GANAXOLONE FOR USE IN TREATING TUBEROUS SCLEROSIS COMPLEX
The disclosure to methods for treating tuberous sclerosis complex or tuberous sclerosis complex-related epilepsy, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutically acceptable pregnenolone neurosteroid, such as ganaxolone, to reduce one or more symptoms of tuberous sclerosis complex or tuberous sclerosis complex-related epilepsy.
1 . A method for treating tuberous sclerosis complex or tuberous sclerosis complex-related epilepsy comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutically acceptable pregnenolone neurosteroid or a pharmaceutically acceptable salt thereof.
2 . The method of claim 1 , wherein the pregnenolone neurosteroid is ganaxolone.
3 . The method of any one of the preceding claims , wherein the pregnenolone neurosteroid is administered three time per day.
4 . The method of any one of claims 1-2 , wherein the pregnenolone neurosteroid is administered twice per day.
5 . The method of any one of the preceding claims , wherein the subject is administered from about 200 mg per day to about 1,800 mg per day of ganaxolone.
6 . The method of any one of claims 1-4 , wherein the subject is administered up to about 1,800 mg per day of ganaxolone.
7 . The method of any preceding claim , wherein ganaxolone is administered about 1,500 mg per day of ganaxolone.
8 . The method of any one of the preceding claims , wherein ganaxolone is administered in an amount of up to 63 mg/kg/day.
9 . The method of any one of the preceding claims , wherein the pregnenolone neurosteroid is administered orally.
10 . The method of any one of the preceding claims , wherein the pregnenolone neurosteroid is administered as an oral suspension.
11 . The method of any one of the preceding claims , wherein the pregnenolone neurosteroid is administered as an oral capsule.
12 . The method of any one of the preceding claims , wherein the tuberous sclerosis complex-related epilepsy is a infantile spasm.
13 . The method of any one of the preceding claims , wherein the tuberous sclerosis complex-related epilepsy is a focal impaired awareness seizure.
14 . The method of any one of the preceding claims , wherein the tuberous sclerosis complex-related epilepsy is a focal seizure.
15 . The method of any one of the preceding claims , wherein the tuberous sclerosis complex-related epilepsy is a generalized seizure.
16 . The method of any one of the preceding claims , wherein administering the pregnenolone neurosteroid reduces the frequency of seizure and/or severity of seizure in the subject relative to baseline.
17 . The method of any one of the preceding claims , wherein administering the pregnenolone neurosteroid results in a reduction in seizure frequency of about 20% or greater relative to baseline seizure frequency.
18 . The method of any one of the preceding claims , wherein administering the pregnenolone neurosteroid results in a reduction in seizure frequency of at least about 35% or greater relative to baseline seizure frequency.
19 . The method of any one of the preceding claims , wherein the subject is monitored by electroencephalogram (EEG).
20 . The method of any one of the preceding claims , wherein seizure activity in the subject is monitored by electroencephalogram (EEG).
21 . The method of any one of the preceding claims , wherein ganaxolone is administered in amount sufficient to provide a ganaxolone plasma concentration in the subject of about 100 ng/mL for approximately 70% or more for a 24 hour-day.
22 . The method of claim 21 , wherein ganaxolone is administered three times a day.
23 . The method of any one the preceding claims , further comprising:
measuring the level of an endogenous neurosteroid in the subject prior to administering the pregnanolone neurosteroid, wherein a subject having a low endogenous neurosteroid indicates that the subject will respond to the pregnanolone neurosteroid; and
administering a therapeutically effective amount of the pregnenolone neurosteroid to the subject having a low endogenous neurosteroid level.
24 . The method of claim 23 , wherein the endogenous neurosteroid is allopregnanolone-sulfate.
25 . The method of any one of claim 23 or 24 , wherein the low endogenous neurosteroid level is an amount of 2500 pg mL −1 or less.
26 . The method of claim 25 , wherein the pregnenolone neurosteroid is ganaxolone.
27 . A method for treating tuberous sclerosis complex or tuberous sclerosis complex-related epilepsy comprising administering to a subject in need thereof ganaxolone in a therapeutically effective amount that produces a ganaxolone plasma concentration of at least about 100 ng/ml for at least about 70% or more for a period of a 24 hour-day.
28 . The method of claim 27 , wherein ganaxolone is administered three times per day.
29 . The method of any one of claim 27 or 28 , wherein ganaxolone is administered orally.
30 . The method of any one of claims 27-29 , wherein ganaxolone is administered as an oral suspension.
31 . The method of any one of claims 27-29 , wherein ganaxolone is administered as an oral capsule.
32 . The method of any one of claims 27-31 , wherein ganaxolone is administered in an amount of up to 63 mg/kg/day.
33 . The method of any one of claims 27-32 , wherein ganaxolone is administered in an amount of up to 1,800 mg per day.
34 . The method of any one of claims 27-32 , wherein ganaxolone is administered in an amount of up to 1,500 mg per day.
35 . The method of any one of claims 27-34 , wherein the tuberous sclerosis complex-related epilepsy is a infantile spasm, a focal impaired awareness seizure, a focal seizure, or a generalized seizure.
36 . The method of any one of claims 27-35 , wherein administering ganaxolone reduces the frequency of seizure and/or severity of seizure in the subject relative to baseline.
37 . The method of any one of claims 27-35 , wherein administering ganaxolone reduces major motor frequency in the subject relative to baseline.
38 . The method of any one of claims 27-35 , wherein administering ganaxolone results in a reduction in seizure frequency of about 20% or greater relative to baseline seizure frequency.
39 . The method of any one of claims 27-35 , wherein administering ganaxolone results in a reduction in seizure frequency of at least about 35% or greater relative to baseline seizure frequency.
40 . The method of any one of claims 27-39 , wherein the subject is monitored by electroencephalogram (EEG).
41 . The method of any one of claims 27-39 , wherein seizure activity in the subject is monitored by electroencephalogram (EEG).
42 . A method of treating a subject having or suspected of having tuberous sclerosis-related epilepsy, comprising
determining whether the subject has a low level of an endogenous neurosteroid; and
administering a therapeutically effective amount of a pharmaceutically acceptable pregnenolone neurosteroid or a pharmaceutically acceptable salt thereof to the subject if the subject has a low level of the endogenous neurosteroid.
43 . The method of claim 42 , wherein the endogenous neurosteroid is allopregnanolone-sulfate, and the pregnenolone neurosteroid is ganaxolone.
44 . The method of any one of claim 42 or 43 , wherein the endogenous neurosteroid is allopregnanolone-sulfate, and the low level of the endogenous stereoid is a level of 2500 pg mL −1 or less.
45 . The method of any one of claims 42-44 , 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.
46 . The method of claim 45 , wherein the pregnenolone neurosteroid is selected from the group consisting of allopregnanolone, pregnenolone, 5-alphaDHP (5-alphadihydroprogesterone), pregnanolone, dehydroepiandrosterone (DHEA), ganaxolone, 3α-Hydroxy-30-methyl-21-(4-cyano-1H-pyrazol-1′-yl)-19-nor-50-pregnan-20-one, pharmaceutically acceptable salts of any of the foregoing, and combinations of any of the foregoing.
47 . The method of any one of claims 42-46 , wherein the pregnenolone neurosteroid is administered orally.
48 . The method of any one of claims 42-47 , wherein the subject is administered up to about 63 mg/kg/day of ganaxolone.
49 . The method of claim 48 , wherein the subject is administered up to about 33 mg/kg/day of ganaxolone.
50 . The method of any one of claims 42-47 , wherein the subject is administered up to about 1,800 mg per day of ganaxolone.
51 . The method of any one of claims 42-47 , wherein the subject is administered up to about 1,500 mg per day of ganaxolone.
52 . The method of claim 42-51 , wherein the tuberous sclerosis complex-related epilepsy is selected from the group consisting of a focal motor seizure, a focal seizure, and a generalized seizure.
53 . The method of any one of claims 42-52 , wherein administering ganaxolone reduces the frequency of seizure and/or severity of seizure in the subject relative to baseline.
54 . The method of any one of claims 42-53 , wherein administering ganaxolone reduces major motor frequency in the subject relative to baseline.
55 . The method of any one of claims 42-53 , wherein administering ganaxolone results in a reduction in seizure frequency of about 20% or greater relative to baseline seizure frequency.
56 . The method of any one of claims 42-53 , wherein administering ganaxolone results in a reduction in seizure frequency of at least about 35% or greater relative to baseline seizure frequency.
57 . The method of any one of claims 42-56 , wherein the subject is monitored by electroencephalogram (EEG).
58 . The method of any one of claims 42-56 , wherein seizure activity in the subject is monitored by electroencephalogram (EEG).
59 . The method of claim 42 , wherein the endogenous neurosteroid is allopregnanolone, and a low level of allopregnanolone is a 200 pg mL −1 or less.
60 . The method of claim 42 , wherein the endogenous neurosteroid comprises allopregnanolone, allopregnanolone-sulfate, pregnenolone, pregnenolone-sulfate, and mixtures thereof.