Tween 80 (ICI Specialty Chemicals)), and polyethylene glycols (e.g., Carbowaxs 3350 and 1450, and Carpool 934 (Union Carbide)), oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl sulfate, sodium docusate, triacetin, vitamin E TPGS, sodium taurocholate, simethicone, phosphotidylcholine, and the like.

[0147] Suitable preservatives for the aqueous suspensions or dispersions described herein include, for example, potassium sorbate, parabens (e.g., methylparaben and propylparaben) and their salts, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl alcohol or benzyl alcohol, or phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride. The preservatives used herein are incorporated into the dosage form at a concentration sufficient to inhibit microbial growth. In one embodiment, the aqueous liquid dispersion may contain methylparaben and propylparaben at concentrations ranging from about 0.01% to about 0.3% by weight of methylparaben based on the weight of the aqueous dispersion, and 0.005% to 0.03% by weight of propylparaben based on the total weight of the aqueous dispersion. In yet another embodiment, the aqueous liquid dispersion may contain 0.05 to about 0.1% by weight of methylparaben and 0.01 to 0.02% by weight of propylparaben based on the total weight of the aqueous dispersion.

[0148] Suitable viscosity enhancing agents for the aqueous suspensions or dispersions described herein include, but are not limited to, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, Plasdone.RTM.S-630, carbomer, polyvinyl alcohol, alginate, acacia, chitosan, and combinations thereof. The concentration of the viscosity enhancing agent will vary depending on the agent selected and the viscosity desired.

[0149] Examples of natural and artificial sweeteners suitable for the aqueous suspensions or dispersions described herein include, for example, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, bavarois, berry, blackcurrant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, silamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, liquorice (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycyrrhetinate (MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidin DC, neohesperidin syrup, glycyrrhetinate ... oteme, orange, pear, peach, peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talc, sucralose, sorbitol, Swiss cream, tagatose, tangerine, thaumatin, tutti frutti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any combination of these flavoring ingredients, such as anise menthol, cherry anise, cinnamon orange, cherry cinnamon, chocolate-mint, honey lemon, lemon lime, lemon mint, menthol eucalyptus, orange cream, vanilla mint, and mixtures thereof. In one embodiment, the aqueous liquid dispersion may include a sweetening or flavoring agent at a concentration ranging from about 0.0001% to about 10.0% by weight of the aqueous dispersion, hi another embodiment, the aqueous liquid dispersion may include a sweetening or flavoring agent at a concentration ranging from about 0.0005% to about 5.0% by weight of the aqueous dispersion.In yet another embodiment, the aqueous liquid dispersion may contain a sweetening or flavoring agent in a concentration ranging from about 0.0001 wt% to 0.1 wt%, from about 0.001% to about 0.01% by weight, or from 0.0005% to 0.004% by weight of the aqueous dispersion.

[0150] In addition to the additives listed above, the liquid ganaxolone formulations may also include inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifying agents.

[0151] In some embodiments, the ganaxolone formulation can be a self-emulsifying drug delivery system (SEDDS). An emulsion is a dispersion of one immiscible phase in another, usually in the form of droplets. Generally, emulsions are created by strong mechanical dispersion. In contrast to emulsions or microemulsions, SEDDS spontaneously form emulsions when added to excess water without any external mechanical dispersion or agitation. The advantage of SEDDS is that only gentle mixing is required to disperse the droplets throughout the solution. In addition, water or an aqueous phase can be added just prior to administration, ensuring stability of unstable or hydrophobic active ingredients. Thus, SEDDS provides an effective delivery system for oral and parenteral delivery of hydrophobic active ingredients. SEDDS can provide improved bioavailability of hydrophobic active ingredients. Methods for making self-emulsifying dosage forms are known in the art and include, but are not limited to, US Pat. Nos. 5,858,401, 6,667,048, and 6,960,563.

[0152] Exemplary emulsifiers include ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, sodium lauryl sulfate, sodium docusate, cholesterol, cholesterol esters, taurocholic acid, phosphotidylcholine, oils (such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, fatty acid esters of sorbitan, or mixtures of these substances.

[0153] In certain preferred embodiments, the liquid pharmaceutical formulation comprises ganaxolone, hydroxypropylmethylcellulose, polyvinyl alcohol, sodium lauryl sulfate, simethicone, methylparaben, propylparaben, sodium benzoate, citric acid, and sodium citrate, and has a pH of 3.8 to 4.2. The suspension may comprise ganaxolone at a concentration of 50 mg / ml. The formulation may further comprise a pharma- ceutically acceptable sweetener (e.g., sucralose) and / or a pharma-ceutically acceptable flavoring agent (e.g., cherry). The formulation may be packaged in, for example, 120 mL, 180 mL, 240 mL, or 480 mL bottles.

[0154] Formulations for oral administration can be oral solid dosage forms (e.g., oral capsules or tablets) or liquids (e.g., oral suspensions containing ganaxolone). In certain embodiments, oral suspensions are administered to patients using an oral syringe.

[0155] In certain embodiments, the liquid formulations of the present invention may be those described and prepared in applicant's prior patent, U.S. Patent No. 8,022,054, entitled "Liquid Ganaxolone Formulations and Methods for the Making and Use Thereof." However, oral liquid (e.g., suspension) formulations of ganaxolone may also be prepared according to other methods known to those of skill in the art.

[0156] In certain preferred embodiments, the oral solid formulations of the present invention may be those formulations described and prepared in applicant's prior patent, U.S. Patent No. 7,858,609, entitled "Solid Ganaxolone Formulations and Methods for the Making and Use Thereof." However, oral solid dosage formulations of ganaxolone may also be prepared according to other methods known to those skilled in the art.

[0157] For example, as described in U.S. Patent No. 7,858,609, an oral solid formulation may include stabilized particles, the particles containing ganaxolone, a hydrophilic polymer, a wetting agent, and an effective amount of a complexing agent to stabilize initial particle growth and particle growth after an end point is reached, the complexing agent being an organic small molecule having a molecular weight less than 550 and containing a moiety selected from the group consisting of a phenol moiety, an aromatic ester moiety, and an aromatic acid moiety, the stabilized particles having a volume weighted mean diameter (D50) of about 50 nm to about 500 nm, and the complexing agent being present in an amount of about 0.05% to about 5% (w / w) based on the weight of the solid particles. The hydrophilic polymer may be in an amount of about 3% to about 50% (w / w) based on the weight of the solid particles. The wetting agent may be in an amount of about 0.01% to about 10% (w / w) based on the weight of the solid particles. Ganaxolone may be present in an amount of about 10% to about 80% (in certain embodiments, forming about 50% to about 80%) based on the weight of the stabilized particles. The stabilized particles, when dispersed in simulated gastric fluid (SGF) or simulated intestinal fluid (SIF) at a concentration of 0.5 to 1 mg ganaxolone / mL and placed in a heat bath at 36°C to 38°C for 1 hour, do not exhibit an increase in volume weighted mean diameter (D50) of more than about 150% compared to the volume weighted mean diameter (D50) of the stabilized particles when dispersed in distilled water under the same conditions. In this case, the volume weighted mean diameter (D50) of the stabilized particles dispersed in SGF or SIF is less than about 750 nm. The stabilized particles, when dispersed in 15 mL of SGF or SIF at a concentration of 0.5 to 1 mg ganaxolone / mL, do not exhibit an increase in D50 of more than about 150% compared to the volume weighted mean diameter (D50) of the stabilized particles when dispersed in distilled water under the same conditions. In this case, the volume weighted mean diameter (D50) of the stabilizing particles dispersed in SGF or SIF is less than about 750 nm. The solid stabilizing particles can be combined with any excipient and prepared for administration in powder form or incorporated into a dosage form selected from the group consisting of tablets or capsules. The complexing agent can be paraben, benzoic acid, phenol, sodium benzoate, methyl anthranilate, etc. The hydrophilic polymer can be a cellulosic polymer, a vinyl polymer, and mixtures thereof.The cellulosic polymer can be a cellulose ether, such as hydroxypropylmethylcellulose. The vinyl polymer can be a polyvinyl alcohol, such as vinylpyrrolidone / vinyl acetate copolymer (S630). The wetting agent can be sodium lauryl sulfate, a pharma- ceutically acceptable salt of docusate, and mixtures thereof. When the particles are incorporated into a solid dosage form, the solid dosage form can further comprise at least one pharma- ceutically acceptable excipient, such as an ionic dispersion modifier, a water-soluble spacer, a disintegrant, a binder, a surfactant, a plasticizer, a lubricant, a diluent, and any combination or mixture thereof. The water-soluble spacer can be a sugar or an ammonium salt, such as fructose, sucrose, glucose, lactose, mannitol. The surfactant can be, for example, a polysorbate. The plasticizer can be, for example, polyethylene glycol. The disintegrant can be cross-linked sodium carboxymethylcellulose, crospovidone, mixtures thereof, and the like.

[0158] Capsules can be prepared, for example, by placing the bulk mixed ganaxolone formulations described herein inside a capsule. In some embodiments, the ganaxolone formulations (non-aqueous suspensions and solutions) are placed in soft gelatin capsules. In other embodiments, the ganaxolone formulations are placed in non-gelatin capsules, such as standard gelatin capsules or HPMC-containing capsules. In other embodiments, the ganaxolone formulations are placed in sprinkle capsules, where the capsule can be swallowed whole or opened and the contents sprinkled on food before eating. In some embodiments of the present invention, the therapeutic dose is divided into multiple (e.g., two, three, or four) capsules. In some embodiments, the entire dose of the ganaxolone formulation is delivered in capsule form.

[0159] In certain embodiments, each capsule contains either 200 mg or 225 mg of ganaxolone, as well as hydroxypropyl methylcellulose, sucrose, polyethylene glycol 3350, polyethylene glycol 400, sodium lauryl sulfate, sodium benzoate, anhydrous citric acid, sodium methylparaben, microcrystalline cellulose, 30% simethicone emulsion, gelatin capsule, polysorbate 80, and sodium chloride. In some embodiments, the capsule is size 00.

[0160] Alternatively, the oral dosage forms of the present invention can be in the form of controlled release dosage forms as described in US Pat. No. 7,858,609.

[0161] In certain preferred embodiments, the oral solid formulation of the invention may be the formulation described and prepared in US Pat. No. 8,367,651.

[0162] As described in U.S. Patent No. 8,367,651, the solid stabilized particles may contain ganaxolone, a hydrophilic polymer, a wetting agent, and an effective amount of a complexing agent to stabilize the initial particle growth and the particle growth after it has reached an end point, the complexing agent being an organic small molecule having a molecular weight less than 550 and containing a moiety selected from the group consisting of a phenolic moiety, an aromatic ester moiety, and an aromatic acid moiety, the stabilized particles having a particle volume weighted mean diameter (D50) of about 50 nm to about 500 nm, and the concentration of ganaxolone in the solid stabilized particles is at least 50% by weight. The hydrophilic polymer may be in an amount of about 3% to about 50% (w / w) based on the weight of the solid particles. The wetting agent may be in an amount of about 0.01% to about 10% (w / w) based on the weight of the solid particles. In some embodiments, the stabilized particles, when dispersed in simulated gastric fluid (SGF) or simulated intestinal fluid (SIF) at a concentration of 0.5-1 mg ganaxolone / mL and placed in a heat bath at 36° C.-38° C. for 1 hour, do not exhibit an increase in volume weighted mean diameter (D50) of more than about 150% compared to the volume weighted mean diameter (D50) of the stabilized particles when dispersed in distilled water under the same conditions. In this case, the volume weighted mean diameter (D50) of the stabilized particles dispersed in SGF or SIF is less than about 750 nm. In some embodiments, the stabilized particles, when dispersed in 15 mL of SGF or SIF at a concentration of 0.5-1 mg ganaxolone / mL compared to the volume weighted mean diameter (D50) of the stabilized particles when dispersed in distilled water under the same conditions, do not exhibit an increase in D50 of more than about 150%. In this case, the volume weighted mean diameter (D50) of the stabilized particles dispersed in SGF or SIF is less than about 750 nm. In some embodiments, ganaxolone may be present in an amount of greater than 50% to about 80% by weight of the particles. In some embodiments, the stabilized particles, when dispersed in simulated gastric fluid (SGF) or simulated intestinal fluid (SIF) at a concentration of 0.5 to 1 mg ganaxolone / mL and placed in a heat bath at 36° C. to 38° C. for 1 hour, do not exhibit an increase in volume weighted mean diameter (D50) of more than about 150% compared to the volume weighted mean diameter (D50) of the stabilized particles when dispersed in distilled water under the same conditions. In this case, the volume weighted mean diameter (D50) of the stabilized particles dispersed in SGF or SIF is less than about 750 nm.In some embodiments, the solid stabilizing particles may be in the form of a powder. In some embodiments, the particles may be incorporated into a dosage form selected from the group consisting of tablets or capsules. In some embodiments, the volume weighted mean diameter (D50) of the stabilizing particles dispersed in distilled water is about 100 nm to about 350 nm. In some embodiments, the complexing agent is selected from the group consisting of parabens, benzoic acid, methyl anthranilate, and pharma- ceutically acceptable salts thereof, and mixtures thereof. In some embodiments, the parabens are selected from the group consisting of methylparaben, ethylparaben, propylparaben, and pharma- ceutically acceptable salts thereof, and mixtures thereof. In some embodiments, the hydrophilic polymer is selected from the group consisting of cellulosic polymers, vinyl polymers, and mixtures thereof. In some embodiments, the cellulosic polymer is a cellulose ether. In some embodiments, the cellulose ether is hydroxypropylmethylcellulose. In some embodiments, the vinyl polymer is polyvinyl alcohol. In some embodiments, the wetting agent is selected from the group consisting of sodium lauryl sulfate, pharma- ceutically acceptable salts of docusate, and mixtures thereof. In some embodiments, the particles are incorporated into a solid dosage form, which further comprises at least one pharma- ceutically acceptable excipient selected from the group consisting of an ionic dispersion modifier, a water-soluble spacer, a disintegrant, a binder, a surfactant, a plasticizer, a lubricant, and any combination or mixture thereof. In some embodiments, the pharma- ceutically acceptable excipient comprises an ionic dispersion modifier. In some embodiments, the ionic dispersion modifier is in an amount of about 1% to about 50% (w / w) based on the weight of the solid particles. In some embodiments, the ionic dispersion modifier is a salt. In some embodiments, the ionic dispersion modifier is an inorganic salt selected from the group consisting of magnesium salts, calcium salts, lithium salts, potassium salts, sodium salts, and mixtures thereof. In some embodiments, the ionic dispersion modifier is an organic salt selected from the group consisting of citrate, succinate, fumarate, malate, maleate, tartrate, glutarate, lactate, and mixtures thereof.In some embodiments, the pharma- ceutically acceptable excipient comprises a water-soluble spacer. In some embodiments, the water-soluble spacer is in an amount of about 2% to about 60% (w / w) based on the weight of the solid particles. In some embodiments, the water-soluble spacer is a sugar or an ammonium salt. In some embodiments, the sugar is selected from the group consisting of fructose, sucrose, glucose, lactose, mannitol, and mixtures thereof. In some embodiments, the disintegrant is selected from the group consisting of cross-linked sodium carboxymethylcellulose, crospovidone, and any combination or mixture thereof. In some embodiments, the surfactant is a polysorbate. In some embodiments, the plasticizer is polyethylene glycol. In some embodiments, the solid dosage form is an immediate release dosage form. In some embodiments, the solid dosage form is a controlled release dosage form. In some embodiments, the particles are incorporated into an oral solid dosage form, the dosage form comprising (i) a controlled release component comprising a first portion of stabilized particles and a controlled release agent, and (ii) an immediate release component comprising a second portion of stabilized particles, the first and second portions of stabilized particles having a volume weighted mean diameter (D50) of about 50 nm to about 500 nm. In some embodiments, the controlled release:immediate release ratio of ganaxolone is about 4:1 to about 1:4. In some embodiments, the dosage form exhibits a therapeutic effect from about 8 to about 24 hours after administration. In some embodiments, the complexing agent is in an amount of about 0.05% to about 5% (w / w) based on the weight of the solid particles. In some embodiments, the complexing agent comprises methylparaben or a salt thereof. In some embodiments, the complexing agent comprises benzoic acid or a salt thereof. In some embodiments, the complexing agent comprises methyl anthranilate. In some embodiments, the formulation comprises about 200 mg to about 800 mg of ganaxolone.

[0163] As further described in U.S. Pat. No. 8,367,651, the solid stabilized particles may also contain ganaxolone, a hydrophilic polymer, a wetting agent, and an effective amount of a complexing agent, the complexing agent being selected from the group of organic small molecules having a molecular weight less than 550 and containing a moiety selected from the group consisting of a phenolic moiety, an aromatic ester moiety, and an aromatic acid moiety, the stabilized particles having a volume weighted mean diameter (D50) of about 50 nm to about 500 nm, and the concentration of ganaxolone in the solid stabilized particles is at least 50% by weight. In some embodiments, the ganaxolone is present in an amount of more than 50% to about 80% by weight of the particle. In some embodiments, the particles are incorporated into a dosage form selected from the group consisting of a tablet or capsule. In some embodiments, the complexing agent is selected from the group consisting of parabens, benzoic acid, methyl anthranilate, and pharma- ceutically acceptable salts thereof and mixtures thereof.

[0164] In certain preferred embodiments, the formulation of the present invention may be a pharmaceutical composition described in US Pat. No. 9,029,355.

[0165] In certain embodiments, the composition may include ganaxolone nanoparticles as described above, further as a formulation as described in U.S. Patent No. 9,029,355. In some embodiments, the pharmaceutical composition is a compressed tablet. In some embodiments, the pharmaceutical composition is contained within a capsule.

[0166] E. Use in combination In certain embodiments, an additional antiepileptic drug is administered before, during, or after the continuous intravenous infusion of ganaxolone. Examples of additional antiepileptic drugs that can be administered are described below in the "Additional Antiepileptic Drugs" section. In some embodiments, the additional antiepileptic drug can be selected from the group consisting of benzodiazepines, phenytoin, fosphenytoin, valproic acid, phenobarbital, and / or levetiracetam. In some embodiments, the antiepileptic drug is a benzodiazepine (e.g., diazepam, lorazepam, etc.).

[0167] In certain embodiments, the additional antiepileptic drug administered with ganaxolone is chlordesmethyldiazepam, loreclezole, methsuximide, dipropylacetamide, pheneturide, 2-fluoro-2-phenyl-1,3-propanediyldicarbamate, ethylphenylhydantoin, 6-methoxytryptoline, N-desmethylclobazam, anthranilic acid, Org 2766, sulthiame, dimethadione, 2-(2,3-dicarboxycyclopropyl)glycine, NCS 382, ​​pipequaline, bretazenil, denzimol, stiripentol, progabide, brivaracetam, U 54494A, Epidiolex, bromide, mephenytoin, ethosuximide, trimethadione, mebeverine, 5-(2-cyclohexylidene-ethyl)-5-ethylbarbituric acid, 2-propyl-2-pentenoic acid, neokyotorphin, 4-phenyl-perhydropyrrole (1,2-a) pyrazine-1,3-dione, alpha-hexachlorocyclohexane, abecarnil, tramiprosate, thioperamide, DN 1417, remacemide, bimethyl, taglutimide, N-(4,4-diphenyl-3-butenyl) nipecotic acid, gaboxadol, ZK 93423, PD 117302, ZK 93426, indeloxazine, milacemide, primidone, ZK 91296, ezogabine, kavain, vanillin, neurotropin, fosphenytoin, zaleplon, CGP 39551, 2-amino-7-phosphonoheptanoic acid, 2-amino-4-phosphonobutyric acid, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid, 2-amino-4-methyl-5-phosphono-3-pentenoic acid, rimcazole, angelicin, tiagabine, levetiracetam, zonisamide, paraldehyde, 2,3-piperidinedicarboxylic acid, 6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione, eslicarbazepine acetate, vigabatrin, 1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-Dihydroimidazol-2-one, Glutamic acid diethyl ester, Fludiazepam, Gidazepam, Ethotoin, Mephobarbital, Acetazolamide, NNC 711, Indol-3-ylpyruvic acid, Rufinamide, Topiramate, Clonazepam, Tiletamine, Riluzole, Progabide, Deramciclane, Doramectin, Chlormethiazole, L 701324, Clorazepate dipotassium, Lacosamide, Thiopental, Valproic acid, Felbamate, 2,3-Dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline, 7-Nitroindazole, GYKI 52466, phenazepam, 4-amino-3-phenylbutyric acid, eperisone, sydnocarb, riodipine, nimetazepam, nitrazepam, meprobamate, clobazam, estazolam, lorazepam, benzobarbital, magnesium sulfate, tizanidine, lamotrigine, flunarizine, pregabalin, gabapentin, phenytoin, phenobarbital, oxcarbazepine, carbamazepine, medazepam, pharma- ceutically acceptable salts thereof, and mixtures of any of the foregoing.

[0168] In certain embodiments, the additional antiepileptic drug administered with ganaxolone is selected from the group consisting of benzodiazepines, phenytoin, fosphenytoin, valproic acid, phenobarbital, and / or levetiracetam.

[0169] In certain embodiments, the additional antiepileptic drug is a benzodiazepine (e.g., diazepam, lorazepam, etc.).

[0170] F. Definition All publications and patents cited in this disclosure are incorporated by reference in their entirety. In the event that any material incorporated by reference contradicts or is inconsistent with this specification, this specification will control for such material. The citation of any reference herein is not an admission that such reference is prior art to this disclosure. When a range of values ​​is expressed, it includes embodiments using any particular value within the range. Furthermore, reference to values ​​stated in a range includes every value within that range. All ranges are inclusive and combinable.

[0171] The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item.

[0172] The term "about" is used synonymously with the term "approximately." When used in reference to doses and amounts of ganaxolone, the term "about" refers to values ​​that are slightly off the quoted value, i.e., around 0.1% to 20%. When used in reference to a period of administration, the term "about" is meant for purposes of the present invention to include 2 hours before and 2 hours after the period. For example, when a period is "about 6 hours," it includes a 4 hour period and an 8 hour period. The term "about" in reference to a recited pharmacokinetic parameter value (e.g., plasma concentration) or range of pharmacokinetic parameter values ​​(e.g., range of plasma concentration values) includes pharmacokinetic parameters and ranges that are within 80% to 120% of the recited value or range.

[0173] An "active agent" is any compound, component, or mixture that, when administered to a subject, alone or in combination with another agent, directly or indirectly exerts a physiological effect on the patient. When the active agent is a compound, it includes salts, solvates (including hydrates) of the free compound or free salt, crystalline and non-crystalline forms, as well as various polymorphs of the compound. The compound may contain one or more asymmetric elements, such as a stereocenter, stereoaxis, e.g., an asymmetric carbon atom, such that the compound may exist in different stereoisomeric forms. Such compounds may be, for example, racemic or optically active forms. In the case of compounds with two or more asymmetric elements, such compounds may further be mixtures of diastereomers. In the case of compounds with asymmetric centers, it should be understood that all optical isomers in pure form and mixtures thereof are included. In addition, compounds with carbon-carbon double bonds may be Z and E forms, and all isomeric forms of the compound are included in the present invention. In such situations, single enantiomers, i.e., optically active forms, may be obtained by asymmetric synthesis, synthesis from optically pure precursors, or resolution of the racemate. Resolution of the racemates can also be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.

[0174] As used herein, the term "antiepileptic drug" is synonymous with the term "antiseizure drug" and refers to a medication used to control seizures and / or epilepsy. The term "antiepileptic drug" encompasses anticonvulsants (i.e., medications that prevent, stop, or reduce seizures) and medications that prevent epileptic seizures.

[0175] As used herein, the term "acute repetitive seizures" (ARS) refers to a condition in epilepsy patients that is marked by multiple seizures occurring over a relatively short period of time (usually 24 hours). ARS can be convulsive or non-convulsive. Although ARS can progress to SE, there are usually periods of recovery (intermissions) between the seizures and / or convulsions.

[0176] The abbreviation "EEG" means electroencephalography.

[0177] As disclosed herein, the terms "serum" and "plasma" may be used interchangeably.

[0178] The term "intravenous bolus" refers to a relatively large dose of a pharmaceutical agent (eg, ganaxolone) administered within a short period of time, eg, 1 to 60 minutes (eg, 3 or 5 minutes).

[0179] The term "Cmax" refers to the plasma concentration of ganaxolone at the time of maximum concentration.

[0180] The abbreviation "eIND" stands for Emergency Investigational New Drug Application.

[0181] The abbreviation "GNX" stands for ganaxolone.

[0182] "Ganaxolone" means 3α-hydroxy-3β-methyl-5α-pregnan-20-one.

[0183] "Infusion" administration is parenteral administration, usually intravenously, but in some embodiments including other parenteral routes such as epidural administration. Infusion administration occurs over a longer period of time than bolus administration, e.g., over a longer period of time than 1 hour (e.g., from about 1 hour to about 120 hours).

[0184] As used herein, the term "subject" refers to a human in need of medical treatment for status epilepticus.

[0185] A "pharmaceutical composition" is a composition that contains at least one active agent, such as a compound or salt, solvate, or hydrate of ganaxolone, and at least one other substance, such as a carrier. A pharmaceutical composition optionally contains one or more additional active agents. Where indicated, the pharmaceutical composition meets the US FDA GMP (Good Manufacturing Practice) standards for human or non-human drugs. A "combination preparation" is a combination of at least two active agents, which can be combined into a single dosage form or provided in separate dosage forms with instructions for using the active agents together to treat disorders such as status epilepticus.

[0186] The term "status epilepticus" (SE) is defined as prolonged, self-contained or recurrent seizures without recovery of consciousness between seizures (Lowenstein and Alldredge, 1998). The International League Against Epilepsy further defines SE as a condition resulting from either failure of mechanisms involved in seizure termination or initiation of mechanisms, which, depending on the type and duration of the seizure, may result in abnormally prolonged seizures (5 min for tonic-clonic SE, 10 min for focal SE with impaired consciousness) and long-term outcomes (after 30 min for tonic-clonic SE, 60 min for focal SE with impaired consciousness), including neuronal death and / or damage, and neuronal network changes. SE includes generalized convulsive status epilepticus (GCSE), nonconvulsive status epilepticus (NCSE), early status epilepticus, definite status epilepticus (ESE), refractory status epilepticus (RSE), and super refractory status epilepticus (SRSE).

[0187] GCSE is defined as status epilepticus, characterized by convulsions associated with tonic-clonic movements of the limbs and impaired mental status, and may result in focal neurological disability lasting hours to days after the episode (Brophy et al, 2012).GCSE is associated with numerous complications, including cardiac arrhythmias, rhabdomyolysis, pulmonary edema, electrolyte and glucose imbalances, and thermoregulation.

[0188] NCSE is defined as EEG findings of seizure activity without convulsive symptoms, but subjects with acute illness are in status epilepticus where mental status impairment may be present during the NCSE episode (Brophy et al, 2012).

[0189] RSE is defined as status epilepticus that is uninterrupted after administration of first-line (i.e., benzodiazepines) and second-line antiseizure medications. Duration is not part of the definition of RSE; RSE is based solely on the medications given and the duration of the seizures (Falco-Walter et al, 2016).

[0190] SRSE is defined as SE that lasts for more than 24 hours after the onset of loss of consciousness and includes cases where SE recurs upon abatement of loss of consciousness or withdrawal ( Shorvon and Ferlisi, 2011 ).

[0191] The term "seizure" or "epileptic seizure" means a transient occurrence of signs and / or symptoms associated with abnormal, excessive, or synchronous neural activity in the brain. Seizures are detected in the brain by measuring EEG activity. There may be (intracranial) seizures that do not manifest as convulsions and are detectable only by EEG activity. The term "seizure activity" encompasses convulsions and EEG seizures.

[0192] A "tapering period" is a period during which the continuous intravenous infusion of ganaxolone is gradually tapered until the intravenous infusion is discontinued.

[0193] The term "therapeutically effective amount" as used herein refers to an amount of ganaxolone sufficient to terminate or reduce the severity of status epilepticus or one or more symptoms thereof. For example, an amount for sufficient seizure suppression. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. The effective amount of ganaxolone will be selected by those skilled in the art depending on the specific patient and disease. It is understood that the therapeutically effective amount may vary from subject to subject due to variations in the metabolism of ganaxolone, the age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician.

[0194] As used herein, the term "treat" or "treatment" refers to any improvement or any result of status epilepticus, such as reducing or eliminating seizure activity, and / or reducing or eliminating convulsions, and / or completely suppressing status epilepticus (i.e., suppressing EEG seizure activity and convulsions). As is readily understood in the art, complete eradication of SE is preferred, but is not a requirement of therapeutic intervention. Treatment may be a cure, remedy, amelioration, alleviation, alteration, amelioration, remission, reversal, or effect on a disorder, symptoms of SE, or predisposition to SE. For example, treatment may achieve seizure suppression.

[0195] 5. Equivalent Other suitable modifications and adaptations of the methods of the invention described herein will be obvious and will be readily apparent to those skilled in the art that may be made using suitable equivalents without departing from the scope of the disclosure or embodiments. While certain compounds and methods have been described in detail above, the same will be more clearly understood by reference to the following examples, which are presented for purposes of illustration and are not intended to be limiting. EXAMPLES

[0196] 6. Working Example The present invention is further illustrated by the following examples, which are not intended to be limiting in any way.

[0197] Example 1: Preliminary Clinical Evidence for the Pharmacokinetics and Pharmacodynamics of Intravenous Ganaxolone A Phase I clinical trial evaluating an IV ganaxolone formulation was conducted. The clinical trial was designed to investigate the safety, pharmacokinetics, and pharmacodynamics of an intravenous bolus of ganaxolone and a continuous intravenous infusion of ganaxolone in 30 healthy subjects. Subjects received either an intravenous bolus of ganaxolone at a dose of 10-20 mg over 2 minutes to 1 hour, or an intravenous bolus of ganaxolone at a dose of 6 mg over 5 minutes and continuous intravenous infusion at a dose of 20 mg / hour for 4 hours.

[0198] Pharmacokinetic analysis demonstrated that all 30 healthy subjects treated with active ganaxolone had quantifiable plasma ganaxolone levels and that ganaxolone plasma concentrations were generally proportional to the administered dose. The plasma concentrations achieved in this study were within the range associated with potential anticonvulsant activity based on previous data from subjects given oral ganaxolone. Analysis of the pharmacodynamic data demonstrated that bispectral index (BIS) scores correlated with the estimated ganaxolone plasma concentration at the time of BIS measurement. As expected, higher plasma concentrations were associated with lower BIS scores (Figure 1). There was little or no delay between the appearance of drug in plasma and the change in BIS score.

[0199] Example 2: Preliminary Clinical Evidence for Efficacy in Subjects with Status Epilepticus Example 2 is an ongoing double-blind, randomized, placebo-controlled Phase 2 study designed to evaluate the safety, tolerability, and efficacy of adjunctive IV GNX in subjects with SE who have failed initial treatment with a benzodiazepine and at least one AED. The study consists of a small open-label arm to optimize infusion parameters and perform a preliminary evaluation of the safety, efficacy, and tolerability of GNX administration, followed by a double-blind arm randomized to receive GNX or placebo in a 1:1 ratio. In both the open-label and double-blind arms, treatment with the investigational drug is adjunctive to standard of care, with subjects receiving a bolus of the investigational drug along with a concurrent continuous infusion treatment, with the goal of administering a therapeutic dose that will terminate seizures as quickly as possible and prevent neurological damage in a durable manner. Specifically, the investigational drug will be added to standard of care when a first second-line IV AED is ineffective in the treatment of SE and a second second-line IV AED is medically indicated. The investigational drug should be administered with the second-line IV AED as close to the start of administration of the second second-line IV AED as possible but before the start of the tertiary IV anesthetic agent for burst suppression.

[0200] Ganaxolone for this study is a proprietary IV formulation solubilized with Captisol® (betadex sulfobutylether sodium). Maximum Captisol® levels will not exceed 50 g per day. Ganaxolone for IV administration will be supplied to the site in individual glass vials containing ganaxolone 3 mg / mL in the open-label group and ganaxolone 5 mg / mL in the double-blind group. Placebo for double-blind IV administration will be supplied to the site in blind-matched vials containing 0.9% sodium chloride solution.

[0201] The primary objective of this study is to determine that IV GNX given concomitantly with second-line IV AED therapy is safe and effective in terminating SE after at least one second-line IV AED therapy has already failed, avoiding escalation of treatment to IV anesthetic agents (third-line agents) for seizure control. Secondary objectives include assessing mortality, terminating seizures in subjects with SE, and evaluating the pharmacokinetics of IV GNX in subjects with SE. Approximately 262 subjects will be enrolled across the open-label and double-blind arms.

[0202] The entire adjunctive GNX therapy infusion treatment is scheduled to take 3 or 5 days (including an 18-hour taper). All subjects will receive a 3-minute bolus and a continuous infusion at a rate of about 10 mg / hour to about 85 mg / hour or about 18 mg / hour to about 80 mg / hour, with an 18-hour taper. Once the study drug is initiated, it will be delivered for 2 full days or 4 full days (48 hours or 96 hours) before taper. At the end of dosing on the second day, a decision will be made to administer study drug for an additional 2 days (i.e., a total of 4 days). If, in the investigator's medical judgment, the subject would continue to benefit from study drug administration, ganaxolone will be administered for an additional 2 days.

[0203] The dose of ganaxolone is reduced and then discontinued. To reduce ganaxolone after 2 or 4 days of treatment, the continuous infusion is reduced by 25% every 6 hours, i.e., 75%, 50%, 25% over 18 hours, then discontinued. If the infusion rate becomes too slow during this 18 hour period to maintain the infusion line, the infusion can be discontinued at that time. If the subject takes less than 2 hours to receive the study drug and / or requires an IV anesthetic for seizure control (a third-line agent), it may be necessary to discontinue the study drug without a reduction in the study drug dose.

[0204] The following dosing schedule is planned:

[0205] Subjects weighing at least 40kg: A continuous infusion is given at 80 mg / hour with a 25 mg bolus dose (over approximately 3 minutes) for 2 hours, followed by a rate of 40 mg / hour for 6 hours, followed by a continuous infusion at 18 mg / hour for the remaining 16 hours on day 1. At the end of the first 24-hour continuous infusion (day 1), the infusion rate is increased to 29 mg / hour for the remainder of the treatment period, i.e., day 2 (24-48 hours) or days 2-4 (24-96 hours). [Table 2]

[0206] For subjects weighing less than 40 kg, dose on a per kilogram basis: A continuous infusion is given at 1.2 mg / kg / hour with a bolus dose of 0.375 mg / kg (over approximately 3 minutes) for 2 hours, followed by a rate of 0.6 mg / kg / hour for 6 hours and 0.27 mg / kg / hour for the remaining 16 hours on day 1. At the end of the first 24-hour continuous infusion (day 1), the infusion rate is increased to 0.435 mg / kg / hour for the remainder of the treatment period, i.e., days 2 (24-48 hours) or days 2-4 (24-96 hours). [Table 3]

[0207] This infusion dosing parameter is expected to result in a daily dose of ganaxolone of approximately 714 mg / day and Captisol of approximately 50 grams / day. Based on PK modeling, it is predicted that maximum ganaxolone concentrations should be maintained within 1,000 ng / mL during the infusion, although some variability is expected due to, for example, differences in subject weight.

[0208] As of March 22, 2019, five subjects had been enrolled in the open-label arm of Study 1042-SE-2001 under the original protocol, which limited daily Captisol exposure to 35 g / day. In all five cases, an initial 3-minute bolus dose of GNX 30 mg concomitant with a 2-hour continuous infusion at 85 mg / hour, followed by a 2-hour GNX infusion at 40 mg / hour, resulted in immediate cessation of seizures as evidenced by EEG activity in SE subjects who were originally resistant to several second-line IV AEDs considered standard of care. According to the investigator, the initial EEG pattern after initiation of the infusion showed "mild" burst suppression, which was maintained for several hours in all subjects. Although some subjects required intubation to secure the airway, none required intubation as a direct result of GNX therapy. In addition, no GNX-related cardiovascular events requiring pharmacological intervention were observed. When GNX exposure was reduced so as not to exceed this limit (20 mg / h for 2 h, then 10 mg / h for the remaining 18 h of day 1), seizure control could not be maintained and recurrence of seizure activity (but not SE) was observed as evidenced by EEG changes. Pharmacokinetic modeling data from these five subjects (Figure 2) suggested that GNX exposure levels of approximately 1000 ng / mL were associated with rapid and complete SE suppression, whereas low GNX exposures below 500 ng / mL were associated with seizure recurrence. In four of the five subjects, seizure activity recurred when GNX plasma concentrations were reduced to below 500 ng / mL.

[0209] Case reports of five subjects are presented below.

[0210] 1. Subject 004-101 Subject 004-101 was a 75-year-old female who presented with a subdural hematoma following a fall (day 1). Levetiracetam was administered initially. On medical examination, the subject was noted to be unresponsive to both verbal and noxious stimuli and bedridden. Pupils were even, round, and light-responsive, with absent corneal and gag reflexes and normal vestibulo-ocular reflexes. Blood pressure and saturation were stable. Due to changes in mental status, the decision was made to intubate the subject to secure the airway. On day 3, an EEG showed partial seizures and an additional injection of levetiracetam was administered, followed by multiple injections of lacosamide. During the trial enrollment deliberations, the subject was informed by family members that she had a history of delayed emergence from anesthesia in the past.

[0211] On day 3, IV GNX was initiated with a 30 mg bolus over 3 minutes and a continuous infusion of 85 mg / hour was administered for 2 hours. Almost immediately, the EEG showed seizure suppression and, according to the principal investigator, the EEG pattern indicated that "the subject was in mild burst suppression." During the second treatment period, administration of study drug was interrupted for 14 minutes while the subject was intubated to secure the airway. The intubation was not considered study drug related and the decision to intubate was made before the GNX infusion was started. The continuous infusion was resumed without events. Administration continued according to protocol, with the infusion rate reduced to 40 mg / hour 2 hours after infusion, 20 mg / hour 4 hours after infusion, and 10 mg / hour 6 hours after infusion. Seizure recurrence occurred approximately 5 hours after initiation of the infusion, at which point the subject was receiving GNX at an infusion rate of 20 mg / hour. GNX was discontinued on day 2. The subject's GNX plasma concentration was below 500 ng / mL at the time of seizure recurrence (Figure 3). Snapshots of the subject's EEG pattern before and after the initiation of GNX are shown in Figure 4.

[0212] 2. Subject 004-102 Subject 004-102 was a 43 year old female with a history of seizures who presented with NCSE (day 1). Previous AED medications included lamotrigine. Subject was intubated and administered a single dose of fosphenytoin followed by levetiracetam. On the same day, a bolus of IV GNX 30 mg was administered over 3 minutes and a continuous infusion (85 mg / hr) was initiated. No seizure activity was noted on the EEG at 60 minutes and 2 hours after initiation of infusion. Per protocol, GNX was sequentially tapered to 40 mg / hr, 20 mg / hr, and 10 mg / hr. The 10 mg / hr dose was continued for the remaining 18 hours of day 1. Subject remained seizure free, but returned to a concerning EEG pattern 5-6 hours after initiation of infusion, at which point subject was administered GNX at an infusion rate of 20 mg / hr. Subject's GNX plasma concentration at the time of seizure recurrence is shown in Figure 5. Return of the EEG pattern occurred around the same time frame and progressed over the next 48 hours, necessitating additional intervention approximately 42.5 hours after initiation of GNX while the subject was receiving GNX at an infusion rate of 20 mg / hour. GNX was discontinued on day 2. Snapshots of the subject's qualitative EEG pattern before and after initiation of GNX are shown in Figure 6.

[0213] 3. Subject 006-101 Subject 006-101 was a 59-year-old female with NCSE (day 1) of unknown etiology. The subject was unresponsive to both verbal and noxious stimuli. A single dose of lacosamide was administered and the subject was intubated to secure the airway. An EEG showed lethargy and epileptiform discharges with limb switches and subject was administered lorazepam with no improvement. On the same day, a bolus of IV GNX 30 mg was administered and a continuous infusion (85 mg / hr) was started. Field reports indicated that SE ceased within 1 minute of bolus administration. No seizure activity was noted on the EEG at 60 minutes and 2 hours after initiation of infusion. Per protocol, GNX was tapered sequentially to 40 mg / hr, 20 mg / hr, and 10 mg / hr. Seizure recurrence occurred approximately 6 hours after initiation of infusion, at which point subject was receiving GNX at an infusion rate of 20 mg / hr. GNX tapering was initiated on day 4. The subject's GNX plasma concentration was below 500 ng / mL at the time of seizure recurrence (Figure 7). Snapshots of the subject's EEG pattern before and after the initiation of GNX are shown in Figure 8.

[0214] The subject's infusion rate was 10 mg / hour when the recurrence of SE occurred. The results of two adjacent PK samples were within the low predicted range for this infusion rate. The PK samples were confirmed to have been taken from the infusion site. The correct analytical procedure performed by the bioanalytical laboratory was confirmed.

[0215] 4. Subject 006-102 Subject 006-102 was an 88-year-old female with a history of seizures and dementia who was transferred from a nursing home (Day 1) after her daughter discovered she had an altered mental status and was unable to verbalize her distress. Family confirmation revealed that the subject had fallen the previous week with a possible blow to the head. A computed tomography (CT) scan confirmed a subdural hematoma (1.4 cm). The subject was intubated, under propofol sedation, and transported from a remote hospital to the study site where she was prepared for evacuation of the subdural hematoma. Propofol was discontinued. During examination, the subject opened her eyes spontaneously, with even, round, and light-responsive pupils. Simple compliance and spontaneous movement of all four limbs were observed. Subject was administered a single dose of levetiracetam on Days 1 and 4, and a twice-daily dose on Day 3. On day 5 prior to GNX administration, three single doses of lorazepam were administered along with multiple doses of levetiracetam and a single dose of lacosamide. On day 5, the subject had a worsening neurological exam and a head CT scan showed signs of stroke in the right cerebral hemisphere. On the same day, when the diagnosis of NCSE was confirmed by EEG, the subject was enrolled in the clinical trial and started on IV GNX 30 mg bolus and continuous infusion (85 mg / hr). Field reports indicated that SE ceased upon administration of the bolus GNX dose. No seizure activity was noted on EEG at 60 minutes, 2 hours, and 4 hours after initiation of infusion. Per protocol, GNX was sequentially tapered to 40 mg / hr, 20 mg / hr, and 10 mg / hr. Seizure recurrence occurred approximately 6 hours after initiation of infusion, at which point the subject was receiving GNX at an infusion rate of 20 mg / hr. GNX tapering was initiated on day 4 of GNX therapy. Subjects' GNX plasma concentrations were below 500 ng / mL at the time of seizure recurrence (Figure 9).

[0216] 5. Target 015-101 Subject 015-101 was a 24 year old female who presented with focal convulsive SE (day 1) secondary to tumor. Recent medical history included convulsive seizures, SE, and glioblastoma multiforme of the parietal lobe. Prior to study enrollment, subject was administered levetiracetam for SE, lorazepam, diazepam, dexamethasone, and multiple doses of levetiracetam for seizure control. On day 3, subject was enrolled in the study and started on IV GNX 30 mg bolus and continuous infusion (85 mg / hr). Initially, subject was alert. Shortly after starting the bolus, subject developed significant somnolence. Subject would awaken when spoken to but required continued stimulation to remain awake or follow commands. Airway was secured, numbness was noted to have resolved, and subject reported no longer feeling convulsions. Subject had a sense of impending doom and mortality. The subject had prominent directional nystagmus and complained of blurred vision. Concurrently, he developed urinary retention with urgency. A bladder scanner showed a urine output of at least 750 mL, and a Foley catheter was placed. Over the next 2 hours, the subject remained drowsy and became increasingly restless. Per protocol, 2 hours after the start of dosing, GNX was reduced to 40 mg / hour. Approximately 10-15 minutes after the infusion rate was reduced to 40 mg / hour, the subject became more alert, speechable, and had an appetite. At this time, there were no seizures. Vital signs remained stable. During the GNX infusion, the concomitant lacosamide was increased due to increasing numbness. Seizures did not recur during the treatment period, and the investigator tapered the study drug after 2 days, per protocol. Once the GNX tapering was complete, the investigator reported no sequelae. The subject's GNX plasma concentrations over time are shown in Figure 10.

[0217] In summary, all five subjects demonstrated immediate cessation of SE with the initiation of the initial bolus and continuous infusion. Based on these data, the US Food and Drug Administration (FDA) permitted an increase in the daily Captisol exposure limit to 50 g / day (increasing the total daily dose of GNX from 500 to 715 mg), allowing GNX exposure to be maintained above approximately 500 ng / ml for approximately 8 hours.

[0218] Under a protocol revised to a Captisol limit of 50 g / day, one subject was enrolled in the open-label study as of March 26, 2019. The male subject presented with NCSE due to tumor. The subject had failed three second-line IV AEDs and was eligible for the study based on the inclusion / exclusion criteria. Within 3 minutes of starting the IV GNX infusion, the RSE ceased and seizure protection was maintained for the remaining 48 hours of GNX treatment. The subject was successfully weaned off GNX (i.e., there was no recurrence of seizures). Based on a preliminary evaluation, the only safety finding associated with GNX was increased sedation (likely attributable to the use of GNX in combination with multiple AEDs with CNS depressant properties as part of standard of care antiseizure therapy). At the time of this report, no pharmacokinetic data were provided.

[0219] In addition, 2 SRSE subjects received GNX pursuant to individual emergency treatment INDs (eINDs).

[0220] Under eIND 131,642, IV GNX was administered to SRSE subjects who had failed to maintain state arrest with ketamine and barbiturates. The dosing regimen on day 1 included 900 mg of GNX, corresponding to a GNX plasma concentration of 900-1200 ng / mL. Because the subject was not likely to continue burst suppression, the clinical team was able to measure response using EEG changes (Figure 11). The effect of GNX began to appear at a dose of 60 mg / h, resulting in complete seizure cessation at a dose of 120 mg / h. However, the dosing plan agreed upon with the FDA required that the initial dose of 120 mg / h on day 1 could not be maintained for >1 hour and then had to be reduced to a dose of 30 mg / h, due to a daily limit of Captisol of 63 g / day. The first seizure recurred within 15-20 minutes of changing the GNX dose from 120 mg / h to 30 mg / h.

[0221] Additionally, under eIND 137,883, IV GNX was administered to SRSE pediatric subjects who had previously failed treatment with levetiracetam, topiramate, clobazam, phenobarbital, rufinamide, perampanel, pentobarbital, and ketamine. At the time of eIND, no pediatric pharmacokinetic data were provided for the IV formulation of GNX. The dosing regimen (initial GNX at 75 mg / h, tapered to 40 mg / h after 1 hour) was based on plasma drug concentration levels measured in adults and was designed to achieve a plasma drug concentration of approximately 1000 ng / mL within 1 hour and maintain that level for an additional 23 hours. At the time of GNX initiation, subjects were intubated and administered pentobarbital at a rate of 2.25 mg / kg / h. At the time of GNX bolus infusion, the EEG showed continued suppression of background activity. This activity continued for approximately 2 hours, at which point pentobarbital was tapered to 1 mg / kg / h. On examination the subject exhibited non-reactive pupils and the GNX infusion was stopped.

[0222] These encouraging data led Marinus to receive clearance from the US FDA to increase the daily Captisol limit from 35 to 50 g / day. One subject who had the increased daily Captisol limit experienced rapid cessation of RSE following GNX treatment despite failure of three second-line IV AEDs and was successfully weaned off GNX without seizure recurrence.

[0223] This study is ongoing and, once completed, will be used to design a pivotal Phase 3 trial in RSE subjects.

[0224] Example 3: Phase 2 open-label dose-ranging study We conducted an open-label, dose-ranging study of IV ganaxolone added to IV AED standard of care in patients with SE who had failed an initial benzodiazepine and at least one second-line IV AED but did not progress to IV anesthetics.The primary objective of this study was to determine that IV ganaxolone, when added to standard of care IV AED therapy, is safe and effective in terminating SE and avoiding escalation of treatment to IV anesthetics for seizure control.Secondary objectives included evaluation of adverse events and evaluation of the pharmacokinetics of IV ganaxolone in patients with SE.

[0225] Eligible patients were treated with continuous adjunctive IV ganaxolone infusion. Initial dosing included a 3-minute bolus (25 or 30 mg) followed by continuous infusion for up to 96 hours at rates ranging from 10 to 85 mg / hour, followed by an 18-hour taper of study drug.

[0226] The study enrolled 17 patients who were assigned to three dose cohorts. The IV solution utilizes Captisol® as an excipient for solubilization of ganaxolone. Per agreement with the Food and Drug Administration (FDA), patients enrolled in study 1042-SE-2001 were not to exceed 50 g / day of Captisol exposure. Given the daily Captisol limit, three different doses of GNX IV solution were investigated: 500, 650, and 713 mg / day of total GNX (referred to as the low, mid, and high dose level cohorts, respectively).

[0227] Detailed infusion parameters for the first 24 hours for each dose group are shown below. [Table 4]

[0228] The main difference between the low and high dose cohorts was the duration of predicted plasma GNX levels ≥ 500ng / ml (4 hours vs. 8 hours, respectively). The main difference between the medium dose cohorts and the low / high dose cohorts was the duration of initial predicted plasma levels of GNX ≥ 700ng / mL (minutes vs. 2 hours, respectively) and the predicted plasma levels of GNX in the medium dose cohort not exceeding 500ng / mL. The predicted 24-hour GNX plasma concentrations associated with each dose cohort are shown in Figure 14.

[0229] The number of patients enrolled in each of the three dose level cohorts is shown in Table 5 below. [Table 5]

[0230] Preliminary results from this open-label dose-finding study 1042-SE-2001 in patients with RSE showed that all patients (100%; n=17) did not require escalation of treatment to IV anesthetics for SE control within the first 24 hours after initiating GNX treatment, thereby meeting the primary endpoint. Sixteen patients (94%) achieved and maintained cessation of SE within the first 24 hours after initiating GNX treatment. Fourteen patients (82%) did not recur the condition for up to 4 weeks without the need for additional IV AEDs or IV anesthetics. A summary is shown in Table 6 below. [Table 6]

[0231] The median time to termination of SE was 5 minutes from the start of GNX treatment (n=15 evaluable patients). (Figure 12) Fourteen of 15 patients achieved termination of SE in less than 30 minutes.

[0232] IV GNX achieved rapid, dose-dependent and sustained reduction in EEG seizure burden in 15 evaluable patients (Figure 15).

[0233] Acute administration of GNX plasma concentrations above 500 ng / mL was associated with improved seizure control on EEG (FIGS. 13A-13D).

[0234] GNX infusions were generally well tolerated in this patient population, and the safety profile of GNX was consistent with its GABAergic mechanism of action. Two participants reported SAEs (severe sedation) assessed as related to GNX treatment, leading to premature discontinuation of GNX. These two cases occurred in participants who were concurrently taking multiple other CNS depressants and did not occur at the time of maximum predicted plasma concentrations of GNX. In certain embodiments, for example, the following are provided: (Item 1) 1. A method for treating status epilepticus (SE), comprising: a) an intravenous bolus of ganaxolone sufficient to suppress SE; and b) a continuous intravenous infusion of ganaxolone sufficient to continuously suppress SE to a subject in need thereof, wherein the continuous intravenous infusion i) is initiated perioperatively with the intravenous bolus; ii) is administered for a target concentration period of at least about 8 hours; and iii) produces a ganaxolone plasma concentration in the subject of at least about 425 ng / ml, at least about 450 ng / ml, at least about 475 ng / ml, or at least about 500 ng / ml throughout the target concentration period. (Item 2) 2. The method of claim 1, wherein the continuous intravenous infusion is commenced simultaneously with administration of the intravenous bolus. (Item 3) 2. The method of claim 1, wherein the intravenous bolus and the continuous intravenous infusion do not result in loss of consciousness in the subject. (Item 4) 4. The method of any one of items 1 to 3, wherein the intravenous bolus produces a ganaxolone plasma concentration in the subject of at least about 500 ng / ml to about 1000 ng / ml. (Item 5) 4. The method of any one of items 1 to 3, wherein the continuous intravenous infusion produces a ganaxolone plasma concentration in the subject of at least about 500 ng / ml to about 1000 ng / ml throughout the treatment period. (Item 6) 6. The method of any one of items 1 to 5, wherein the amount of ganaxolone administered to the subject per hour by continuous intravenous infusion is decreased over a period of about 24 hours from the start of the continuous intravenous infusion. (Item 7) 7. The method of any one of items 1 to 6, wherein the amount of ganaxolone administered to the subject per hour by continuous intravenous infusion is decreased about 2 hours after initiation of the continuous intravenous infusion. (Item 8) 8. The method of claim 7, wherein the amount of ganaxolone administered to the subject per hour by continuous intravenous infusion is reduced by about 50% about 2 hours after initiation of the continuous intravenous infusion, compared to the dose per hour at the initiation of the continuous intravenous infusion. (Item 9) 9. The method according to any one of items 1 to 8, wherein the amount of ganaxolone administered to the subject per hour by continuous intravenous infusion is decreased from about 10 hours to about 14 hours after initiation of the continuous intravenous infusion. (Item 10) 10. The method of claim 9, wherein the amount of ganaxolone administered to the subject per hour by continuous intravenous infusion is reduced by about 75% about 10 hours to about 14 hours after initiation of the continuous intravenous infusion, compared to the hourly dose at the initiation of the continuous intravenous infusion. (Item 11) 11. The method according to any one of items 1 to 10, wherein the amount of ganaxolone administered to the subject per hour by continuous intravenous infusion is decreased about 2 hours after initiation of the continuous intravenous infusion and further decreased about 10 hours to about 14 hours after initiation of the continuous intravenous infusion. (Item 12) 12. The method of claim 11, wherein the amount of ganaxolone administered to the subject per hour by continuous intravenous infusion is reduced by about 50% at about 2 hours after the start of the continuous infusion, compared to the hourly dose at the start of the continuous intravenous infusion, and further reduced by about 75% at about 10 to about 14 hours after the start of the continuous infusion, compared to the hourly dose at the start of the continuous intravenous infusion. (Item 13) The method of any one of the preceding items, wherein the continuous intravenous infusion is administered for a treatment period of about 36 hours after initiation of the continuous intravenous infusion. (Item 14) The method of any one of the preceding items, wherein the treatment period of said continuous intravenous infusion is for a period of at least about 8 hours to about 36 hours after the initiation of said continuous intravenous infusion. (Item 15) The method of any one of the preceding items, wherein the amount of ganaxolone administered to the subject per hour by continuous intravenous infusion is increased about 24 hours after initiation of the continuous intravenous infusion. (Item 16) 16. The method of claim 15, wherein the amount of ganaxolone administered to the subject per hour by continuous intravenous infusion is increased by up to about 45% compared to the hourly dose starting 24 hours after the start of the continuous intravenous infusion. (Item 17) 17. The method of claim 15 or 16, wherein the amount of ganaxolone administered to the subject per hour by continuous intravenous infusion is increased over a period of up to about 12 hours. (Item 18) c) The method of any one of the preceding items, further comprising continuing to administer said continuous intravenous infusion for a tapering period following said target concentration period. (Item 19) The method of any one of the preceding items, wherein the tapering period begins about 36 hours from the initiation of the continuous intravenous infusion. (Item 20) 20. The method of claim 18 or 19, wherein the amount of ganaxolone administered to the subject per hour by continuous intravenous infusion during the tapering period is reduced by about one third every about four hours. (Item 21) The method of any one of the preceding items, wherein the amount of the ganaxolone administered to the subject per hour by continuous intravenous infusion is reduced by slowing the infusion rate. (Item 22) The method of any one of the preceding items, wherein about 5 mg to about 40 mg of ganaxolone is administered to the subject at the start of the intravenous bolus. (Item 23) The method of any one of the preceding items, wherein about 30 mg of ganaxolone is administered to the subject at the start of the intravenous bolus. (Item 24) The method of any one of the preceding items, wherein the intravenous bolus is administered to the subject for about 1 minute to 5 minutes. (Item 25) The method of any one of the preceding items, wherein about 20 mg of ganaxolone per hour to about 80 mg of ganaxolone per hour is infused to said subject during said continuous infusion treatment period. (Item 26) The method of any one of the preceding items, wherein about 80 mg of ganaxolone per hour is infused into the subject at the start of the continuous intravenous infusion. (Item 27) The method of any one of the preceding items, wherein the amount of ganaxolone infused to the subject by the continuous intravenous infusion is reduced to about 40 mg of ganaxolone per hour, and further reduced to about 20 mg of ganaxolone per hour during the treatment period. (Item 28) The method of any one of the preceding items, wherein about 80 mg of ganaxolone per hour is administered to said subject by said continuous intravenous infusion from the start and for at least about 2 hours thereafter. (Item 29) The method of any one of the preceding paragraphs, wherein about 40 mg of ganaxolone per hour is administered to the subject by continuous intravenous infusion starting about 2 hours after initiation and continuing for about 6 to about 10 hours thereafter. (Item 30) The method of any one of the preceding items, wherein about 20 mg of ganaxolone per hour is administered to the subject by continuous intravenous infusion starting about 12 hours after initiation and continuing for about 12 to about 24 hours thereafter. (Item 31) The method of any one of the preceding items, wherein the amount of ganaxolone infused to the subject by continuous intravenous infusion is increased to a maximum of about 45 mg of ganaxolone per hour starting about 24 hours after initiation and for a maximum of about 12 hours thereafter. (Item 32) 32. The method of claim 31, wherein the amount of ganaxolone administered to the subject by continuous intravenous infusion does not exceed 45 mg of ganaxolone per hour. (Item 33) 2. The method of any one of the preceding items, wherein the continuous infusion is administered before or after the intravenous bolus. (Item 34) The method of any one of the preceding items, wherein the subject is refractory to a first-line seizure medication, a second-line seizure medication, or a tertiary seizure medication. (Item 35) The method of any one of the preceding items, wherein the primary seizure medication is a benzodiazepine. (Item 36) 36. The method of claim 35, wherein the secondary seizure medication is fosphenytoin, valproic acid, or levetiracetam. (Item 37) 36. The method of claim 35, wherein the tertiary seizure medication is thiopental, midazolam, pentobarbital, or propofol. (Item 38) The method of any one of the preceding items, wherein the subject is refractory to at least one anti-seizure medication. (Item 39) The method of any one of the preceding items, wherein the subject is refractory to treatment with a benzodiazepine and at least one anti-seizure medication. (Item 40) 13. The method of any one of the preceding items, wherein said status epilepticus is convulsive status epilepticus. (Item 41) 13. The method of any one of the preceding items, wherein said status epilepticus is non-convulsive status epilepticus. (Item 42) 2. The method of any one of the preceding items, wherein the subject has refractory status epilepticus. (Item 43) 2. The method of any one of the preceding items, wherein the subject has extremely refractory status epilepticus. (Item 44) The method of any one of the preceding items, wherein the subject is monitored by electroencephalogram (EEG). (Item 45) The method of any one of the preceding items, wherein the subject is monitored for seizure activity by EEG. (Item 46) The method of any one of the preceding items, wherein the intravenous administration of ganaxolone further comprises sulfobutylether-β-cyclodextrin. (Item 47) 46. ​​The method of item 45, wherein the ganaxolone and sulfobutylether-β-cyclodextrin are administered in one formulation. (Item 48) The method of any one of the preceding items, wherein one or more intravenous boluses of ganaxolone can be administered to the subject during said continuous intravenous infusion. (Item 49) The method of any one of the preceding items, wherein the bolus results in a reduction in the seizure burden of about 20% or less, or a reduction in the seizure burden of at least about 50%, as compared to the seizure burden in the 30 minutes immediately preceding administration of the bolus. (Item 50) 50. The method of claim 49, wherein the continuous infusion maintains the seizure burden at about 20% or less, or maintains the seizure burden at at least about 50% less than the seizure burden in the 30 minutes immediately preceding administration of the bolus. (Item 51) 1. Use of ganaxolone for treating status epilepticus in a subject in need thereof, comprising: a) An intravenous bolus of ganaxolone sufficient to stop the seizure; b) the use of i) initiated perioperatively using an intravenous bolus; ii) administered for a treatment period of at least about 8 hours; and iii) continuous intravenous infusion of ganaxolone throughout the treatment period in an amount sufficient to prevent recurrence of seizures, producing in the subject a ganaxolone plasma concentration of at least about 425 ng / ml, at least about 450 ng / ml, at least about 475 ng / ml, or at least about 500 ng / ml. (Item 52) A pharmaceutical composition for treating status epilepticus comprising ganaxolone as an active ingredient, the pharmaceutical composition being suitable for intravenous administration as an intravenous bolus of ganaxolone in an amount sufficient to terminate seizures and for continuous intravenous infusion of ganaxolone in an amount sufficient to prevent recurrence of seizures, the continuous intravenous infusion i) being initiated perioperatively using the intravenous bolus; ii) being administered for a treatment period of at least about 8 hours; and iii) producing in the subject a ganaxolone plasma concentration of at least about 425 ng / ml, at least about 450 ng / ml, at least about 475 ng / ml, or at least about 500 ng / ml throughout the treatment period. (Item 53) 1. Use of ganaxolone in the manufacture of a medicament for the treatment of status epilepticus in a subject in need thereof, comprising: a) An intravenous bolus of ganaxolone sufficient to stop the seizure; b) said use comprising: i) initiated perioperatively using said intravenous bolus; ii) administered for a treatment period of at least about 8 hours; and iii) continuous intravenous infusion of ganaxolone throughout said treatment period in an amount sufficient to prevent recurrence of attacks, producing a ganaxolone plasma concentration in said subject of at least about 425 ng / ml, at least about 450 ng / ml, at least about 475 ng / ml, or at least about 500 ng / ml. (Item 54) 1. A method for treating status epilepticus comprising administering to a subject experiencing status epilepticus a therapeutic dose of ganaxolone in a manner to achieve and maintain a plasma concentration of ganaxolone of from about 50 ng / ml to about 3500 ng / ml over a period of from about 30 minutes to about 120 hours, said administration reducing or eliminating seizure activity and / or reducing or eliminating convulsions and / or completely suppressing status epilepticus.

Claims

[Claim 1] The invention described in the specification.

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