THERAPEUTIC REGIMENS AND METHODS FOR IMPROVING VISUAL FUNCTION IN VISUAL DISORDERS ASSOCIATED WITH AN ENDOGENOUS RETINOID DEFICIENCY
Therapeutic regimes for improving visual function in a subject having a deficiency in endogenously produced 11-cis retinal comprising administering the synthetic retinal derivative as a divided dose over 2-7 days then providing a resting period of 7-28 days after which the second dose of the synthetic retinal derivative is administered. Preferred synthetic retinal derivatives are 9- or 11-cis-retinyl esters. Disorders associated with deficiency in endogenously produced 11-cis retinal include retinitis pigmentosa and Leber congenital amaurosis.
1 . A method of improving visual function in a subject having a deficiency in endogenously produced 11-cis retinal comprising:
a. administering a first therapeutic dose of a synthetic retinal derivative to a subject in need thereof, wherein the first therapeutic dose is administered as a divided dose over a period of from about 2 to about 7 days;
b. providing a resting period of from about 7 to about 28 days; and
c. administering a second therapeutic dose of the synthetic retinal derivative to said subject following the end of the resting period.
2 . The method of claim 1 , wherein the subject has retinitis pigmentosa (RP).
3 . The method of claim 2 , wherein the subject has moderate to severe RP.
4 . The method of claim 2 , wherein the subject has mild RP.
5 . The method of claim 2 , wherein the subject has early onset or juvenile RP.
6 . The method of claim 1 , wherein the subject has Leber congenital amaurosis (LCA)
7 . The method of claim 1 , wherein the subject has a LRAT gene mutation.
8 . The method of claim 1 , wherein the subject has a RPE65 gene mutation.
9 . The method of any of claims 1 - 8 , wherein the synthetic retinal derivative provides replacement of endogenously produced 11-cis-retinal.
10 . The method of any of claims 1 - 9 , wherein the method further comprises repeating steps b and c one or more times.
11 . The method of any of claims 1 - 10 , wherein the first therapeutic dose is administered as a divided dose over a period of 7 days.
12 . The method of any of claims 1 - 11 , wherein the resting period is from about 7 days to about 21 days.
13 . The method of claim 12 , wherein the resting period is about 21 days.
14 . The method of claim 12 , wherein the resting period is about 14 days.
15 . The method of claim 12 , wherein the resting period is about 7 days.
16 . The method of any of claims 1 - 15 , wherein the subject is a human subject.
17 . A method of improving visual function in a subject having a deficiency in endogenously produced 11-cis retinal, said method comprising:
a. administering a first therapeutic dose of a 9- or 11-cis-retinyl ester to a subject in need thereof, wherein the first therapeutic dose is administered as a divided dose over a period of from about 2 to about 7 days;
b. providing a resting period of from about 7 to about 28 days; and
c. administering a second therapeutic dose of the 9- or 11-cis-retinyl ester to said subject following the end of the resting period.
18 . The method of claim 17 , wherein the subject has retinitis pigmentosa (RP).
19 . The method of claim 18 , wherein the subject has moderate to severe RP.
20 . The method of claim 18 , wherein the subject has mild RP.
21 . The method of claim 18 , wherein the subject has early onset or juvenile RP.
22 . The method of claim 17 , wherein the subject has Leber congenital amaurosis.
23 . The method of claim 17 , wherein the subject has a LRAT gene mutation.
24 . The method of claim 17 , wherein the subject has a RPE65 gene mutation.
25 . The method of any of claims 17 - 24 , wherein the method further comprises repeating steps b and c one or more times.
26 . The method of any of claims 17 - 25 , wherein the first therapeutic dose is administered as a divided dose over a period of 7 days.
27 . The method of any of claims 17 - 26 , wherein the resting period is from about 7 days to about 21 days.
28 . The method of claim 27 , wherein the resting period is about 21 days.
29 . The method of claim 27 , wherein the resting period is about 14 days.
30 . The method of a claim 27 , wherein the resting period is about 7 days.
31 . The method of any of claims 17 - 30 , wherein the first therapeutic dose is from about 280 mg/m 2 to about 420 mg/m 2 .
32 . The method of claim 31 , wherein the first therapeutic dose is about 280 mg/m 2 .
33 . The method of claim 31 , wherein the first therapeutic dose is about 420 mg/m 2 .
34 . The method of any of claims 17 - 30 , wherein the first therapeutic dose is about 10 mg/m 2 per day.
35 . The method of any of claims 17 - 30 , wherein the first therapeutic dose is about 20 mg/m 2 per day.
36 . The method of any of claims 17 - 32 , wherein the first therapeutic dose is about 40 mg/m 2 per day.
37 . The method of any of claims 17 - 31 , wherein the first therapeutic dose is about 60 mg/m 2 per day.
38 . The method of any of claims 17 - 37 , wherein the therapeutic doses are administered orally.
39 . The method of any of claims 17 - 38 , wherein the second therapeutic dose is administered for substantially the same period and in substantially the same amount as the first therapeutic dose.
40 . The method of any of claims 17 - 39 , wherein the retinyl ester is a 9-cis-retinyl ester.
41 . The method of claim 40 , wherein the retinyl ester is 9-cis-retinyl acetate.
42 . The method of any of claims 17 - 39 , wherein the retinyl ester is 11-cis-retinyl acetate.
43 . The method of any of claims 17 - 42 , wherein the subject is a human subject.
44 . A kit for improving visual function in a subject having a deficiency in endogenously produced 11-cis retinal, the kit comprising,
a. at least a first therapeutic dose of a 9- or 11-cis-retinyl ester; and,
b. instructions for use that direct that the first therapeutic dose is administered as a divided dose over a period of from about 2 to about 7 days and that provides a resting period between the first therapeutic dose and a second dose, wherein the resting period is from about 7 to about 28 days.
45 . The kit of claim 44 , wherein the subject has Leber congenital Amaurosis (LCA).
46 . The kit of claim 44 , wherein the subject has retinitis pigmentosa (RP).
47 . A dosing regimen for improving visual function of a subject having a deficiency in endogenously produced 11-cis retinal, wherein the dosing regimen comprises at least, a first therapeutic dose, a second therapeutic dose and a resting period between the first therapeutic dose and the second therapeutic dose, the regimen comprising;
a. administering a first dose of a 9- or 11-cis-retinyl ester over a period of from about 2 to about 7 days to a subject in need thereof;
b. providing a resting period of from about 7 to about 28 days between the first therapeutic dose and the second therapeutic dose; and
c. administering the second therapeutic dose of a 9- or 11-cis-retinyl ester following the end of the resting period to the subject in need thereof.
48 . The dosing regimen of claim 47 , wherein the subject has Leber congenital Amaurosis (LCA).
49 . A method of improving visual function in a subject having an endogenous retinoid deficiency comprising:
a. administering a first therapeutic dose of a 9- or 11-cis-retinyl ester to a subject in need thereof, wherein the first therapeutic dose is administered as a divided dose over a period of from about 2 to about 7 days;
b. providing a resting period of from about 7 to about 28 days; and
c. administering a second therapeutic dose of the 9- or 11-cis-retinyl ester, following the end of the resting period to said subject.
50 . The method of claim 49 , wherein the subject is deficient in endogenously produced 11-cis-retinal.
51 . The method of claim 49 or 50 , wherein the subject has retinitis pigmentosa (RP).
52 . The method of claim 51 , wherein the subject has early onset or juvenile RP.
53 . The method of claim 51 , wherein the subject has moderate to severe RP.
54 . The method of claim 51 , wherein the subject has mild retinitis pigmentosa (RP).
55 . The method of claim 49 or 50 , wherein the subject has Leber congenital amaurosis (LCA).
56 . The method of any of claims 49 - 55 , wherein the 9- or 11-cis-retinyl ester provides replacement of endogenously produced 11-cis-retinal.
57 . The method of claim 49 or 50 , wherein the subject has a LRAT gene mutation.
58 . The method of claim 49 or 50 , wherein the subject has a RPE65 gene mutation.
59 . The method of any of claims 49 - 58 , wherein the method further comprises repeating steps b and c one or more times.
60 . The method of any of claims 49 - 59 , wherein the first therapeutic dose is administered as a divided dose over a period of 7 days.
61 . The method of any of claims 49 - 60 , wherein the resting period is from about 7 days to about 21 days.
62 . The method of claim 61 , wherein the resting period is about 21 days.
63 . The method of claim 61 , wherein the resting period is about 14 days.
64 . The method of claim 61 , wherein the resting period is about 7 days.
65 . The method of any of claims 49 - 64 , wherein the first therapeutic dose is from about 280 mg/m 2 to about 420 mg/m 2 .
66 . The method of claim 65 , wherein the first therapeutic dose is about 280 mg/m 2 .
67 . The method of claim 65 , wherein the first therapeutic dose is about 420 mg/m 2 .
68 . The method of any of claims 49 - 64 , wherein the first therapeutic dose is about 10 mg/m 2 per day.
69 . The method of any of claims 49 - 64 , wherein the first therapeutic dose is about 20 mg/m 2 per day.
70 . The method of any of claims 49 - 66 , wherein the first therapeutic dose is about 40 mg/m 2 per day.
71 . The method of any of claims 49 - 65 , wherein the first therapeutic dose is about 60 mg/m 2 per day.
72 . The method of any of claims 49 - 71 , wherein the therapeutic doses are administered orally.
73 . The method of any of claims 49 - 72 , wherein the second therapeutic dose is administered for substantially the same period and in substantially the same amount as the first therapeutic dose.
74 . The method of any of claims 49 - 73 , wherein the retinyl ester is a 9-cis-retinyl ester.
75 . The method of claim 74 , wherein the retinyl ester is 9-cis-retinyl acetate.
76 . The method of any of claims 49 - 73 , wherein the retinyl ester is 11-cis-retinyl acetate.
77 . The method of any of claims 49 - 76 , wherein improving visual function comprises increasing visual field in an eye by at least 20% from baseline as measured by Goldmann Visual Field (GVF) analysis.
78 . The method of any of claims 49 - 77 , wherein improving visual function comprises increasing visual acuity in an eye by greater than or equal to 5 letters from baseline as measured using an Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart.
79 . The method of any of claims 49 - 78 , wherein improving visual function comprises a clinically significant increase in retinal sensitivity from baseline.
80 . The method of any of claims 49 - 79 , wherein the subject is a human subject.
81 . A method of improving visual function in a subject with retinitis pigmentosa (RP) comprising:
a. administering a first therapeutic dose of a 9-cis-retinyl acetate, wherein the first therapeutic dose is administered at about 40 mg/m 2 to about 60 mg/m 2 per day over a period of 7 days to a subject in need thereof;
b. providing a resting period of from about 7 days to about 21 days; and
c. administering a second therapeutic dose of the 9-cis-retinyl acetate following the end of the resting period to a subject in need thereof.
82 . The method of claim 81 , wherein said subject is deficient in endogenously produced 11-cis-retinal.
83 . The method of claim 81 or 82 , wherein the subject has moderate to severe retinitis pigmentosa (RP).
84 . The method of claim 81 or 82 , wherein the subject has mild retinitis pigmentosa (RP).
85 . The method of claim 81 or 82 , wherein the subject has early onset or juvenile retinitis pigmentosa (RP).
86 . The method of any of claims 81 - 85 , wherein the 9-cis-retinyl acetate provides replacement of endogenously produced 11-cis-retinal.
87 . The method of claim 81 or 82 , wherein said subject has a LRAT gene mutation.
88 . The method of claim 81 or 82 , wherein said subject has a RPE65 gene mutation.
89 . The method of any of claims 81 - 88 , wherein the method further comprises repeating steps b and c one or more times.
90 . The method of any of claims 81 - 89 , wherein the resting period is about 21 days.
91 . The method of any of claims 81 - 89 , wherein the resting period is about 14 days.
92 . The method of any of claims 81 - 89 , wherein the resting period is about 7 days.
93 . The method of any of claims 81 - 92 , wherein the improving visual function comprises increasing visual field in an eye by at least 20% from baseline as measured by Goldmann Visual Field (GVF) analysis, or increasing visual acuity in an eye by greater than or equal to 5 letters from baseline as measured using an Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart, or both.
94 . The method of any of claims 81 - 93 , wherein the second therapeutic dose is administered for substantially the same period and in substantially the same amount as the first therapeutic dose.
95 . The method of any of claims 81 - 94 , wherein the therapeutic doses are administered orally.
96 . The method of any of claims 81 - 95 , wherein the subject is a human subject.
97 . A method of improving visual function of a subject having an endogenous retinoid deficiency comprising administering at least a first and second therapeutic dose of 9- or 11-cis-retinyl ester to a subject in need thereof, wherein the first therapeutic dose is administered as a divided dose over a period of from about 2 to about 7 days, wherein a resting time period between the first dose and the second does is from about 7 to about 28 days, and wherein improving visual function comprises increasing visual field in an eye by at least 20% from baseline as measured by Goldmann Visual Field (GVF) analysis, increasing visual acuity in an eye by greater than or equal to 5 letters from baseline as measured using an Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart, or both.
98 . The method of claim 97 , wherein said subject is deficient in endogenously produced 11-cis-retinal.
99 . The method of claim 97 or 98 , wherein the subject has retinitis pigmentosa (RP).
100 . The method of claim 98 , wherein the subject has moderate to severe retinitis pigmentosa (RP).
101 . The method of claim 98 , wherein the subject has mild retinitis pigmentosa (RP).
102 . The method of claim 96 or 97 , wherein the subject has Leber congenital amaurosis (LCA).
103 . The method of any of claims 96 - 102 , wherein the 9- or 11-cis-retinyl ester provides replacement of endogenously produced 11-cis-retinal.
104 . The method of claim 96 or 97 , wherein said subject has a LRAT gene mutation.
105 . The method of claim 96 or 97 , wherein said subject has a RPE65 gene mutation.
106 . The method of any of claims 96 - 105 , wherein the first dose is administered as a divided dose over a period of 7 days.
107 . The method of any of claims 96 - 106 , wherein the resting period is from about 7 days to about 21 days.
108 . The method of claim 107 , wherein the resting period is about 21 days.
109 . The method of claim 107 , wherein the resting period is about 14 days.
110 . The method of claim 107 , wherein the resting period is about 7 days.
111 . The method of any of claims 96 - 110 , wherein the first therapeutic dose is from about 280 mg/m 2 to about 420 mg/m 2 .
112 . The method of claim 111 , wherein the first therapeutic dose is about 280 mg/m 2 .
113 . The method of any of claims 96 - 110 , wherein the first therapeutic dose is about 10 mg/m 2 per day.
114 . The method of any of claims 96 - 110 , wherein the first therapeutic dose is about 20 mg/m 2 per day.
115 . The method of any of claims 96 - 112 , wherein the first therapeutic dose is about 40 mg/m 2 per day.
116 . The method of any of claims 96 - 111 , wherein the first therapeutic dose is about 60 mg/m 2 per day.
117 . The method of any of claims 96 - 116 , wherein the therapeutic dose is administered orally.
118 . The method of any of claims 96 - 117 , wherein the second therapeutic dose is administered for substantially the same period and in substantially the same amount as the first therapeutic dose.
119 . The method of any of claims 96 - 118 , wherein the retinyl ester is a 9-cis-retinyl ester.
120 . The method of claim 119 , wherein the 9-cis-retinyl ester is a 9-cis-retinyl acetate.
121 . The method of any of claims 96 - 118 , wherein the retinyl ester is 11-cis-retinyl acetate.
122 . The method of any of claims 96 - 121 , wherein the subject is a human subject.
123 . A kit for improving visual function in a subject with retinitis pigmentosa (RP), the kit comprising,
a. at least a first therapeutic dose of a 9- or 11-cis-retinyl ester; and,
b. instructions for use that direct that the first therapeutic dose is administered as a divided dose over a period of from about 2 to about 7 days and provides a resting period between the first therapeutic dose and a second dose, wherein the resting period is from about 7 to about 28 days.
124 . The kit of claim 123 , wherein said subject is deficient in endogenously produced 11-cis-retinal.
125 . The method of claim 123 or 124 , wherein the subject has early onset or juvenile RP.
126 . The kit of claim 123 or 124 , wherein the subject has moderate to severe RP.
127 . The kit of claim 123 or 124 , wherein the subject has mild RP.
128 . The kit of any of claims 123 - 127 , wherein the 9- or 11-cis-retinyl ester provides replacement of endogenously produced 11-cis-retinal.
129 . The kit of claim 123 or 124 , wherein said subject has a LRAT gene mutation.
130 . The kit of claim 123 or 124 , wherein said subject has a RPE65 gene mutation.
131 . The kit of any of claims 123 - 130 , wherein the instructions direct that the first dose is administered in a divided dose over a period of 7 days.
132 . The kit of any of claims 123 - 131 , wherein the instructions direct that the resting period is from about 7 days to about 21 days.
133 . The kit of claim 132 , wherein the instructions direct that the resting period is about 21 days.
134 . The kit of claim 132 , wherein the instructions direct that the resting period is about 14 days.
135 . The kit of any of claim 132 , wherein the instructions direct that the resting period is about 7 days.
136 . The kit of any of claims 123 - 135 , wherein the first therapeutic dose is from about 280 mg/m 2 to about 420 mg/m 2 .
137 . The kit of claim 136 , wherein the first therapeutic dose is about 280 mg/m 2 .
138 . The kit of any of claims 123 - 135 , wherein the instructions direct that the first therapeutic dose is about 10 mg/m 2 per day.
139 . The kit of any of claims 123 - 135 , wherein the instructions direct that the first therapeutic dose is about 20 mg/m 2 per day.
140 . The kit of any of claims 123 - 137 , wherein the instructions direct that the first therapeutic dose is about 40 mg/m 2 per day.
141 . The kit of any of claims 123 - 136 , wherein the instructions direct that the first therapeutic dose is about 60 mg/m 2 per day.
142 . The kit of any of claims 123 - 141 , wherein the therapeutic dose is administered orally.
143 . The kit of any of claims 123 - 142 , wherein the second therapeutic dose is administered for substantially the same period and in substantially the same amount as the first therapeutic dose.
144 . The kit of any of claims 123 - 143 , wherein the retinyl ester is 9-cis-retinyl acetate.
145 . The kit of any of claims 123 - 143 , wherein the retinyl ester is 11-cis-retinyl acetate.
146 . The kit of any of claims 123 - 145 , wherein improving visual function comprises increasing visual field in an eye by at least 20% from baseline as measured by Goldmann Visual Field (GVF) analysis.
147 . The kit of any of claims 123 - 146 , wherein improving visual function comprises increasing visual acuity in an eye by greater than or equal to 5 letters from baseline as measured using an Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart.
148 . The kit of any of claims 123 - 147 , wherein improving visual function comprises a clinically significant increase in retinal sensitivity from baseline.
149 . The kit of any of claims 123 - 148 , wherein the subject is a human subject.
150 . A dosing regimen for improving visual function of a subject with retinitis pigmentosa (RP), wherein the dosing regimen comprises at least, a first therapeutic dose, a second therapeutic dose and a resting period between the first therapeutic dose and the second therapeutic dose, the regimen comprising;
a. administering a first dose of a 9- or 11-cis-retinyl ester over a period of from about 2 to about 7 days to a subject in need thereof;
b. providing a resting period of from about 7 to about 28 days between the first therapeutic dose and the second therapeutic dose; and
c. administering the second therapeutic dose of a 9- or 11-cis-retinyl ester following the end of the resting period to the subject in need thereof.
151 . The dosing regimen of claim 150 , wherein said subject is deficient in endogenously produced 11-cis-retinal.
152 . The method of claim 150 or 151 , wherein the subject has early onset or juvenile retinitis pigmentosa (RP).
153 . The dosing regimen of claim 150 or 151 , wherein the subject has moderate to severe retinitis pigmentosa (RP).
154 . The dosing regimen of claim 150 or 151 , wherein the subject has mild retinitis pigmentosa (RP).
155 . The dosing regimen of any of claims 150 - 154 , wherein the 9- or 11-cis-retinyl ester provides replacement of endogenously produced 11-cis-retinal.
156 . The dosing regimen of claim 150 or 151 , wherein said subject has a LRAT gene mutation.
157 . The dosing regimen of claim 150 or 151 , wherein said subject has a RPE65 gene mutation.
158 . The dosing regimen of any of claims 150 - 157 , wherein the method further comprises repeating steps b and c one or more times.
159 . The dosing regimen of any of claims 150 - 158 , wherein the first dose is administered in a divided dose over a period of 7 days.
160 . The dosing regimen of any of claims 150 - 159 , wherein the resting period is from about 7 days to about 21 days.
161 . The dosing regimen of claim 160 , wherein the resting period is about 21 days.
162 . The dosing regimen of claim 160 , wherein the resting period is about 14 days.
163 . The dosing regimen of claim 160 , wherein the resting period is about 7 days.
164 . The dosing regimen of any of claims 150 - 163 , wherein the first therapeutic dose is from about 280 mg/m 2 to about 420 mg/m 2 .
165 . The dosing regimen of claim 164 , wherein the first therapeutic dose is about 280 mg/m 2 .
166 . The dosing regimen of any of claims 150 - 163 , wherein the first therapeutic dose is about 10 mg/m 2 per day.
167 . The dosing regimen of any of claims 150 - 163 , wherein the first therapeutic dose is about 20 mg/m 2 per day.
168 . The dosing regimen of any of claims 150 - 165 , wherein the first therapeutic dose is about 40 mg/m 2 per day.
169 . The dosing regimen of any of claims 150 - 164 , wherein the first therapeutic dose is about 60 mg/m 2 per day.
170 . The dosing regimen of any of claims 150 - 169 , wherein the therapeutic doses are administered orally.
171 . The dosing regimen of any of claims 150 - 170 , wherein the second therapeutic dose is administered for substantially the same period and in substantially the same amount as the first therapeutic dose.
172 . The dosing regimen of any of claims 150 - 171 , wherein the retinyl ester is 9-cis-retinyl acetate.
173 . The dosing regimen of any of claims 150 - 171 , wherein the retinyl ester is 11-cis-retinyl acetate.
174 . The dosing regimen of any of claims 150 - 173 , wherein the improving visual function comprises increasing visual field in an eye by at least 20% from baseline as measured by Goldmann Visual Field (GVF) analysis.
175 . The dosing regimen of any of claims 150 - 174 , wherein the improving visual function comprises increasing visual acuity in an eye by greater than or equal to 5 letters from baseline as measured using an Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart.
176 . The dosing regimen of any of claims 150 - 175 , wherein the improving visual function comprises a clinically significant increase in retinal sensitivity from baseline.
177 . The dosing regimen of any of claims 150 - 176 , wherein the subject is a human subject.
178 . A dosing regimen for improving visual function of a subject with retinitis pigmentosa (RP), wherein the dosing regimen comprises at least, a first therapeutic dose, a second therapeutic dose and a resting period between the first therapeutic dose and the second therapeutic dose, the regimen comprising:
a. administering the first therapeutic dose of a 9-cis-retinyl acetate, wherein the first therapeutic dose is administered at about 40 mg/m 2 per day over a period of 7 days to a subject in need thereof;
b. providing a resting period from about 7 days to about 21 days; and
c. administering a second therapeutic dose of a 9-cis-retinyl acetate following the end of the resting period to the subject.
179 . The dosing regimen of claim 178 , wherein said subject is deficient in endogenously produced 11-cis-retinal.
180 . The dosing regimen of claim 178 or 179 , wherein the 9-cis-retinyl acetate provides replacement of endogenously produced 11-cis-retinal.
181 . The dosing regimen of claim 178 or 179 , wherein said subject has a LRAT gene mutation.
182 . The dosing regimen of claim 178 or 179 , wherein said subject has a RPE65 gene mutation.
183 . The dosing regimen of claim 178 or 179 , wherein the subject has moderate to severe RP)
184 . The dosing regimen of claim 178 or 179 , wherein the subject has mild RP.
185 . The dosing regimen of claim 178 or 179 , wherein the subject has early onset or juvenile RP.
186 . The dosing regimen of any of claims 178 - 185 , wherein the method further comprises repeating steps b and c one or more times.
187 . The dosing regimen of any of claims 178 - 186 , wherein the second therapeutic dose is administered for substantially the same period and in substantially the same amount as the first therapeutic dose.
188 . The dosing regimen of any of claims 178 - 187 , wherein improving visual function comprises increasing visual field in an eye by at least 20% from baseline as measured by Goldmann Visual Field (GVF) analysis, or increasing visual acuity in an eye by greater than or equal to 5 letters from baseline as measured using an Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart, or both.
189 . The dosing regimen of any of claims 178 - 188 , wherein the therapeutic doses are administered orally.
190 . The dosing regimen of any of claims 178 - 189 , wherein the subject is a human subject.