Alnylam Pharmaceuticals, Inc. · NASDAQ:ALNY
Alnylam Pharmaceuticals — Technical Presentation (October 2026)
69 slides from Alnylam Pharmaceuticals's technical presentation, Oct 26, 2026
Slide 1: Brezosiran (ALN-HTT02)
Brezosiran (ALN-HTT02) An Investigational RNAi Therapeutic Targeting Exon 1 of the Huntingtin Gene to Slow Progression of Huntington’s Disease October 26, 2026 © 2026 Alnylam Pharmaceuticals, Inc.
Slide 2: Agenda
Agenda Pushkal Garg, M.D. 01 Introduction Chief Research & Development Officer 02 About Brezosiran Kevin Sloan, Ph.D. Vice President, Development Programs, (ALN-HTT02) ALN-HTT02 Program Lead 03 Targeting HTT1a in HTT Gill Bates, Ph.D. Professor of Molecular Neuroscience, Co-Director of the Lowering
Slide 3: Disclaimer
Disclaimer Alnylam has engaged Dr. Bates as an independent academic speaking in her personal scientific capacity. She is not speaking on behalf of University College London or UCL Consultants today; nothing said by Dr. Bates constitutes investment advice nor should it be relied on in making investme
Slide 4: Alnylam Forward-Looking Statements
Alnylam Forward-Looking Statements This presentation contains forward-looking statements. Forward-looking statements include statements regarding Alnylam’s expectations, beliefs, goals, plans or prospects, including, without limitation, statements regarding: the potential safety or efficacy of brezo
Slide 5: Agenda
Agenda Pushkal Garg, M.D. 01 Introduction Chief Research & Development Officer 02 About Brezosiran Kevin Sloan, Ph.D. Vice President, Development Programs, (ALN-HTT02) ALN-HTT02 Program Lead 03 Targeting HTT1a in HTT Gill Bates, Ph.D. Professor of Molecular Neuroscience, Co-Director of the Lowering
Slide 6: Pioneering a Generational Class of RNAi Medicines
Pioneering a Generational Class of RNAi Medicines Silence any gene in genome Upstream of today’s medicines Catalytic mechanism Highly potent Highly specific and reversible Infrequent administration Building a Portfolio of RNAi Therapeutics with Transformational Patient Impact
Slide 7: Disciplined R&D Maximizes the Transformative Potential of RNAi
Disciplined R&D Maximizes the Transformative Potential of RNAi S U S TA I N A B L E I N N O VAT I O N E N G I N E S T R AT E G I C P R I N C I P L E S Tissue Aim to Delivery Address diseases with high expand into 10 TISSUES morbidity & mortality by 2030 Pursue high conviction targets Strong biologic
Slide 8: Industry Leading Pipeline of RNAi Therapeutics
Industry Leading Pipeline of RNAi Therapeutics PHASE 1 PHASE 2 PHASE 3 Nucresiran ATTR Amyloidosis with Cardiomyopathy TTR Nucresiran hATTR Amyloidosis with Polyneuropathy Zilebesiran2 Hypertension CARDIOVASCULAR Zilebesiran REVERSIR2 Hypertension Rapirosiran (ALN-HSD)1 Metabolic Dysfunction-Associa
Slide 9: Expect Significant Clinical Milestones Over Next Two Years
Expect Significant Clinical Milestones Over Next Two Years 1 Product launch* 4+ Pivotal studies ongoing 5+ Pivotal studies ongoing 3 Pivotal studies ongoing 4 Key data readouts 5+ Key data readouts 5+ Key data readouts 2026 2027 2028 3-4 New IND/CTA Filings Per Year * Assuming positive phase 3 data
Slide 10: C16 Conjugates Unlocked the CNS for RNAi Therapeutics
C16 Conjugates Unlocked the CNS for RNAi Therapeutics Advancing a growing pipeline of investigational CNS-targeted RNAi therapeutics in collaboration with Regeneron Preclinical Results of mivelsiran in NHPs Phase 1 Multiple-Dose Results of Mivelsiran in Early-Onset AD PHASE 1 PHASE 2 Brezosiran (ALN
Slide 11: Agenda
Agenda Pushkal Garg, M.D. 01 Introduction Chief Research & Development Officer 02 About Brezosiran Kevin Sloan, Ph.D. Vice President, Development Programs, (ALN-HTT02) ALN-HTT02 Program Lead 03 Targeting HTT1a in HTT Gill Bates, Ph.D. Professor of Molecular Neuroscience, Co-Director of the Lowering
Slide 12: Huntington's Disease Robs Generations of Patients of Body and Mind
Huntington’s Disease (HD) Robs Generations of Patients of Body and Mind Progressive, fatal monogenic neurodegenerative disease Movement: chorea, incoordination, falls Thinking: executive dysfunction, memory loss Mood: depression, apathy, personality change, suicidality Woody Guthrie Nancy Wexler & p
Slide 13: HD is Caused by a CAG Repeat Expansion in the HTT Gene
HD is Caused by a CAG Repeat Expansion in the Huntingtin (HTT) Gene Inherited CAG repeats ≥40 Expect to develop HD with lifetime CAG repeat further expands over time Somatic instability mHTT accumulation Full-length and HTT1a Gato et al., 2020 Neuronal toxicity H D - I S S S TA G I N G Stage 0 Stage
Slide 14: One Gene, Two Potential Culprits
One Gene, Two Potential Culprits One gene, two proteins The mutant gene gives rise to full-length mutant HTT (67 exons) HTT mRNA and a shorter, toxic isoform, HTT1a (exon 1 only)² HTT1a mRNA (Exon 1) (Exon 1-67) Both likely contribute to disease HTT1a protein Full-length HTT protein Full-length muta
Slide 15: Technical Challenges Have Slowed Progress in the Field
Technical Challenges Have Slowed Progress in the Field Exposure-related tolerability issues have prevented exploration of deep HTT lowering Dose-dependent NfL increases observed with tominersen ASO NfL increases observed with WVE-003 allele-selective ASO Our approach is poised to answer a key questi
Slide 16: Brezosiran Targets Exon 1 of HTT
Brezosiran Targets Exon 1 of HTT Intrathecally administered investigational HTT Alleles in HD C16-RNAi therapeutic FL Wild type FL Mutant HTT1a Targets HTT exon 1 Binds a conserved mRNA sequence within exon 1 Exon Brezo- Exon Brezo- Exon 1 siran 1 siran 1 CAG Designed to lower all HTT species in CNS
Slide 17: Brezosiran Durably Lowered HTT in Non-Human Primates
Brezosiran Durably Lowered HTT Throughout the Brain with an Encouraging Safety Profile in Non-Human Primates1 Deep and dose-dependent Multiple Multiple IT Doses IT Doses of ALN-HTT02 of ALN-HTT02 HTT protein lowering sustained for Single IT Dose (Q3M for 6 Months) (Q3M for 6 Months) Multiple IT Dose
Slide 18: Brezosiran Offers Three Key Reasons for Hope
Brezosiran Offers Three Key Reasons for Hope THERAPEUTIC APPROACH: Brezosiran is designed to reduce the production of all huntingtin protein (HTT) species in the CNS DESIGN ELEMENTS: Safety & durability of C16-siRNA delivery platform Potential to fully explore deep & widespread HTT-lowering througho
Slide 19: Agenda
Agenda Pushkal Garg, M.D. 01 Introduction Chief Research & Development Officer 02 About Brezosiran Kevin Sloan, Ph.D. Vice President, Development Programs, (ALN-HTT02) ALN-HTT02 Program Lead 03 Targeting HTT1a in HTT Gill Bates, Ph.D. Professor of Molecular Neuroscience, Co-Director of the Lowering
Slide 20: Targeting HTT1a in HTT lowering strategies
Targeting HTT1a in HTT lowering strategies Professor Gillian Bates
Slide 21: Huntington's disease
Huntington’s disease Autosomal dominant • midlife to late age onset • movement disorder • psychiatric disturbances • cognitive decline • systemic features Video: Adult-onset Huntington’s disease Sarah Tabrizi
Slide 22: The HTT gene and huntingtin (HTT) protein
The HTT gene and huntingtin (HTT) protein CAG CAG CAG…. Glutamines QQQ……. ≥ 40 Huntington’s disease 36-39 incomplete penetrance 6-35 unaffected 180 kb DNA 1 2 3 66 67 huntingtin protein (HTT) multifunctional scaffold protein Mutation imparts a gain of function MacDonald 1998
Slide 23: The neuropathology of Huntington's disease
The neuropathology of Huntington’s disease Unaffected Huntington’s disease HD Brain Cerebral Cortex • generalized atrophy • selective neuronal cell death • nuclear and cytoplasmic inclusions • anti-HTT antibodies to N-terminus • aggregate pathology • presymptomatic Gutekunst et al. 1999. J. Neurosci
Slide 24: Somatic CAG repeat expansion: the driver of HD phenotypes
Somatic CAG repeat expansion: the driver of HD phenotypes
Slide 25: The molecular basis of Huntington's disease
The molecular basis of Huntington’s disease Repeats of several ≥ 40 CAGs = 100 CAGs in brain fully penetrant mutation Somatic CAG regions repeat expansion total functional capacity Genetic modifiers in DNA damage repair pathways Absence of specific mismatch repair proteins prevents somatic CAG expan
Slide 26: Step 2: the alternative processing of the HTT transcript
Step 2: the alternative processing of the HTT transcript
Slide 27: The molecular basis of Huntington's disease
The molecular basis of Huntington’s disease CAG CAG CAG…. HTT gene 1 2 3 66 67 1 1 67 HTT1a mRNA HTT mRNA Proteolytic fragments HTT1a protein Cells with aggregated HTT HTT protein (exon 1 HTT) Is HTT1a the effector through which CAG repeat expansion exerts its pathogenic consequences?
Slide 28: Alternative processing of huntingtin pre-mRNA
Alternative processing of huntingtin pre-mRNA CAG CAG CAG…. polyA site Distal polyA site 1 2 3 4 66 67 HTT gene Human HTT Mouse Htt Intron 1 ~12 kb ~20 kb Position of cryptic polyA sites 2710 + 7327 bp 680 + 1145 bp Name of small transcript HTT1a Htt1a Sathasivam et al. 2013 PNAS 110: 2366-2370; Neu
Slide 29: The allelic series of knock-in mice as a model of CAG expansion
The allelic series of knock-in mice as a model of CAG expansion Knock-in mouse lines Human HTT exon 1 (CAG 20-190) Mouse Htt (exons 2 – 67) Mouse Htt intron 1 Mouse Htt exon 1 Mouse Htt (exons 2 – 67) CAG repeat series Knock-in mouse line CAG repeat size HdhQ20 20 • HTT1a transcript and HTT1a protei
Slide 30: HTT1a levels increase with expanded CAG repeats
HTT1a levels increase with expanded CAG repeats HTT1a transcripts Soluble HTT1a levels Donor: 2B7-Tb Acceptor: 1B12-d2 ✱✱✱ 0.8 ✱✱✱ ✱✱✱ HTRF Signal (AU) 0.6 ✱✱✱ ✱✱✱ 0.4 ✱✱✱ ✱✱✱ ✱✱✱ 0.2 ✱✱✱ ✱✱✱ 0.0 WT HET HOM WT HET HOM WT HET HOM WT HET HOM WT HET HOM WT HET HOM WT HE HdhQ20 HdhQ50 HdhQ80 HdhQ111 CAG
Slide 31: Can HTT1a be detected in human cells / tissues?
Can HTT1a be detected in human cells / tissues?
Slide 32: HTT1a mRNA in postmortem brain
HTT1a mRNA in postmortem brain Sensory Motor Cortex Hippocampus • HTT1a levels increase with increasing CAG repeat length • HTT1a most apparent in juvenile onset brains with longer CAG repeats.
Slide 33: CAG expansion in individual SPNs in HD post-mortem brain
CAG expansion in individual SPNs in HD post-mortem brain • Expansions occur in specific sets of neurons • In MSNs in the striatum, 95 – 98% expansions in the range up to 100 CAGs • Higher proportion of cells with long CAG expansions in brains from juvenile HD Handsaker et al. 2025 Cell 188, 1-17
Slide 34: HTT1a inclusions in postmortem brain
HTT1a inclusions in postmortem brain Age:89+ - HD Age:70 - control Huntington's disease, Vonsattel grade 3/4 Age related changes, LOW burden of AD pathology N-terminus of S830 S830 HTT 1B12 = HTT1a 1B12 1B12 specific x40 x10 Ed Smith and Osama Al Dalahmah
Slide 35: HTT Lowering
HTT Lowering
Slide 36: Strategies for targeting huntingtin transcripts
Strategies for targeting huntingtin transcripts Full-length HTT alone • Agents that target HTT downstream of exon 1 Full-length HTT and HTT1a • Agents that target exon 1 HTT HTT1a alone • Agents that target intron 1 HTT in the cytoplasm
Slide 37: HTT lowering
HTT lowering • What is the relative pathogenesis of HTT1a and full length mutant HTT? • Should we target: - full-length HTT alone? - HTT1a alone? - full-length HTT and HTT1a?
Slide 38: Genetic approach to decrease HTT1a protein levels in a mouse model of HD
Genetic approach to decrease HTT1a protein levels in a mouse model of HD • Remove the cryptic polyA sites from intron 1 of HdhQ150 knock in mice • Prevent generation of HTT1a protein: HdhQ150ΔI
Slide 39: Analysis of soluble mutant HTT in HdhQ150ΔI mice
Analysis of soluble mutant HTT in HdhQ150ΔI mice IP and western analysis (whole brain 2 months of age) IP: 3B5H10 3B5H10 3B5H10 3B5H10 HdhQ150I HdhQ150I HdhQ150I HdhQ150I HdhQ150 HdhQ150 HdhQ150 HdhQ150 WT WT WT WT FL-HTT 250 150 100 HTT1a 75 ID: S830 (Exon1 53Q) CHDI-0148 (aa77-90) MW8 (aa83-90
Slide 40: HTT aggregation delayed in HdhQ150ΔI mice
HTT aggregation delayed in HdhQ150ΔI mice 1B12 – HTT1a specific antibody Papadopoulou et al. 2026 Brain awag040 online.
Slide 41: CSF biomarkers at wild-type levels in HdhQ150ΔI mice
CSF biomarkers at wild-type levels in HdhQ150ΔI mice CSF Neurofilament light chain BRP39 (mouse YKL40) Reduction of HTT1a: • Delays HTT aggregation • rescues levels of NEFL and BRP39 – translatable biomarkers Papadopoulou et al. 2026 Brain awag040 online.
Slide 42: Comparison of ASOs targeting full-length Htt and Htt1a
Human HTT exon 1 (CAG 111) Mouse Htt (exons 2 – 67) HdhQ111 Mouse Htt intron 1 Mouse Htt exon 1 Mouse Htt (exons 2 – 67) Comparison of ASOs targeting: • Mutant and wild type full-length Htt • Htt1a and full-length mutant Htt
Slide 43: ASOs targeting Htt transcripts
ASOs targeting Htt transcripts Jeff Carroll • mutASO: Htt1a and full-length mutant Htt • panASO: full-length WT and full-length mutant Htt Bragg et al. 2026 Sci Transl Med 18, eadv0702
Slide 44: mutASO targeting Htt and HTT1a delays molecular phenotypes
mutASO targeting Htt and HTT1a delays molecular phenotypes HdhQ111 mice Aggregation in the striatum Aggregation delayed by lowering HTT1a and not full-length HTT Bragg et al. 2026 Sci Transl Med 18, eadv0702
Slide 45: mutASO targeting Htt and Htt1a delays molecular phenotypes
mutASO targeting Htt and Htt1a delays molecular phenotypes PanASO: full-length wildtype and mutant Htt had neglibable effect MutASO: full length mutant Htt and Htt1a had profound effects Bragg et al. 2026 Sci Transl Med 18, eadv0702
Slide 46: Comparison siRNAs targeting full-length Htt and Htt1a
Human HTT exon 1 (CAG 190) Mouse Htt (exons 2 – 67) zQ175 Mouse Htt intron 1 Mouse Htt exon 1 Mouse Htt (exons 2 – 67) Comparison siRNAs targeting: • Mutant and wild type full-length Htt • Htt1a alone
Slide 47: siRNAs targeting Htt transcripts
siRNAs targeting Htt transcripts siRNAs against full length Htt siRNAs against intron1 Anastasia Khvorova HTT-10150 (3’-UTR) I-486 and I-634 1 month post administration in vivo: • 10150: specific to full-length Htt: decreases WT and mutant Htt by ~80% • 486/634: specific to Htt1a: decrease Htt1a by
Slide 48: Preclinical trial to lower Htt or Htt1a levels with siRNAs
Preclinical trial to lower Htt or Htt1a levels with siRNAs Mice: zQ175 and WT Bilateral ICV injection 10 nmol / ventricle • Untreated • NTS = non-targeting siRNA • 10150 = siRNA to full-length Htt • 634/486 = siRNA to Htt1a 4 months post administration: potency and durability were greatest in the hi
Slide 49: Effect of lowering HTT or HTT1a on hippocampal HTT aggregation
Effect of lowering HTT or HTT1a on hippocampal HTT aggregation CA1 region of the hippocampus 10150 634/486 UNT NTS Full-length HTT HTT1a Decrease in HTT1a but not HTT has profound effect on nuclear aggregation in the CA1 Papadopoulou et al. 2026 Sci Transl Med, 18 eadw2495
Slide 50: Effect of lowering HTT or HTT1a on hippocampal HTT aggregation
Effect of lowering HTT or HTT1a on hippocampal HTT aggregation CA3 region of the hippocampus 10150 634/486 UNT NTS Full-length HTT HTT1a Decrease in HTT1a more effective than decreasing full-length HTT in the CA3 Papadopoulou et al. 2026 Sci Transl Med, 18 eadw2495
Slide 51: Conclusion
Conclusion Effect of lowering HTT or HTT1a on hippocampal transcriptome Full-length HTT - DOUBLE HTT1a - DOUBLE Full-length HTT - LATE HTT1a - LATE Lowering HTT1a by ~50%: • profound improvements in molecular phenotypes Lowering full-length HTT by ~80%: • some improvements in molecular phenotypes Pa
Slide 52: Conclusion
Conclusion Implications from preclinical research • Targeting strategy should include HTT1a • Targeting HTT1a + full-length mutant HTT together may have added benefit
Slide 53: Acknowledgements
Bates Lab, UCL Max Delbrück Center CHDI Foundation Sarah Aldous Erich Wanker David Howland Shahad Arzouni George McAllister Marie Bondulich University of Ulm Vahri Beaumont Maria Canibano-Pico Andreas Neueder Brenda Lager Sandra Fienko Ramee Lee Rachel Flomen UMASS Deanna Marchionini Casandra Gomez-
Slide 54: Agenda
Agenda Pushkal Garg, M.D. 01 Introduction Chief Research & Development Officer 02 About Brezosiran Kevin Sloan, Ph.D. Vice President, Development Programs, (ALN-HTT02) ALN-HTT02 Program Lead 03 Targeting HTT1a in HTT Gill Bates, Ph.D. Professor of Molecular Neuroscience, Co-Director of the Lowering
Slide 55: Phase 1b Study of Brezosiran Ongoing in Adults with HD
Phase 1b Study of Brezosiran Ongoing in Adults with HD Study Designed in Partnership with the HD Community Phase 1b, Randomized, Double-blind, Placebo-Controlled Trial STUDY OBJECTIVE KEY INCLUSION CRITERIA • Evaluate the safety, tolerability, and PK/PD effects of single IT • Aged 25–70 years doses
Slide 56: Phase 1b Study Design
Phase 1b Study of Brezosiran Underway in Adults with HD Study Designed in Partnership with the HD Community Dose 1 or placebo (2:1) N=6 ENDPOINTS OLE Dose 2 or placebo (2:1) N=6 (brezosiran or placebo) Unblinding at Month 6a Primary endpoint All participants can • Safety and tolerability Randomizati
Slide 57: Baseline Patient Characteristics were Similar Across Cohorts
Baseline Patient Characteristics were Similar Across Cohorts Brezosiran Brezosiran Brezosiran Brezosiran Brezosiran Demographic/Characteristic dose 1 or placebo dose 2 or placebo dose 3 or placebo dose 4 or placebo dose 5 or placebo (N=6) (N=6) (N=12) (N=12) (N=12) Age, years, mean (SD) 52.2 (8.8) 5
Slide 58: Robust, Dose-Dependent CSF mHTT Reduction Demonstrated with SMC Assay
Robust, Dose-Dependent CSF mHTT Reduction Demonstrated with SMC Assay Up to 64% Mean Reduction at Month 3 and up to 80% Individual Reduction in CSF mHTT After a Single IT Dose of Brezosiran Placebo (N=12) Participants with Brezosiran Dose 1 (N=5) measurement below LLoQ, n (%) Brezosiran Dose 2 (N=4)
Slide 59: Deep, Durable HTT-Lowering Confirmed with NULISA Assay
Deep, Durable HTT-Lowering Confirmed with NULISA Assay Up to 60% Mean Reduction at Month 3 and up to 83% Individual Reduction in CSF mHTT After a Single IT Dose of Brezosiran Placebo (N=12) Participants with Assay measurement Brezosiran Dose 1 (N=5) below LLoQ, n (%) Brezosiran Dose 2 (N=4) SMC 16 (
Slide 60: Blinded Safety Summary Supports Encouraging Safety Profile
Blinded Safety Summary Supports Encouraging Safety Profile Active and Placebo Participants Pooled Within Cohort Owing to Ongoing Blinded Study Brezosiran Brezosiran Brezosiran Brezosiran Brezosiran Category dose 1 or placebo dose 2 or placebo dose 3 or placebo dose 4 or placebo dose 5 or placebo (N=
Slide 61: No Increase in CSF Inflammatory Markers
No Increase in CSF Inflammatory Markers CSF Total Protein CSF WBC Placebo (N=12) Brezosiran Dose 2 (N=4) Brezosiran Dose 4 (N=9) Brezosiran Dose 1 (N=5) Brezosiran Dose 3 (N=9) Brezosiran Dose 5 (N=9) CSF total protein data from one participant in each of the dose 3 and dose 4 groups, and the 12-mon
Slide 62: No Dose-Dependent Increases in CSF NfL
No Dose-Dependent Increases in CSF NfL NfL is a biomarker of neuroaxonal injury CSF NfL – Absolute CSF NfL – Fold Change Placebo range Placebo range Placebo range Placebo (N=12) Brezosiran Dose 2 (N=4) Brezosiran Dose 4 (N=9) Brezosiran Dose 1 (N=5) Brezosiran Dose 3 (N=9) Brezosiran Dose 5 (N=9) Sh
Slide 63: No Dose-Dependent Increases in Ventricle Size
No Dose-Dependent Increases in Ventricle Size No Increases Beyond Placebo Range Despite Robust mHTT-Lowering Placebo range Placebo range Placebo (N=12) Brezosiran Dose 1 (N=5) Brezosiran Dose 2 (N=4) Brezosiran Dose 3 (N=9) Brezosiran Dose 4 (N=9) Brezosiran Dose 5 (N=9) Placebo Brezosiran dose 1 Br
Slide 64: Advancing Parallel Studies as Part of Commitment to HD Community
Advancing Parallel Studies as Part of Commitment to HD Community Investing in a large, placebo-controlled pivotal study, pending regulatory alignment ONGOING ONGOING Phase 1b study Phase 1b open-label extension study (adults with HD) (adults with HD) Single ascending dose study to characterize All p
Slide 65: Brezosiran's Potential: Differentiated Approach to Lower All Forms of HTT
Brezosiran’s Potential: Differentiated Approach to Lower All Forms of HTT with Encouraging Safety To Date INCLUSIVE EXON-1 D E E P, D U R A B L E ENCOURAGING T A R G E T I N G S T R AT E G Y H T T- L O W E R I N G SAFETY PROFILE No evidence to date of: Approach designed to lower all Initial Phase 1b
Slide 66: Opportunity to Impact a Sizeable, High Unmet Need Population
Opportunity to Impact a Sizeable, High Unmet Need Population Efficient Commercialization Path for an Effective HD Therapeutic Genetically identifiable patient population Established Huntington Disease Center of Excellence network Growing provider familiarity with intrathecal injection Diagnosed Symp
Slide 67: Alyssa: Living with the Huntington's disease gene
Alyssa Living with the Huntington's disease gene
Slide 68: Agenda
Agenda Pushkal Garg, M.D. 01 Introduction Chief Research & Development Officer 02 About Brezosiran Kevin Sloan, Ph.D. Vice President, Development Programs, (ALN-HTT02) ALN-HTT02 Program Lead 03 Targeting HTT1a in HTT Gill Bates, Ph.D. Professor of Molecular Neuroscience, Co-Director of the Lowering
Slide 69: Silence diseased genes, amplify life
Silence diseased “Amplify life ver i it ae “YAlnylam
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