GANAXOLONE FOR USE IN TREATING GENETIC EPILEPTIC DISORDERS
The disclosure provides a method of treating a mammal having a genetic epileptic disorder, comprising chronically administering a pharmaceutically acceptable pregnenolone neurosteroid to a mammal having a genetic epileptic disorder in an amount effective to reduce the seizure frequency in the mammal. In certain preferred embodiments, the mammal is a human patient who has a CDKL5 genetic mutation. In certain preferred embodiments, the patient has a low endogenous level of a neurosteroid(s). In certain preferred embodiments, the pregnenolone neurosteroid is ganaxolone.
1 . A method of treating a mammal having an epileptic disorder, comprising
determining whether a mammal has a low level of an endogeneous neurosteroid, and
if the mammal has the low level of the endogenous neurosteroid, chronically administering a pharmaceutically acceptable pregnenolone neurosteroid to the mammal.
2 . The method of claim 1 , wherein the mammal is a human.
3 . The method of claim 2 , wherein the epilepic disorder is selected from the group consisting of CDKL5 deficiency disorder, PCDH19-related epilepsy, Lennox Gastaut Syndrome, Rett syndrome, and Fragile X Syndrome.
4 . The method of claim 1 , wherein the endogenous neurosteroid is allopregnanolone-sulfate, and the low level of the endogenous steroid is a level of 2500 pg mL −1 or less.
5 . The method of claim 1 , wherein the pregnenolone neurosteroid is a compound of Formula IA:
or a pharmaceutically acceptable salt thereof, wherein:
X is O, S, or NR 10 ;
R 1 is hydrogen, hydroxyl, —CH 2 A, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl, or optionally substituted arylalkyl;
A is hydroxyl, O, S, NR 11 , optionally substituted nitrogen-containing five-membered heteroaryl, optionally substituted nitrogen-containing five-membered heteroaryl or optionally substituted nitrogen-containing bicyclic heteroaryl or bicyclic heterocyclyl,
R 4 is hydrogen, hydroxyl, oxo, optionally substituted alkyl, or optionally substituted heteroalkyl,
R 2 , R 3 , R 5 , R 6 , and R 7 are each independently absent, hydrogen, hydroxyl, halogen, optionally substituted a C 1 -C 6 alkyl, optionally substituted a C 1 -C 6 alkoxyl (e.g., methoxyl) or optionally substituted heteroalkyl;
R 8 and R 9 are each independently selected from a group consisting of hydrogen, a C 1 -C 6 alkyl (e.g., methyl), a halogenated C 1 -C 6 alkyl (e.g., trifluoromethyl) or C 1 -C 6 alkoxyl (e.g., methoxyl), or R 8 and R 9 form an oxo group;
R 10 is hydrogen, hydroxyl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl, or optionally substituted arylalkyl where each alkyl is a C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, (C 3 -C 6 cycloalkyl)C 1 -C 4 alkyl, and optionally contains a single bond replaced by a double or triple bond;
each heteroalkyl group is an alkyl group in which one or more methyl group is replaced by an independently chosen —O—, —S—, —N(R 10 )—, —S(═O)— or —S(═O) 2 —, where R 10 is hydrogen, alkyl, or alkyl in which one or more methylene group is replaced by —O—, —S—, —NH, or —N-alkyl;
R 11 is —H 2 or —HR 12 ;
R 12 is C 1 -C 6 alkyl or C 1 -C 6 alkoxy.
6 . The method of claim 2 , wherein the pregnenolone neurosteroid is selected from the group consisting of allopregnanolone, pregnenolone, 5-alphaDHP (5-alphadihydroprogesterone), pregnanolone, dehydroepiandrosterone (DHEA), ganaxolone, 3α-Hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1′-yl)-19-nor-5β-pregnan-20-one, pharmaceutically acceptable salts of any of the foregoing, and combinations of any of the foregoing.
7 . The method of claim 6 , wherein the pregnenolone neurosteroid is ganaxolone.
8 . The method of claim 7 , wherein ganaxolone is administered orally.
9 . The method of claim 7 , wherein ganaxolone is administered as an oral suspension up to a total of 63 mg/kg/day.
10 . A method of treating an epileptic encephalopathy, comprising
identifying a human patient suffering from the epileptic encephalopathy,
determining if the human patient has a low level of an endogenous neurosteroid, and
if the human patient has a low level of an endogenous neurosteroid, administering the human patient a dosage regimen of a pharmaceutically acceptable pregnenolone neurosteroid in an amount effective to reduce the frequency of seizures in the human patient.
11 . The method of claim 10 , wherein the epileptic encephalopathy is CDKL5 deficiency disorder.
12 . The method of claim 1 , wherein the human patient has a CDKL5 genetic mutation.
13 . The method of claim 10 , wherein the epileptic encephalopathy is selected from the group consisting of CDKL5 deficiency disorder, PCDH19-related epilepsy, Lennox-Gastaut Syndrome, Ohtahara syndrome, early myoclonic epileptic encephalopathy, West syndrome, Dravet syndrome, Angelman Syndrome, and other diseases, e.g., X-linked myoclonic seizures, spasticity and intellectual disability syndrome, idiopathic infantile epileptic-dyskinetic encephalopathy, epilepsy and mental retardation limited to females, and severe infantile multifocal epilepsy.
14 . The method of claim 10 , wherein the pregnenolone neurosteroid is a compound of Formula IA:
or a pharmaceutically acceptable salt thereof, wherein:
X is O, S, or NR 10 ;
R 1 is hydrogen, hydroxyl, —CH 2 A, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl, or optionally substituted arylalkyl;
A is hydroxyl, O, S, NR 11 , optionally substituted nitrogen-containing five-membered heteroaryl, or optionally substituted nitrogen-containing bicyclic heteroaryl or bicyclic heterocyclyl,
R 4 is hydrogen, hydroxyl, oxo, optionally substituted alkyl, or optionally substituted heteroalkyl,
R 2 , R 3 , R 5 , R 6 , and R 7 are each independently absent, hydrogen, hydroxyl, halogen, optionally substituted a C 1 -C 6 alkyl, optionally substituted a C 1 -C 6 alkoxyl (e.g., methoxyl) or optionally substituted heteroalkyl;
R 8 and R 9 are each independently selected from a group consisting of hydrogen, a C 1 -C 6 alkyl (e.g., methyl), a halogenated C 1 -C 6 alkyl (e.g., trifluoromethyl) or C 1 -C 6 alkoxyl (e.g., methoxyl), or R 8 and R 9 form an oxo group;
R 10 is hydrogen, hydroxyl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl, or optionally substituted arylalkyl where each alkyl is a C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, (C 3 -C 6 cycloalkyl)C 1 -C 4 alkyl, and optionally contains a single bond replaced by a double or triple bond;
each heteroalkyl group is an alkyl group in which one or more methyl group is replaced by an independently chosen —O—, —S—, —N(R 10 )—, —S(═O)— or —S(═O) 2 —, where R 10 is hydrogen, alkyl, or alkyl in which one or more methylene group is replaced by —O—, —S—, —NH, or —N-alkyl;
R 11 is —H 2 or —HR 12 ;
R 12 is C 1 -C 6 alkyl or C 1 -C 6 alkoxy.
15 . The method of claim 10 , wherein the pregnenolone neurosteroid is selected from the group consisting of pregnenolone, 5-alphaDHP (5-alphadihydroprogesterone), pregnanolone, dehydroepiandrosterone (DHEA), ganaxolone, 3α-Hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1′-yl)-19-nor-5β-pregnan-20-one, pharmaceutically acceptable salts of any of the foregoing, and combinations of any of the foregoing.
16 . The method of claim 15 , wherein the pregnenolone neurosteroid is ganaxolone.
17 . The method of claim 10 , further comprising:
establishing a baseline seizure frequency,
initially administering a dose of ganaxolone to the patient in an amount from about 0.5 mg/kg/day to about 15 mg/kg/day; and
progressively increasing the dose of ganaxolone over the course of 4 weeks to an amount from about 18 mg/kg/day to about 60 mg/kg/day, wherein the total dose of ganaxolone is up to about 1800 mg/day.
18 . The method of claim 10 , wherein the endogenous neurosteroid is allopregnanolone-sulfate, and the low level of the endogenous neurostereoid is a level of 2500 pg mL −1 or less.
19 . The method of claim 10 , wherein the endogenous neurosteroid is allopregnanolone, and the low level of the endogenous neurostereoid is a level of 200 pg mL −1 or less.
20 . The method of claim 1 , wherein the endogenous neurosteroid is allopregnanolone, and the low level of the endogenous neurostereoid is a level of 200 pg mL −1 or less.