Compositions for treating muscular dystrophy

• US 9,506,058 B2
• Filed: 03/14/2014
• Issued: 11/29/2016
• Est. Priority Date: 03/15/2013
• Status: Active Grant

• Current Assignee: Sarepta Therapeutics, Inc.
• Original Assignee: Sarepta Therapeutics, Inc.
• Inventors: Kaye, Edward M.
• Primary Examiner(s): Vivlemore, Tracy
• Assistant Examiner(s): POLIAKOVA-GEORGAN, EKATERINA
• Application Number:
  US14/214,567
• Publication Number:
  US 20140315862A1
• Time in Patent Office: 991 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/7125 Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 2310/33 of the base
• CPC Class Codes: C12N 2320/30 Special therapeutic applications

Abstract

Improved compositions and methods for treating muscular dystrophy by administering antisense molecules capable of binding to a selected target site in the human dystrophin gene to induce exon skipping are described.

Claims

1. A method for treating a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 51 skipping, comprising intravenously administering to the patient eteplirsen at a dose of about 30 mg/kg weekly for more than 120 weeks, such that disease progression in the patient is delayed, thereby treating the patient.

2. The method according to claim 1, wherein the patient is a pediatric patient.

3. The method according to claim 1, wherein the patient is administered an oral corticosteroid for at least 24 weeks prior to the first dose of eteplirsen.

23. The method of claim 1, wherein the patient is 7 years of age or older.

24. The method of claim 1, further comprising administering to the patient a corticosteroid.

25. The method of claim 24, wherein the corticosteroid is Betamethasone, Budesonide, Cortisone, Dexamethasone, Hydrocortisone, Methylprednisolone, Prednisolone, or Prednisone.

26. The method of claim 24, wherein the corticosteroid is administered prior to, in conjunction with, or subsequent to administration of eteplirsen.

27. The method of claim 1, further comprising confirming that the patient has a mutation in the DMD gene that is amenable to exon 51 skipping.

4. A method for reducing the loss of ambulation in a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 51 skipping, comprising intravenously administering to the patient eteplirsen at a dose of about 30 mg/kg weekly for more than 120 weeks, thereby reducing the loss of ambulation relative to baseline, in the patient.

5. The method according to claim 4, wherein the patient is a pediatric patient.

6. The method according to claim 4, wherein the patient is administered an oral corticosteroid for at least 24 weeks prior to the first dose of eteplirsen.

10. The method of claim 4, wherein the dystrophin protein production is measured by reverse transcription polymerase chain reaction (RT-PCR), Western blot analysis, or immunohistochemical detection.

11. The method of claim 4, wherein ambulation is measured using the North Star Ambulatory Assessment.

7. A method for restoring an mRNA reading frame to induce dystrophin protein production in a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 51 skipping, comprising intravenously administering to the patient eteplirsen at a dose of about 30 mg/kg weekly for more than 120 weeks, thereby restoring the mRNA reading frame to induce dystrophin protein production in the patient.

8. The method according to claim 7, wherein the patient is a pediatric patient.

9. The method according to claim 7, wherein the patient is administered an oral corticosteroid for at least 24 weeks prior to the first dose of eteplirsen.

12. A method for treating a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 51 skipping, comprising intravenously administering to the patient eteplirsen at a dose of about 30 mg/kg weekly for more than 120 weeks, such that disease progression in the patient is delayed as measured by the 6 Minute Walk Test (6MWT), thereby treating the patient.

13. A method for reducing the loss of ambulation in a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 51 skipping, comprising intravenously administering to the patient eteplirsen at a dose of about 30 mg/kg weekly for more than 120 weeks, thereby reducing the loss of ambulation relative to baseline in the patient as measured by the 6 Minute Walk Test (6MWT).

14. The method of claim 13, wherein the patient loses less than 5% ambulation, relative to baseline, as measured by the 6 Minute Walk Test (6MWT) by 120 weeks.

15. The method of claim 13, wherein the patient loses no greater than 13.9 meters walking distance relative to baseline, as measured by the 6 Minute Walk Test (6MWT) by 120 weeks.

16. The method of claim 13, wherein the patient maintains ambulation for more than 1.5 years following treatment.

17. A method for reducing loss of pulmonary function in a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 51 skipping, comprising intravenously administering to the patient eteplirsen at a dose of 30 mg/kg weekly for more than 120 weeks, thereby reducing the loss of pulmonary function in the patient relative to baseline.

18. The method of claim 17, wherein pulmonary function is measured as Maximum Inspiratory Pressure (MIP).

19. The method of claim 17, wherein respiratory muscle function in the patient improves at least 14.6% relative to baseline pulmonary function as measured as Maximum Inspiratory Pressure (MIP).

20. The method of claim 17, wherein pulmonary function is measured as Maximum Expiratory Pressure (MEP).

21. The method of claim 17, wherein respiratory muscle function in the patient improves at least 15% relative to baseline pulmonary function as measured as Maximum Expiratory Pressure (MEP).

22. The method of claim 17, wherein pulmonary function is measured as Forced Vital Capacity (FVC).

28. A method for treating a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 51 skipping, comprising intravenously administering to the patient eteplirsen at a dose of about 30 mg/kg weekly for more than 120 weeks to thereby treat DMD, wherein by 120 weeks of treatment respiratory muscle function in the patient improves at least 14.6% relative to baseline pulmonary function as measured as Maximum Inspiratory Pressure (MIP).

29. A method for treating a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 51 skipping, comprising intravenously administering to the patient eteplirsen at a dose of about 30 mg/kg weekly for more than 120 weeks to thereby treat DMD, wherein by 120 weeks of treatment respiratory muscle function in the patient improves at least 15% relative to baseline pulmonary function as measured as Maximum Expiratory Pressure (MEP).