Mivelsiran compositions and methods of use thereof
Patent Information
- Authority / Receiving Office
- HK · HK
- Patent Type
- Applications
- Current Assignee / Owner
- ALNYLAM PHARMACEUTICALS INC
- Filing Date
- 2026-05-04
- Publication Date
- 2026-07-17
Smart Images
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Abstract
Description
This invention relates to double-stranded RNA (dsRNAi) formulations and compositions targeting the APP gene, as well as methods for inhibiting APP gene expression using such dsRNAi formulations and compositions, and methods for treating subjects suffering from APP-related diseases or conditions such as Alzheimer's disease (e.g., early-onset Alzheimer's disease). Abstract
Claims
CLAIMSWe claim:1 . A method for inhibiting the expression of amyloid precursor protein (APP) in a subject having an APP-associated disease in need thereof, comprising administering to the subject a fixed dose of about 25 mg to about 225 mg of mivelsiran or an equivalent amount of a pharmaceutically acceptable salt thereof (e.g., sodium salt), thereby inhibiting the expression of APP in the subject.
2. A method for treating or preventing an APP-associated disease in a subject in need thereof, the method comprising administering to the subject a fixed dose of about 25 mg to about 225 mg of mivelsiran or an equivalent amount of a pharmaceutically acceptable salt thereof (e.g., sodium salt), thereby treating or preventing an APP-associated disease in the subject.
3. The method of any one of claims 1-2, wherein the subject is a human.
4. The method of any one of claims 1-3, wherein the APP-associated disorder is Alzheimer’s disease (AD).
5. The method of claim 4, wherein the Alzheimer’s disease is early-onset Alzheimer’s disease (EOAD).
6. The method of any one of claims 1-5, wherein the subject shows a decrease in the level of sAPPa and / or sAPPp in the cerebral spinal fluid (CSF) following administration of mivelsiran or the equivalent amount of a pharmaceutically acceptable salt thereof (e.g., sodium salt).
7. The method of claim 6, wherein the subject shows an at least about 40% decrease in the level of sAPPa and / or sAPPp in the cerebral spinal fluid (CSF).
8. The method of claim 6, wherein the subject shows an about 50% to about 90% decrease in the level of sAPPa and / or sAPPp in the cerebral spinal fluid (CSF).
9. The method of claim 6, wherein the subject shows the decrease in the level of sAPPa and / or sAPPp in the CSF that is sustained for at least 3 months.
10. The method of claim 9, wherein the subject shows at least about 40% decrease in the level of sAPPa and / or sAPPp in the CSF that is sustained for at least 3 months.
11. The method of claim 9, wherein the subject shows an at least about 40% decrease in the level of sAPPa and / or sAPPp in the CSF that is sustained for at least 6 months.
12. The method of claim 9, wherein the subject shows an at least about 40% decrease in the level of sAPPa and / or sAPPp in the CSF that is sustained for at least 10 months.
13. The method of claim 9, wherein the subject shows an at least about 55% decrease in the level of sAPPa and / or sAPPp in the CSF that is sustained for at least 3 months.
14. The method of claim 9, wherein the subject shows an at least about 55% decrease in the level of sAPPa and / or sAPPp in the CSF that is sustained for at least 6 months.
15. The method of claim 9, wherein the subject shows an at least about 55% decrease in the level of sAPPa and / or sAPPp in the CSF that is sustained for at least 10 months.
16. The method of claim 9, wherein the subject shows an at least about 20% decrease in the level of sAPPa and / or sAPPp in the CSF that is sustained for at least 12 months.
17. The method of any one of claims 1-16, wherein the subject shows a decrease in Ap accumulation following administration of mivelsiran or the equivalent amount of a pharmaceutically acceptable salt thereof (e.g., sodium salt).
18. The method of claim 17, wherein the subject shows a decrease in intracellular and / or extracellular Ap40 and / or Ap42.
19. The method of any one of claims 1-18, wherein the subject shows a decrease in amyloid plaque formation and / or accumulation.
20. The method of any one of claims 1-19, wherein the subject shows a decrease in a level of a disease biomarker in a body fluid of the subject.21 . The method of claim 20, wherein the body fluid is a cerebrospinal fluid (CSF) or a plasma.
22. The method of claim 20, wherein the body fluid is the CSF, and the disease biomarker in the CSF that is decreased is selected from the group consisting of A|340, A 42, neurofilament light chain protein (NfL), neurofilament heavy chain protein (NfH), apolipoprotein E (APOE), neurogranin, synaptosome associated protein 25 (SNAP25), S100 calcium binding protein B (S OB), t-Tau, and p-Tau.
23. The method of claim 22, wherein the disease biomarker in the CSF that is decreased is Ap42 and / or Ap40.
24. The method of claim 23, wherein the subject shows an at least about 30% decrease in the level of A 42 and / or at least about 50% decrease in the level of A 4O in the CSF.
25. The method of claim 23, wherein the subject shows an at least about 40% decrease in the level of A 42 and / or at least about 60% decrease in the level of A 4O in the CSF of the subject.
26. The method of claim 20, wherein the body fluid is the plasma, and the disease biomarker in the plasma that is decreased is selected from the group consisting of sAPPa, sAPPp, A|340, Ap42, NfL, t-Tau, and p-Tau.
27. The method of any one of claims 1-26, wherein neurotoxicity or neuroinflammation is not produced or increased following administration of mivelsiran or the equivalent amount of a pharmaceutically acceptable salt thereof (e.g., sodium salt).
28. The method of any one of claims 1-27, wherein a level of an inflammatory biomarker is not increased following administration of mivelsiran or the equivalent amount of a pharmaceutically acceptable salt thereof (e.g., sodium salt).
29. The method of claim 28, wherein the inflammatory biomarker is selected from the group consisting of complement component 3 (C3), complement component 5 (C5), interleukin-6 (IL-6), interleukin-1 (IL-1), tumor necrosis factor (TNF), monocyte chemoattractant protein-1 (MCP-1), and chitinase-3-like protein 1 (YKL-40).
30. The method of any one of claims 8-29, wherein the decrease or the increase is relative to a reference level.
31. The method of claim 30, wherein the reference level is a level observed in the subject prior to the administration, or a level observed in a subject administered a placebo.
32. The method of claim 30, wherein the reference level is a predetermined threshold level.
33. The method of any one of claims 1-33, wherein the administration improves one or more signs and / or symptoms of the APP-associated disorder in the subject.
34. The method of claim 33, wherein the administration improves the subject’s score in one or more of Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13-item Version (ADAS-Cog13), Clinical Dementia Rating (CDR), Neuropsychiatric Inventory Questionnaire (NPI-Q), Pittsburgh Sleep Quality Index (PSQI), and the Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC).
35. The method of any one of claims 1-34, wherein the fixed dose of mivelsiran is 25 mg to 75 mg, 30 mg to 75 mg, 35 mg to 75 mg, 40 mg to 75 mg, 45 mg to 75 mg, 50 mg to 75 mg, 25 mg to 60 mg, 30 mg to 60 mg, 35 mg to 60 mg, 40 mg to 60 mg, 45 mg to 60 mg, 50 mg to 60 mg, 25 mg to 50 mg, 30 mg to 50 mg, 35 mg to 50 mg, 40 mg to 50 mg, 45 mg to 50 mg, 25 mg to 100 mg, 50 mg to 100 mg, 75 mg to 100 mg, 25 mg to 150 mg, 30 mg to 150 mg, 35 mg to 150 mg, 40 mg to 150 mg, 45 mg to 150 mg, 50 mg to 150 mg, 75 mg to 150 mg, 100 mg to 150 mg, 50 mg to 75 mg, 75 mg to 100 mg, 100 mg to 150 mg, 150 mg to 225 mg, or an equivalent amount of a pharmaceutically acceptable salt thereof (e.g., sodium salt).
36. The method of claim 35, wherein the fixed dose is about 25 mg to about 100 mg or about 50 mg to about 100 mg or about 75 mg to about 150 mg of mivelsiran or an equivalent amount of a pharmaceutically acceptable salt thereof (e.g., sodium salt).
37. The method of claim 35, wherein the fixed dose is about 75 mg to about 100 mg or about 100 mg to about 150 mg of mivelsiran or an equivalent amount of a pharmaceutically acceptable salt thereof (e.g., sodium salt).
38. The method of any one of claims 1-37, wherein the fixed dose is about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135mg, about 140 mg, about 145 mg, or about 150 mg of mivelsiran or an equivalent amount of a pharmaceutically acceptable salt thereof (e.g., sodium salt).
39. The method of any one of claims 1-38, wherein mivelsiran or an equivalent amount of a pharmaceutically acceptable salt thereof is administered to the subject as a single dose.
40. The method of any one of claims 1-39, wherein a multiple dose regimen of the fixed dose of mivelsiran or an equivalent amount of a pharmaceutically acceptable salt thereof is administered to the subject.
41. The method of claim 40, wherein a cumulative annual dose of mivelsiran is 450 mg or less, or an equivalent amount of a pharmaceutically acceptable salt thereof (e.g., sodium salt).
42. The method of claim 40 or 41 , wherein each dose in the multiple dose regimen is administered at least 3 months apart.
43. The method of claim 40 or 41 , wherein each dose in the multiple dose regimen is administered at least 6 months apart.
44. The method of claim 40 or 41 , wherein each dose in the multiple dose regimen is administered at least 9 months apart.
45. The method of claim 40 or 41 , wherein each dose in the multiple dose regimen is administered at least 12 months apart.
46. The method of any one of claims 1-45, wherein mivelsiran or an equivalent amount of a pharmaceutically acceptable salt thereof (e.g., sodium salt) is administered to the subject intrathecally.
47. The method of any one of claims 1-46, wherein the subject, before administration of mivelsiran or an equivalent amount of a pharmaceutically acceptable salt thereof (e.g., sodium salt), is positive for amyloid by PET upon administration of an amyloid PET agent, optionally wherein the amyloid PET agent is18F-labeled.
48. The method of any one of claims 1-47, wherein the CSF of the subject, before administration of mivelsiran or an equivalent amount of a pharmaceutically acceptable salt thereof (e.g., sodiumsalt): (i) is abnormal for Ap42, total tau (t-Tau), and phosphorylated tau (p-Tau); (ii) has an abnormal p-Tau / A|342 ratio or A|342 to p-tau index (PTI); or (iii) has an abnormal t-tau / A|342 ratio or Ap42 to t- tau index (ATI).
49. The method of any one of claims 1-48, wherein the subject, before administration of mivelsiran or an equivalent amount of a pharmaceutically acceptable salt thereof (e.g., sodium salt), scores greater than 20 on a Mini Mental State Examination (MMSE).
50. The method of any one of claims 1-49, wherein the subject, before administration of mivelsiran or an equivalent amount of a pharmaceutically acceptable salt thereof (e.g., sodium salt), has a Clinical Dementia Rating (CDR) Global score of 0.5 or 1 .0.
51. The method of any one of claims 1-50, wherein the subject, before administration of mivelsiran or an equivalent amount of a pharmaceutically acceptable salt thereof (e.g., sodium salt), has a clinical diagnosis of mild cognitive impairment or mild dementia due to Alzheimer’s disease, and / or has an onset of Alzheimer’s disease at an age younger than 65 years.