Slides
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© 2026 Alnylam Pharmaceuticals, Inc. Brezosiran (ALN-HTT02) An Investigational RNAi Therapeutic Targeting Exon 1 of the Huntingtin Gene to Slow Progression of Huntington’s Disease October 26, 2026
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Agenda Agenda Kevin Sloan, Ph.D. Vice President, Development Programs, ALN-HTT02 Program Lead 02 About Brezosiran (ALN-HTT02) Gill Bates, Ph.D. Professor of Molecular Neuroscience, Co-Director of the Huntington’s Disease Centre, University College London 03 Targeting HTT1a in HTT Lowering Strategies 05 Q&A Session 04 Clinical Data and Progress Toby Ferguson, M.D., Ph.D. Senior Vice President, Neuroscience Therapeutic Area Head Pushkal Garg, M.D. Chief Research & Development Officer01 Introduction
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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 investment decisions.
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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 brezosiran as a treatment for Huntington’s disease, including through the potential lowering of all HTT isoforms; the potential size of the patient population with Huntington’s disease and the potential market opportunity for an effective treatment for Huntington’s disease; the potential for Alnylam to initiate a pivotal, placebo-controlled efficacy study of brezosiran in adults with Huntington’s disease in 2027; the potential for Alnylam to build a portfolio of RNAi therapeutics with transformational patient impact; the transformative potential of RNAi; and the timing of key data readouts from Alnylam’s clinical trials, the number of pivotal studies Alnylam will have ongoing at any time, the number of new IND/CTA filings Alnylam will make in any calendar year, and the potential for Alnylam to launch additional products and the timing of any such product launches. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation, risks and uncertainties relating to: Alnylam’s ability to successfully execute on its Alnylam 2030 strategy; Alnylam’s ability to successfully launch, market and sell Alnylam’s approved products globally; Alnylam’s ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for Alnylam’s product candidates; actions or advice of regulatory agencies and Alnylam’s ability to obtain and maintain regulatory approval for its product candidates, as well as favorable pricing and reimbursement; delays, interruptions or failures in the manufacture and supply of Alnylam’s marketed products or its product candidates; obtaining, maintaining and protecting intellectual property; Alnylam’s ability to manage its growth and operating expenses through disciplined investment in operations; Alnylam’s ability to maintain strategic business collaborations; Alnylam’s dependence on third parties for the development and commercialization of certain products; the outcome of litigation and government investigations; the risk of future litigation and government investigations; and unexpected expenditures; as well as those risks and uncertainties more fully discussed in the “Risk Factors” filed with Alnylam’s most recent periodic report (Quarterly Report on Form10-Q or Annual Report on Form 10-K) filed with the SEC and in its other SEC filings. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.
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Agenda Agenda Kevin Sloan, Ph.D. Vice President, Development Programs, ALN-HTT02 Program Lead 02 About Brezosiran (ALN-HTT02) Gill Bates, Ph.D. Professor of Molecular Neuroscience, Co-Director of the Huntington’s Disease Centre, University College London 03 Targeting HTT1a in HTT Lowering Strategies 05 Q&A Session 04 Clinical Data and Progress Toby Ferguson, M.D., Ph.D. Senior Vice President, Neuroscience Therapeutic Area Head Pushkal Garg, M.D. Chief Research & Development Officer01 Introduction
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Pioneering a Generational Class of RNAi Medicines Silence any gene in genome Catalytic mechanism Highly specific and reversible Upstream of today’s medicines Highly potent Infrequent administration Building a Portfolio of RNAi Therapeutics with Transformational Patient Impact
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Access to 2 MILLION lives through genetics databases Potency Specificity Durability Reversibility Multiplexing S T R AT E G I C P R I N C I P L E SS U S TA I N A B L E I N N O VAT I O N E N G I N E Disciplined R&D Maximizes the Transformative Potential of RNAi Aim to expand into 10 TISSUES by 2030 Tissue Delivery Platform DesignsHuman Genetics RNAi Address diseases with high morbidity & mortality Encouraging market opportunity & access dynamics Drive to clear clinical proof-of-concept Potential to halt or reverse disease, & be best-in-class Pursue high conviction targets Strong biologic rationale, informed by human genetics
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Industry Leading Pipeline of RNAi Therapeutics 1 Out-licensed with milestones and/or royalties; 2 Partnered, Alnylam-led development with U.S. profit split and milestones/royalties ex -U.S.; 3 Partner-led with profit split; 4 Partnered, Alnylam-led with profit split; Alnylam-owned, -led, or –co-developed PHASE 1 PHASE 2 PHASE 3 TTR Nucresiran Nucresiran CARDIOVASCULAR Zilebesiran2 Zilebesiran REVERSIR2 METABOLIC Rapirosiran (ALN-HSD)1 ALN-ANG31 ALN-4324 (GRB14) ALN-PNP1 ALN-CIDEB1 ALN-2232 (ACVR1C) ALN-6222 (INHBE) ALN-APOC31 NEUROSCIENCE Cemdisiran1 Mivelsiran Mivelsiran ALN-SOD3 Brezosiran (ALN-HTT02)4 ALN-5288 (MAPT)4 ALN-SNCA1 HEMATOLOGY Cemdisiran1 ALN-6400 (PLG) ALN-6400 (PLG) AG-236 (ALN-TMP)1 ALN-CFB1 OTHER Cemdisiran1 Elebsiran1 ALN-BCAT ALN-4285 ALN-4915 ALN-F12021 ATTR Amyloidosis with Cardiomyopathy hATTR Amyloidosis with Polyneuropathy Hypertension Hypertension Metabolic Dysfunction-Associated Steatohepatitis (MASH) Dyslipidemia Type 2 Diabetes Mellitus Metabolic Dysfunction-Associated Steatohepatitis (MASH) MASH Myasthenia Gravis Cerebral Amyloid Angiopathy Alzheimer’s Disease SOD1 Amyotrophic Lateral Sclerosis Huntington’s Disease Alzheimer’s Disease Paroxysmal Nocturnal Hemoglobinuria Hereditary Hemorrhagic Telangiectasia Polycythemia Vera Paroxysmal Nocturnal Hemoglobinuria Hepatitis D Virus Infection Diabetic Kidney Disease Hepatocellular Carcinoma Geographic Atrophy Healthy Volunteers Obesity & Weight Management Parkinson’s Disease Healthy Volunteers Healthy Volunteers Obesity & Weight Management Von Willebrand Disease
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* Assuming positive phase 3 data and regulatory approval Expect Significant Clinical Milestones Over Next Two Years 3-4 New IND/CTA Filings Per Year 4 Key data readouts 3 Pivotal studies ongoing 2026 5+ Key data readouts 4+ Pivotal studies ongoing 2027 5+ Key data readouts 5+ Pivotal studies ongoing 1 Product launch* 2028
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1. Out-licensed to Regeneron with milestones and/or royalties, 2) Partnered with Regeneron, Regeneron -led with profit split, 3. Partnered with Regeneron, Alnylam-led with profit split Phase 1 Multiple-Dose Results of Mivelsiran in Early-Onset AD Preclinical Results of mivelsiran in NHPs P H A S E 1 P H A S E 2 Brezosiran (ALN-HTT02) | Huntington’s Disease3 ALN-5222 (MAPT) | Alzheimer’s Disease3 ALN-SNCA | Parkinson’s Disease1 Mivelsiran | Cerebral Amyloid Angiopathy (CAA) Mivelsiran | Down Syndrome-Associated Alzheimer’s Disease (DS-AD) ALN-SOD | SOD1 Amyotrophic Lateral Sclerosis (ALS)2 C16 Conjugates Unlocked the CNS for RNAi Therapeutics Advancing a growing pipeline of investigational CNS-targeted RNAi therapeutics in collaboration with Regeneron
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Agenda Agenda Kevin Sloan, Ph.D. Vice President, Development Programs, ALN-HTT02 Program Lead 02 About Brezosiran (ALN-HTT02) Gill Bates, Ph.D. Professor of Molecular Neuroscience, Co-Director of the Huntington’s Disease Centre, University College London 03 Targeting HTT1a in HTT Lowering Strategies 05 Q&A Session 04 Clinical Data and Progress Toby Ferguson, M.D., Ph.D. Senior Vice President, Neuroscience Therapeutic Area Head Pushkal Garg, M.D. Chief Research & Development Officer01 Introduction
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1. Liu et al., J Neurol 2015; Internal analysis based on: Lanska et al., Neurology 1988; Rodrigues et al., Mov Disord Clin Pract 2017. 2. Internal analysis based on: Medina et al., Mov Disord 2022; Ibanez et al., Nat Med 2024. Huntington’s Disease (HD) Robs Generations of Patients of Body and Mind Progressive, fatal monogenic neurodegenerative disease Average lifespan shortened to ~10–30y1 from diagnosis Mid-40s typical symptom onset, during prime working years 50% chance each child of an affected parent inherits HD >100K symptomatic patients globally2 Movement: chorea, incoordination, falls Thinking: executive dysfunction, memory loss Mood: depression, apathy, personality change, suicidality Nancy Wexler & patient PATIENT & HD RESEARCH PIONEER Woody Guthrie PATIENT
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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 Neuronal toxicity HD - I S S S TA G I N G Stage 0 CAG repeats ≥40 Stage 1 Biomarker changes (imaging, CSF) Stage 2 Clinical signs and symptoms Stage 3 Functional decline Gato et al., 2020
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One gene, two proteins The mutant gene gives rise to full-length mutant HTT (67 exons) and a shorter, toxic isoform, HTT1a (exon 1 only)² Both likely contribute to disease Full-length mutant HTT and the shorter HTT1a isoform implicated as toxicity drivers²˙⁴⁻⁶ Many approaches miss HTT1a Not all HTT-lowering strategies in development effectively address the shorter isoform¹˙⁷ CAG, cytosine-adenine-guanine; HD, Huntington's disease; HTT, huntingtin. 1. Tabrizi SJ, et al. Lancet Neurol. 2022;21(7):645-658. 2. Sampaio C. Parkinsonism Relat Disord. 2024;122:106049. 3. Bates GP, et al. Nat Rev Dis Primers. 2015;1:15005. 4. Handsaker, Cell 2025 https://doi.org/10.1016/j.cell .2024.11.0385. ; 5. Landles, Brain Com 2024 https://doi.org/10.1093/braincomms/fcae410; 6. Neueder, Sci Rep 2017 https://doi.org/10.1038/s41598-017-01510-z; 7. Ferguson MW, et al. J Cent Nerv Syst Dis. 2022;14:11795735221092517. One Gene, Two Potential Culprits HTT1a protein Full-length HTT protein HTT1a mRNA (Exon 1) HTT mRNA (Exon 1-67) mHTT accumulation
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HD, Huntington's disease; HTT, huntingtin; NfL, neurofilament light chain. Classes shown are illustrative of published experience across the field; no cross -trial or head-to-head comparisons are implied. Data fr om Roche tominersen GENERATION-HD presented at HSG 2024. Data from Wave WVE -003 SELECT-HD presented at EHDN 2024. Technical Challenges Have Slowed Progress in the Field Exposure-related tolerability issues have prevented exploration of deep HTT lowering NfL increases observed with WVE-003 allele-selective ASO Dose-dependent NfL increases observed with tominersen ASO Our approach is poised to answer a key question in the field: Can HTT-lowering provide safe and effective therapeutic benefit?
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Intrathecally administered investigational C16-RNAi therapeutic HTT Alleles in HD Therapeutic Hypothesis C16, 2′-O-hexadecyl; CNS, central nervous system; HD, Huntington’s disease; HTT, huntingtin; HTT1a, huntingtin exon 1 protein; RNA interference. Brezosiran Targets Exon 1 of HTT FL Wild type Exon 1 CAG repeats (<36) Exons 2-67 FL Mutant CAG repeats (>39) Exons 2-67 Exon 1 Brezo- siran Brezo- siran HTT1a CAG repeats (>39) Exon 1 Targets HTT exon 1 Binds a conserved mRNA sequence within exon 1 Designed to lower all HTT species in CNS Includes full-length mHTT, HTT1a and wtHTT Fully reversible No permanent changes
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CSF, cerebrospinal fluid; CNS, central nervous system; HD, Huntington’s disease; HTT, huntingtin; IT, intrathecal. 1. Sloan K, et al. Oral Presentation at the European Huntington's Disease Network and Enroll-HD 2024 Meeting. September 12-14, 2024. Strasbourg, France (recording available online at EHDN.org). Brezosiran Durably Lowered HTT Throughout the Brain with an Encouraging Safety Profile in Non-Human Primates1 Single IT Dose HTT Protein Remaining, % Month 3 All Animals Well-Dosed Animals 0 20 40 60 80 100 120 Multiple IT Doses of ALN-HTT02 (Q3M for 6 Months) % HTT Protein Remaining (rel. to aCSF Control) >90% >80% aCSF Low Dose Mid Dose High Dose (24h CSF drug levels > 1,000 ng/mL) All Animals Well-Dosed Animals 0 20 40 60 80 100 120 Multiple IT Doses of ALN-HTT02 (Q3M for 6 Months) % HTT Protein Remaining (rel. to aCSF Control) >90% >80% aCSF Low Dose Mid Dose High Dose (24h CSF drug levels > 1,000 ng/mL) All Animals Well-Dosed Animals 0 20 40 60 80 100 120 Multiple IT Doses of ALN-HTT02 (Q3M for 6 Months) % HTT Protein Remaining (rel. to aCSF Control) >90% >80% aCSF Low Dose Mid Dose High Dose (24h CSF drug levels > 1,000 ng/mL) Multiple IT Doses HTT Protein Remaining, % Month 6 Deep and dose-dependent HTT protein lowering sustained for months after a single intrathecal dose Widespread across the CNS HTT lowering in cortex and striatum Encouraging safety Across multiple NHP studies up to 12 months in duration: • No neurological abnormalities • No changes in CSF inflammatory markers or neurofilament light chain (NfL) • No histological changes No adverse findings, even after deep wtHTT-lowering >90%
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Brezosiran is an investigational therapeutic in development for Huntington’s Disease. The safety and efficacy of brezosiran have not been established or approved by the FDA, EMA or any other health authority. Safety and efficacy brezosiran are currently being evaluated by these regulatory authorities. Brezosiran Offers Three Key Reasons for Hope T H E R A P E U T I CA P P R O A C H: Brezosiran is designed to reduce the production of all huntingtin protein (HTT) species in the CNS D E S I G N E L E M E N T S: Safety & durability of C16-siRNA delivery platform Potential to fully explore deep & widespread HTT-lowering throughout the brain Inclusive targeting strategy to lower all HTT isoforms, including HTT1a
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Agenda Agenda Kevin Sloan, Ph.D. Vice President, Development Programs, ALN-HTT02 Program Lead 02 About Brezosiran (ALN-HTT02) Gill Bates, Ph.D. Professor of Molecular Neuroscience, Co-Director of the Huntington’s Disease Centre, University College London 03 Targeting HTT1a in HTT Lowering Strategies 05 Q&A Session 04 Clinical Data and Progress Toby Ferguson, M.D., Ph.D. Senior Vice President, Neuroscience Therapeutic Area Head Pushkal Garg, M.D. Chief Research & Development Officer01 Introduction
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Targeting HTT1a in HTT lowering strategies Professor Gillian Bates
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Huntington’s disease Autosomal dominant • cognitive decline • midlife to late age onset • movement disorder • psychiatric disturbances • systemic features Video: Adult-onset Huntington’s disease Sarah Tabrizi
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180 kb DNA 66 67321 CAG CAG CAG…. ≥ 40 unaffected Huntington’s disease 36-39 6-35 incomplete penetrance Mutation imparts a gain of function MacDonald 1998 The HTT gene and huntingtin (HTT) protein huntingtin protein (HTT) Glutamines QQQ……. multifunctional scaffold protein
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The neuropathology of Huntington’s disease • selective neuronal cell death Unaffected Huntington’s disease Gutekunst et al. 1999. J. Neurosci. 19 (7) 2522-2534 HD Brain Cerebral Cortex • anti-HTT antibodies to N-terminus • nuclear and cytoplasmic inclusions • generalized atrophy • aggregate pathology • presymptomatic
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Somatic CAG repeat expansion: the driver of HD phenotypes
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The molecular basis of Huntington’s disease • Somatic CAG repeat expansion in brain drives the age at onset and rate of disease progression ≥ 40 CAGs = fully penetrant mutation Repeats of several 100 CAGs in brain regionsSomatic CAG repeat expansion Genetic modifiers in DNA damage repair pathways Absence of specific mismatch repair proteins prevents somatic CAG expansion in mice total functional capacity
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Step 2: the alternative processing of the HTT transcript
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671 HTT mRNA HTT gene 66 67321 CAG CAG CAG…. Cells with aggregated HTT The molecular basis of Huntington’s disease HTT protein Proteolytic fragments 1 HTT1a mRNA HTT1a protein (exon 1 HTT) Is HTT1a the effector through which CAG repeat expansion exerts its pathogenic consequences?
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polyA site CAG CAG CAG…. Distal polyA site HTT gene 1 2 3 4 66 67 Alternative processing of huntingtin pre-mRNA 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; Neueder et al. 2017 Scientific Reports 7: 1307
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The allelic series of knock-in mice as a model of CAG expansion • HTT1a transcript and HTT1a protein levels Knock-in mouse line CAG repeat size HdhQ20 20 HdhQ50 50 HdhQ80 80 HdhQ111 111 CAG140 140 zQ175 190 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) Knock-in mouse lines CAG repeat series Brenda Lager CHDI Foundation / Britt Callaghan, JAX
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HTT1a levels increase with expanded CAG repeats HTT1a transcript and HTT1a protein levels increase with increasing CAG repeat length. Landles et al. 2024 Brain Comm. 6, fcae410 HTT1a transcripts Soluble HTT1a levels WT HET HOM WT HET HOM WT HET HOM WT HET HOM WT HET HOM WT HET HOM WT HET 0.0 0.2 0.4 0.6 0.8HTRF Signal (AU) Donor: 2B7-Tb Acceptor: 1B12-d2 ✱✱✱ ✱✱✱ ✱✱✱ ✱✱✱ ✱✱✱ ✱✱✱ ✱✱✱ ✱✱✱ ✱✱✱ ✱✱✱ HdhQ20 HdhQ50 HdhQ80 HdhQ111 CAG140 zQ175 N171-82Q
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Can HTT1a be detected in human cells / tissues?
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HTT1a mRNA in postmortem brain Kirupa Sathasivam 20 40 60 80 100 120 140 -1 0 1 2 3 4 5 ManSMC CAG neat Vs %HTT1a CAG repeat length 20 40 60 80 100 120 140 -1 0 1 2 3 4 Man Hipp CAG neat Vs %HTT1a Sensory Motor Cortex Hippocampus R2 = 0.4608 p = 0.0005 R2 = 0.5369 p = 0.0002 • HTT1a levels increase with increasing CAG repeat length • HTT1a most apparent in juvenile onset brains with longer CAG repeats.
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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 Handsaker et al. 2025 Cell 188, 1-17 • Higher proportion of cells with long CAG expansions in brains from juvenile HD
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Age:89+ - HD Huntington's disease, Vonsattel grade 3/4 Age:70 - control Age related changes, LOW burden of AD pathology S830 S830 HTT1a inclusions in postmortem brain 1B12 x40 1B12 x10 1B12 = HTT1a specific Ed Smith and Osama Al Dalahmah N-terminus of HTT
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HTT Lowering
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Strategies for targeting huntingtin transcripts Full-length HTT alone • Agents that target HTT downstream of exon 1 • Agents that target exon 1 HTT Full-length HTT and HTT1a • Agents that target intron 1 HTT in the cytoplasm HTT1a alone
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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?
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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
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IP and western analysis (whole brain 2 months of age) Analysis of soluble mutant HTT in HdhQ150ΔI mice Papadopoulou et al. 2026 Brain awag040 online. ID: WT HdhQ150 HdhQ150I 250 75 150 100 WT HdhQ150 HdhQ150I S830 (Exon1 53Q) CHDI-0148 (aa77-90) WT HdhQ150 HdhQ150I MW8 (aa83-90) WT HdhQ150 HdhQ150I IP: 3B5H103B5H10 3B5H10 3B5H10 AB2644 (Exon2) FL-HTT HTT1a
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HTT aggregation delayed in HdhQ150ΔI mice 1B12 – HTT1a specific antibody Papadopoulou et al. 2026 Brain awag040 online.
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CSF biomarkers at wild-type levels in HdhQ150ΔI mice Reduction of HTT1a: Neurofilament light chain CSF BRP39 (mouse YKL40) Papadopoulou et al. 2026 Brain awag040 online. • rescues levels of NEFL and BRP39 – translatable biomarkers • Delays HTT aggregation
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Comparison of ASOs targeting: • Mutant and wild type full-length Htt • Htt1a and full-length mutant Htt Human HTT exon 1 (CAG 111) Mouse Htt (exons 2 – 67) Mouse Htt intron 1 Mouse Htt exon 1 Mouse Htt (exons 2 – 67) HdhQ111
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ASOs targeting Htt transcripts Bragg et al. 2026 Sci Transl Med 18, eadv0702 • panASO: full-length WT and full-length mutant Htt Jeff Carroll • mutASO: Htt1a and full-length mutant Htt
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Bragg et al. 2026 Sci Transl Med 18, eadv0702 HdhQ111 mice Aggregation in the striatum mutASO targeting Htt and HTT1a delays molecular phenotypes Aggregation delayed by lowering HTT1a and not full-length HTT
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mutASO targeting Htt and Htt1a delays molecular phenotypes Bragg et al. 2026 Sci Transl Med 18, eadv0702 PanASO: full-length wildtype and mutant Htt had neglibable effect MutASO: full length mutant Htt and Htt1a had profound effects
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Comparison siRNAs targeting: • Mutant and wild type full-length Htt • Htt1a alone Human HTT exon 1 (CAG 190) Mouse Htt (exons 2 – 67) Mouse Htt intron 1 Mouse Htt exon 1 Mouse Htt (exons 2 – 67) zQ175
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HTT-10150 (3’-UTR) siRNAs against full length Htt I-486 and I-634 siRNAs against intron1 Anastasia Khvorova siRNAs targeting Htt transcripts • 10150: specific to full-length Htt: decreases WT and mutant Htt by ~80% • 486/634: specific to Htt1a: decrease Htt1a by ~50% 1 month post administration in vivo: Papadopoulou et al. 2026 Sci Transl Med, 18 eadw2495
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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 hippocampus Papadopoulou et al. 2026 Sci Transl Med, 18 eadw2495
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CA1 region of the hippocampus Effect of lowering HTT or HTT1a on hippocampal HTT aggregation Decrease in HTT1a but not HTT has profound effect on nuclear aggregation in the CA1 UNT NTS 10150 634/486 Full-length HTT HTT1a Papadopoulou et al. 2026 Sci Transl Med, 18 eadw2495
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CA3 region of the hippocampus Effect of lowering HTT or HTT1a on hippocampal HTT aggregation UNT NTS 10150 634/486 Full-length HTT HTT1a Papadopoulou et al. 2026 Sci Transl Med, 18 eadw2495 Decrease in HTT1a more effective than decreasing full-length HTT in the CA3
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Conclusion Lowering HTT1a by ~50%: • profound improvements in molecular phenotypes Lowering full-length HTT by ~80%: • some improvements in molecular phenotypes Effect of lowering HTT or HTT1a on hippocampal transcriptome Full-length HTT - DOUBLE Full-length HTT - LATE HTT1a - LATE HTT1a - DOUBLE Papadopoulou et al. 2026 Sci Transl Med, 18 eadw2495
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Conclusion • Targeting HTT1a + full-length mutant HTT together may have added benefit • Targeting strategy should include HTT1a Implications from preclinical research
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Max Delbrück Center Erich Wanker University of Ulm Andreas Neueder UMASS Anastasia Khvorova Neil Aronin Julia Alterman Dan O’Reilly University of Washington Jeff Carroll Bobby Bragg Rancho BioSciences Jon Greene John Obenauer CHDI Foundation David Howland George McAllister Vahri Beaumont Brenda Lager Ramee Lee Deanna Marchionini Liliana Menalled Balajee Somalinga Tom Vogt Jackson Laboratory Britt Callaghan Bates Lab, UCL Sarah Aldous Shahad Arzouni Marie Bondulich Maria Canibano-Pico Sandra Fienko Rachel Flomen Casandra Gomez-Paredes Georgina Osborne Aikaterini Papadopoulou Jemima Phillips Christian Landles Iulia Nita Zixin Khan Kirupa Sathasivam Edward Smith
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Agenda Kevin Sloan, Ph.D. Vice President, Development Programs, ALN-HTT02 Program Lead 02 About Brezosiran (ALN-HTT02) Gill Bates, Ph.D. Professor of Molecular Neuroscience, Co-Director of the Huntington’s Disease Centre, University College London 03 Targeting HTT1a in HTT Lowering Strategies 05 Q&A Session 04 Clinical Data and Progress Toby Ferguson, M.D., Ph.D. Senior Vice President, Neuroscience Therapeutic Area Head Pushkal Garg, M.D. Chief Research & Development Officer01 Introduction
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HD, Huntington’s disease; HD-ISS, Huntington’s Disease-Integrated Staging System; IT, intrathecal; PD, pharmacodynamic; PK, pharmacokinetic. 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 • Evaluate the safety, tolerability, and PK/PD effects of single IT doses of brezosiran S T U D Y O B J E C T I V E • Aged 25–70 years • Genetically confirmed HD with >39 CAG repeats • HD-ISS Stage 2 or early Stage 3 K E Y I N C L U S I O N C R I T E R I A
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Phase 1b Study of Brezosiran Underway in Adults with HD Study Designed in Partnership with the HD Community Randomization (brezosiran or placebo) Single Ascending IT Dosea Dose 1 or placebo (2:1) N=6 Dose 2 or placebo (2:1) N=6 Dose 4 or placebo (3:1) N=12 Dose 3 or placebo (3:1) N=12 Dose 5 or placebo (3:1) N=12 Dose 6 or placebo (3:1) N=12 Variable follow-up period (including open-label active dose for participants who received placebo) 6-Month Double-Blind Period OLE All participants can join OLE Receiving brezosiran every 6 months 36-Month OLE Unblinding at Month 6a 0–12 Month Follow-Up Period IT brezosiran or placebo aThe decision to proceed to the next dosing cohort is determined by the Safety Review Committee. Each cohort is unblinded after al l participants in a cohort have reached Month 6. bPK and PD are secondary endpoints for single-ascending doses and exploratory for repeat doses. CSF, cerebrospinal fluid; HD, Huntington’s disease; IT, intrathecal; mHTT, mutant huntingtin; OLE, open -label extension; PD, pharmacodynamic; PK, pharmacokinetic. Dose escalation up to 3 × between cohorts Primary endpoint • Safety and tolerability Secondary/exploratory endpointsb • PK: CSF and plasma profile of brezosiran • PD: Change from baseline in mHTT levels in CSF Exploratory endpoints • Clinical, imaging, and biomarker measures of disease progression and safety E N D P O I N T S
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BMI, body mass index; CAP100, CAG Age Product 100 score; HD -ISS, Huntington's Disease Integrated Staging System; SD, standard de viation. Baseline Patient Characteristics were Similar Across Cohorts Demographic/Characteristic Brezosiran dose 1 or placebo (N=6) Brezosiran dose 2 or placebo (N=6) Brezosiran dose 3 or placebo (N=12) Brezosiran dose 4 or placebo (N=12) Brezosiran dose 5 or placebo (N=12) Age, years, mean (SD) 52.2 (8.8) 54.7 (9.0) 45.4 (11.0) 51.3 (8.8) 49.9 (8.7) Female, n (%) 1 (16.7) 2 (33.3) 8 (66.7) 5 (41.7) 6 (50.0) White, n (%) 5 (83.3) 6 (100.0) 12 (100.0) 10 (83.3) 11 (91.7) BMI, kg/m2, mean (SD) 25.8 (4.4) 30.4 (4.3) 28.2 (6.2) 26.1 (4.6) 27.1 (4.9) HD-ISS stage, n (%) 2 1 (16.7) 4 (66.7) 7 (58.3) 4 (33.3) 6 (50.0) 3 5 (83.3) 2 (33.3) 5 (41.7) 8 (66.7) 6 (50.0) Number of CAG repeats, mean (SD) 43.8 (1.6) 42.5 (2.0) 44.8 (4.0) 43.3 (2.1) 43.0 (1.8) CAP100, mean (SD) 111.0 (23.0) 103.1 (4.5) 98.4 (14.0) 102.5 (8.2) 98.4 (11.8) Total Functional Capacity, mean (SD) 12.2 (0.8) 12.0 (1.3) 12.5 (0.7) 11.8 (1.1) 12.2 (1.0)
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a,bPost-baseline values reported as less than the LLoQ are set to LLoQ/2, which is the case for 16 participants in figurea and 12 in tableb. LLoQ = 26.5 fM. BL, baseline; CSF, cerebrospinal fluid; IT, intrathecal; LLoQ, lower limit of quantification; mHTT, mutant huntingtin; SD, standard deviation; SE, standard error; SMC, single molecule counting immunoassay. 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 Participants with measurement below LLoQ, n (%) SMC 16 (33.3) 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) mHTT reduction Placebo (N=12) Brezosiran Dose 1 (N=5) Dose 2 (N=4) Dose 3 (N=9) Dose 4 (N=9) Dose 5 (N=9) Mean maximum observed, % (SD)b 2.9 (25.5) 35.6 (18.0) 45.5 (15.7) 52.9 (22.5) 65.7 (11.8) 64.8 (10.2) Minimum individual, %b −36.8 19.0 23.5 6.7 49.3 52.0 Maximum individual, %b 60.8 63.2 59.7 79.6 80.7 77.2
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We gratefully acknowledge the CHDI Foundation and Alamar Biosciences for establishing the NULISA assay, the Alnylam BioA team, Evotec, and Alamar Biosciences for enabling clinical sample testing. BL, baseline; LLoQ, lower limit of quantification; mHTT, mutant huntingtin; NULISA, NUcleic acid Linked Immuno-Sandwich Assay; SD, standard deviation; SE, standard error; SMC, single molecule counting immunoassay. 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 Assay Participants with measurement below LLoQ, n (%) SMC 16 (33.3) NULISA 0 (0) 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) mHTT reduction Placebo (N=12) Brezosiran Dose 1 (N=5) Dose 2 (N=4) Dose 3 (N=9) Dose 4 (N=9) Dose 5 (N=9) Mean maximum observed, % (SD)b 4.9 (13.2) 28.4 (15.0) 32.2 (26.2) 52.7 (16.2) 57.3 (13.5) 59.2 (12.5) Minimum individual, %b −16.4 14.1 0.9 14.9 37.0 38.1 Maximum individual, %b 21.1 53.7 57.2 66.8 76.6 83.0
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Blinded Safety Summary Supports Encouraging Safety Profile Active and Placebo Participants Pooled Within Cohort Owing to Ongoing Blinded Study Data shown for double-blind period as of September 10, 2026. aTwo severe AEs were reported: radius fracture and likely bacterial meningitis; both were also reported as serious AEs. bOne participant experienced headache; assessed as severe, non-serious; the event was resolved. cFour serious AEs were reported: acute myocardial infarction (resolved with sequelae), radius fracture (resolved), post -lumbar puncture syndrome (resolved), and likely bacterial meningitis (resolving). None was assessed as related to study drug. dOne patient had one mild event of asthenia assessed as mild, unrelated to study drug or lumbar puncture; the event was resolved. eOne patient had one mild event of feeling of imbalance not related to study drug or lumbar puncture; the event was resolved. AE, adverse event; SD, standard deviation. Category Brezosiran dose 1 or placebo (N=6) Brezosiran dose 2 or placebo (N=6) Brezosiran dose 3 or placebo (N=12) Brezosiran dose 4 or placebo (N=12) Brezosiran dose 5 or placebo (N=12) Duration of study drug exposure, months, mean (SD) 18.7 (2.3) 12.5 (3.7) 6.9 (0.9) 11.4 (0.3) 4.7 (0.5) At least one AE, n (%) 6 (100.0) 6 (100.0) 10 (83.3) 11 (91.7) 12 (100.0) At least one severe AE, n (%) 0 1 (16.7) 0 2 (16.7)a 0 Related to study drug 0 1 (16.7)b 0 0 0 Related to lumbar puncture 0 1 (16.7) 0 1 (8.3) 0 At least one serious AE, n (%) 0 0 0 4 (33.3)c 0 Related to study drug 0 0 0 0 0 Related to lumbar puncture 0 0 0 2 (16.7) 0 Death, n (%) 0 0 0 0 0 At least one AE of clinical interest, n (%) 1 (16.7)d 0 0 1 (8.3)e 0
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CSF total protein data from one participant in each of the dose 3 and dose 4 groups, and the 12 -month data point from one partic ipant in the dose 1 group, were excluded owing to suspected site input error. Dashed lines denote typical reference values. BL, baseline; CSF, cerebrospinal fluid; SE, standard error; WBC, white blood cell. No Increase in CSF Inflammatory Markers CSF Total Protein CSF WBC 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)
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Shaded placebo range indicates maximum and minimum observed individual placebo values. BL, baseline; CSF, cerebrospinal fluid ; NfL, neurofilament light chain; SE, standard error. No Dose-Dependent Increases in CSF NfL NfL is a biomarker of neuroaxonal injury 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) CSF NfL – Absolute CSF NfL – Fold Change Placebo range Placebo range Placebo range
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Shaded placebo range indicates maximum and minimum observed individual placebo values. BL, baseline; mHTT, mutant huntingtin; NULISA, NUcleic acid Linked Immuno-Sandwich Assay; SD, standard deviation; SE, standard error. No Dose-Dependent Increases in Ventricle Size No Increases Beyond Placebo Range Despite Robust mHTT-Lowering NULISA assay 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) Mean maximum observed mHTT reduction, % (SD) 4.9 (13.2) 28.4 (15.0) 32.2 (26.2) 52.7 (16.2) 57.3 (13.5) 59.2 (12.5) 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 range Placebo range
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Illustrative only; sequencing is not to scale and no specific start dates or study durations are implied. Advancing Parallel Studies as Part of Commitment to HD Community Investing in a large, placebo-controlled pivotal study, pending regulatory alignment PLAN TO INITIATE IN 2027 Phase 1b study (adults with HD) Single ascending dose study to characterize target engagement and safety of brezosiran Phase 1b open-label extension study (adults with HD) All participants eligible; repeat dosing every 6 months Further characterizing safety of sustained HTT lowering and potential efficacy trends over time Pivotal, placebo-controlled efficacy study (adults with HD) Definitive efficacy study to test whether brezosiran can slow HD progression ONGOINGONGOING
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Initial Phase 1b results show a 60%-64% mean reduction in CSF mHTT at month 3 and up to 83% individual reduction from baseline Approach designed to lower all HTT isoforms, including HTT1a I N C L U S I V E E X O N- 1 TA R G E T I N G S T R AT E G Y No evidence to date of: • CNS inflammation (CSF protein, WBC) • NfL increases • Ventricular enlargement . Brezosiran is an investigational therapeutic in development for Huntington’s Disease. The safety and efficacy of brezosiran have not been established or approved by the FDA, EMA or any other health authority. Safety and efficacy brezosiran are currently being evaluated by these regulatory authorities. CNS, central nervous system; HD, Huntington’s disease; HTT, huntingtin; NfL, neurofilament light chain; OLE, open-label extension; RNAi: RNA interference Brezosiran’s Potential: Differentiated Approach to Lower All Forms of HTT with Encouraging Safety To Date D E E P, D U R A B L E H T T- L O W E R I N G E N C O U R A G I N G S A F E T Y P R O F I L E
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Diagnosed Symptomatic Patients ~100K Global1 ~33K US1 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 Strong patient advocacy groups Opportunity to Impact a Sizeable, High Unmet Need Population 1. Internal analysis based on: Medina et al., Mov Disord 2022; Ibanez et al., Nat Med 2024; Bruzelius et al., Mov Disord 2019; E xuzides et al., Neuroepidemiology 2022; Fisher et al., Mov Disord 2014. P O T E N T I A L M U LT I- B I L L I O N D O L L A R O P P O R T U N I T Y
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Agenda Agenda Kevin Sloan, Ph.D. Vice President, Development Programs, ALN-HTT02 Program Lead 02 About Brezosiran (ALN-HTT02) Gill Bates, Ph.D. Professor of Molecular Neuroscience, Co-Director of the Huntington’s Disease Centre, University College London 03 Targeting HTT1a in HTT Lowering Strategies 05 Q&A Session 04 Clinical Data and Progress Toby Ferguson, M.D., Ph.D. Senior Vice President, Neuroscience Therapeutic Area Head Pushkal Garg, M.D. Chief Research & Development Officer01 Introduction