Alnylam Pharmaceuticals, Inc. · NASDAQ:ALNY
Alnylam Pharmaceuticals — International Stroke Conference (ISC) 2025
20 slides from Alnylam Pharmaceuticals's conference presentation, Feb 5, 2025
Slide 1: Targeting Cerebral Amyloid Angiopathy at its Source: APP-Targeted siRNA in Rodent Models
Targeting Cerebral Amyloid Angiopathy at its Source: An Amyloid-beta Precursor Protein- Targeted siRNA Reduced Vascular Amyloid- Beta and Hemorrhage in Rodent Models Kirk Brown1, Lan T. H. Dang1, Feng Xu2, Xiaoyue Zhu2, Louis-Philippe Croteau1, Sarah LeBlanc1, Mark Schlegel1, Adam Castoreno1, Kevin
Slide 2: Disclosures
Disclosures Presenter: Kirk Brown, PhD Conflict Disclosure Paid Employee and Stockholder of Alnylam Pharmaceuticals Alnylam Pharmaceuticals Mivelsiran: Mivelsiran is an investigational drug being studied for the treatment of cerebral amyloid angiopathy and Alzheimer's disease. Mivelsiran is not appr
Slide 3: CAA is a Serious, Progressive Cerebrovascular Disease Characterized by Deposition of Aβ
CAA is a Serious, Progressive Cerebrovascular Disease Characterized by Deposition of Aβ in Cerebral Blood Vessels • Amyloid-beta (Aβ) accumulation leads to altered Lobar Hemorrhagic Lesions3,8,a cerebrovascular physiology and nonhemorrhagic and hemorrhagic brain injury1–5 Intracerebral hemorrhage •
Slide 4: The Amyloidogenic Pathway Underlies CAA Pathophysiology
The Amyloidogenic Pathway Underlies CAA Pathophysiology • APP mRNA encodes APP1 Nucleus APP gene • APP is cleaved to produce Aβ2 APP mRNA Aβ accumulation may be • Aβ deposits in the vessel walls Ribosome driven by genetic variants that impact Aβ production or of small arteries, arterioles, by reduce
Slide 5: RNA Interference Harnesses an Endogenous Process that Regulates Gene Expression
RNA Interference Harnesses an Endogenous Process that Regulates Gene Expression RNAi Mechanism of Action3,a • Synthetic small interfering RNAs Synthetic gene- specific siRNA (siRNAs) target entry into this cellular mechanism1 siRNA enters RISC and unzips • siRNAs direct the targeted Target mRNA siRN
Slide 6: Mivelsiran is Designed to Reduce APP Production
Mivelsiran is Designed to Reduce APP Production Nucleus APP gene • Mivelsiran is an Mivelsiran APP mRNA investigational therapeutic currently in development for treatment of CAA and AD Ribosome APP protein CAA • Targets APP production in the -CTF AICD CNS AICD Intracellular -secretase -secretase
Slide 7: APP-Lowering siRNA in Rodent Models
APP-Lowering siRNA in Rodent Models
Slide 8: Rodent Models of Aβ-related Pathology Used to Assess Impact of APP-Lowering siRNA
Rodent Models of Aβ-related Pathology Used to Assess Impact of APP-Lowering siRNA CVN mouse model1,2 rTg-DI rat model3 • Transgenic model of AD and CAA, which develop over time • Transgenic model of CAA • APP Swedish, Dutch, and Iowa variants expressed • APP Dutch and Iowa APP variants expressed • L
Slide 9: Timeline of Aβ Accumulation and Occurrence of CMBs Assessed in Interventional Rodent Studies
Timeline of Aβ Accumulation and Occurrence of CMBs Assessed in Interventional Rodent Studies CVN mouse study rTg-DI rat study APP mRNA APP mRNA expression assesseda expression assesseda Age (months) 3 4 6 9 12 Age (months) 3 4 6 9 12 Disease Disease Single dose Single dose 120ug by ICV IHC – A, αSM
Slide 10: APP mRNA Expression in Models After Single Dose of siRNA
APP mRNA Expression in Models After Single Dose of siRNA CVN mouse – Hippocampusa,b rTg-DI rat – Hemibraina,c 3 months post-dose 1 month post-dose APP APP APP APP 150 150 p=0.0072 P = 0.0072 Remaining Remaining (%) (%) Messageremaining, Messageremaining, aCSF) aCSF) aCSF aCSF 100 −38.9% 100 −58.4% t
Slide 11: CVN Mouse Model Data
| || CVN Mouse Model Data
Slide 12: Plaque Deposition in Mouse Hippocampus
Plaque Deposition in Mouse Hippocampus Parenchymal Aβ Vascular Aβ Plaques/Vessel 2.0 Pp=0.0212 = 0.0212 Pp=0.0136 = 0.0136 3 Pp=0.0424 = 0.0424 Pp=0.0383 = 0.0383 % Amyloid-beta/Area # Aβ Plaques/Vessel 1.5 Aβ/Area (%) −45.5% 2 1.0 −45.6% −55.6% # Amyloid-beta 1 0.5 −60.2% 0.0 0 SF SF A A A A SF SF
Slide 13: rTg-DI Transgenic Rat Model Data
rTg-DI Transgenic Rat Model Data
Slide 14: Amyloid Deposition in Rat Hippocampus
Amyloid Deposition in Rat Hippocampus Amyloid deposits in vessels Vascular area occupied by amyloid 6 months post-dose 6 months post-dose Pp<0.0001 < 0.0001 6 % Amyloid-beta/Area Aβ/Area (%) 4 −81.2% 2 ThioS (Amyloid) aCSF APP-lowering 0 Control siRNA A SF N aC R si PP A rTg-DI transgenic rats had a
Slide 15: Number and Size of CMBs in Rat Thalamus
Number and Size of CMBs in Rat 6 months post-dose Thalamus Cerebral microbleed occurrencea 6 months post-dose Hemosiderin+ Count/CMBs Count/CMBs Count/CMBs 150 Hemosiderin+ Count/CMBs 100 p=0.0108 P = 0.0108 aCSF APP-lowering 80 (bleed areas) Control siRNA 100 (animals) 60 Hemosiderin+ Hemosiderin+
Slide 16: Mivelsiran Clinical Trials
| || Mivelsiran Clinical Trials
Slide 17: Early-Onset AD Data Support Development in CAA
Phase 1 Early-Onset AD Data Support Development in CAA Phase 1 Early-Onset Alzheimer’s Disease Early-Onset Alzheimer’s Disease 1 Single and Multiple Ascending Dose Study Alzheimer’s Disease (e.g., early-onset AD, autosomal dominant AD, Down syndrome AD) Phase 2 Cerebral Amyloid Angiopathy cAPPricorn
Slide 18: Mivelsiran Phase 1 Study in Patients with Early-Onset AD
Mivelsiran Phase 1 Study in Patients with Early-Onset AD Aβ40a Adverse Events Mivelsiran Mivelsiran Mivelsiran Mivelsiran 25 mg or 35 mg or 50 mg or 75 mg or Patients with events placebo placebo placebo placebo (N=6, PY=6.9) (N=8, PY=4.8) (N=8, PY=7.6) (N=14, PY=13.5) Time from randomization, 13.89
Slide 19: cAPPricorn-1 Study Design
For US HCPs Only cAPPricorn-1 Study Design Scan to View Congress Poster Presented Phase 2 Multiple-Dose Study Evaluating Efficacy, Safety, and Pharmacodynamics Sporadic CAAa (Primary Efficacy Cohort) R Determined via Boston criteria v2.0 Mivelsiran IT Safety Mivelsiran IT follow-up Dutch-type CAAa P
Slide 20: Summary
For US HCPs Only Summary Scan to View Congress Presentation • Mivelsiran is an investigational RNAi therapeutic designed to reduce APP production, thereby reducing downstream Aβ accumulation and potentially slowing CAA progression • When compared with controls, a single dose of an APP-lowering siRNA
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