Treatment methods for muscular dystrophy
Inventors
Sun, Huadong • East, Lilly • Tinsley, Jon • ELKINS, Jake
Assignees
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Publication Number
US-12286630-B2
Publication Date
2025-04-29
Expiration Date
Abstract
New dosing regimens for treating muscular dystrophy in a patient suffering from Duchenne muscular dystrophy (DMD) with an antisense oligonucleotide conjugate that causes skipping of an exon in the human dystrophin gene are described. Also described is a method of treating a patient with an antisense oligomer CPP conjugate and a magnesium supplement.
Core Innovation
The invention relates to a method of treating a patient with Duchenne muscular dystrophy (DMD) who has a mutation that is amenable to exon skipping by administering an antisense oligomer conjugate of Formula (I), or a pharmaceutically acceptable salt thereof. The conjugate includes a nucleobase-defined targeting sequence complementary to an exon annealing site in dystrophin pre-mRNA, and a T′ moiety selected from defined options including a cell-penetrating peptide, with R100 as a cell-penetrating peptide, R200 as hydrogen, and R1 as C1-C6 alkyl.
The method administers the conjugate at a dose equivalent to the dose of the 6HCl salt of the conjugate according to a schedule of once every four weeks. The schedule is based on patient weight bands and is intended to achieve mean AUC exposure within specified ranges, including about 100 and about 200 ug·h/mL or between about 200 and about 500 ug·h/mL.
The method further comprises administering a magnesium supplement to the patient. The disclosed embodiments also mention the conjugate in ±6HCl hydrochloride salt form and Formula (VIIIA) and Formula (VIIIB).
Claims Coverage
Two independent claims are identified. Across them, the covered inventive features center on a Formula (I) antisense oligomer conjugate with a nucleobase-defined targeting sequence complementary to a dystrophin pre-mRNA exon annealing site, a T′ moiety selection including a cell-penetrating peptide option, weight-based once-every-four-weeks dosing to achieve mean AUC targets, and co-administration of a magnesium supplement; one claim further narrows the mutation to exon 51 skipping.
Antisense oligomer conjugate of Formula (I) with nucleobase-defined exon-annealing targeting
Administering an antisense oligomer conjugate of Formula (I), or a pharmaceutically acceptable salt thereof, wherein each Nu is a nucleobase that together form a targeting sequence complementary to an exon annealing site in dystrophin pre-mRNA.
T′ moiety selection using R100 cell-penetrating peptide, R200 hydrogen, and R1 C1-C6 alkyl
The method includes a T′ moiety selected from defined options, wherein R100 is a cell-penetrating peptide, R200 is hydrogen, and R1 is C1-C6 alkyl.
Weight-based once every four weeks dosing to match 6HCl-salt equivalent dose and mean AUC targets
Administering at a dose equivalent to the dose of the 6HCl salt of the conjugate according to a schedule of once every four weeks, with specified dose ranges for patient weight bands, to achieve a mean AUC of about 100 and about 200 ug·h/mL or between about 200 and about 500 ug·h/mL.
Co-administration of magnesium supplement
Further comprising administering a magnesium supplement to the patient.
DMD treatment for mutations amenable to exon 51 skipping
A method of treating a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation amenable to exon 51 skipping.
DMD treatment for mutations amenable to exon skipping
A method of treating a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation that is amenable to exon skipping.
Both independent claims cover treatment of DMD using a Formula (I) antisense oligomer conjugate with a nucleobase-defined targeting sequence complementary to a dystrophin pre-mRNA exon annealing site and a T′ moiety including a cell-penetrating peptide option, with 6HCl-equivalent dosing once every four weeks to reach specified mean AUC ranges, and with co-administration of a magnesium supplement. One independent claim further requires the mutation to be amenable to exon 51 skipping.
Stated Advantages
Achieving a mean AUC of about 100 and about 200 ug·h/mL, or between about 200 and about 500 ug·h/mL.
Dosing intended to reduce exposure variability and avoid underexposure and overexposure.
Achieving plasma exposure targets using body weight bands to control mean AUC and Cmax variability.
Documented Applications
Treating a patient with Duchenne muscular dystrophy (DMD) who has a mutation amenable to exon skipping by administering a Formula (I) antisense oligomer conjugate targeting an exon annealing site in dystrophin pre-mRNA.
Treating a patient with Duchenne muscular dystrophy (DMD) who has a mutation amenable to exon 51 skipping.
Treatment of Duchenne muscular dystrophy (DMD) in patients with mutations amenable to exon skipping, including mutations amenable to exon 51 skipping.
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