Treatment of amyotrophic lateral sclerosis
AssigneeBiogen MA Inc.
InventorsYingying Liu, Peng Sun, Stephanie Melillo Fradette, Danielle LeeZetta Graham, Janice Chun Yee Wong
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Abstract
The disclosure provides the use of neurofilament light chain levels for selecting a subject with a mutation in the superoxide dismutase 1 (SOD 1) gene for treatment with a SOD 1-targeting antisense oligonucleotide or salt thereof. The disclosed methods can be used in the treatment amyotrophic lateral sclerosis, including clinically presymptomatic amyotrophic lateral sclerosis.
Claims19
A method of treating amyotrophic lateral sclerosis associated with a mutation in the superoxide dismutase 1 (SOD1) gene in a human subject in need thereof, the method comprising administering to the human subject a pharmaceutical composition comprising a therapeutically effective amount of an antisense oligonucleotide according to the following formula:
- mCes Aeo Ges Geo Aes Tds Ads mCds Ads Tds Tds Tds mCds Tds Ads mCeo Aes Geo mCes Te (nucleobase sequence of SEQ ID NO:1), wherein,
- A=an adenine,
- mC=a 5-methylcytosine
- G=a guanine,
- T=a thymine,
- e=a 2′-O-methoxyethylribose modified sugar,
- d=a 2′-deoxyribose sugar,
- s=a phosphorothioate internucleoside linkage, and
- o=a phosphodiester internucleoside linkage;
- or a pharmaceutically acceptable salt thereof,
- wherein the human subject has a neurofilament light chain level of at least 44 pg/ml prior to initiation of the treatment.
A method of treating amyotrophic lateral sclerosis associated with a mutation in the SOD1 gene in a human subject in need thereof, the method comprising:
- measuring a neurofilament light chain level of at least 44 pg/ml in a biological sample obtained from the human subject before initiation of treatment;
- and
- administering to the human subject a pharmaceutical composition comprising a therapeutically effective amount of an antisense oligonucleotide according to the following formula:
- mCes Aeo Ges Geo Aes Tds Ads mCds Ads Tds Tds Tds mCds Tds Ads mCeo Aes Geo mCes Te (nucleobase sequence of SEQ ID NO:1), wherein,
- A=an adenine,
- mC=a 5-methylcytosine
- G=a guanine,
- T=a thymine,
- e=a 2′-O-methoxyethylribose modified sugar,
- d=a 2′-deoxyribose sugar,
- s=a phosphorothioate internucleoside linkage, and
- o=a phosphodiester internucleoside linkage;
- or a pharmaceutically acceptable salt thereof.
The method of any one of the preceding claims, wherein the pharmaceutical composition is administered by intrathecal administration.
The method of any one of the preceding claims, wherein the pharmaceutical composition delivers a fixed dose of about 100 mg of the antisense oligonucleotide.
The method of any one of the preceding claims, wherein the mutation in the SOD1 gene is A4V.
The method of any one of the preceding claims, wherein the mutation in the SOD1 gene is A4V, H46R, G93S, A4T, G141X, D133A, V148G, N139K, G85R, G93A, V14G, C6S, 1113T, D49K, G37R, A89V, E100G, D90A, T137A, E100K, G41A, G41D, G41S, G13R, G72S, L8V, F20C, Q22L, H48R, T54R, 5591, V87A, T88deltaTAD, A89T, V97M, S105deltaSL, V118L, D124G, L114F, D90A, G12R, G147R, C6F, C6G, D101G, D101H, G114A, G85S, H43R, L106F, L106V, L38V, or R115G.
The method of any one of the preceding claims, wherein the human subject is clinically presymptomatic of amyotrophic lateral sclerosis.
The method of any one of the preceding claims, wherein the human subject is administered loading doses of the pharmaceutical composition followed by maintenance doses of the pharmaceutical composition.
Dependencies are inferred from the claim text.