Alnylam Pharmaceuticals, Inc. · NASDAQ:ALNY
Alnylam Pharmaceuticals — Technical Presentation (June 2026)
61 slides from Alnylam Pharmaceuticals's technical presentation, Jun 25, 2026
Slide 1: ALN-6400: An Investigational RNAi Therapeutic Targeting Plasminogen
ALN-6400 An Investigational RNAi Therapeutic Targeting Plasminogen to Address Rare Bleeding Disorders June 25, 2026 © 2026 Alnylam Pharmaceuticals, Inc. 1
Slide 2: Alnylam Forward-Looking Statements
Alnylam Forward-Looking Statements This presentation contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. All statements other than historical statements of fact regarding Alnylam’s ability to achi
Slide 3: Introduction
Introduction Pushkal Garg, M.D. Chief Research & Development Officer 3
Slide 4: Agenda
Agenda Pushkal Garg, M.D. 01 Introduction Chief Research & Development Officer John Gansner, M.D., Ph.D. 02 ALN-6400 Opportunity Executive Director, ALN-6400 Program Lead Hanny Al-Samkari, M.D. 03 Physician Perspective Harvard Medical School Massachusetts General Hospital Martina Slingsby, Ph.D. 04
Slide 5: 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 5
Slide 6: Alnylam's Sustainable Innovation Engine
Alnylam’s Sustainable Innovation Engine Modular Drug Discovery Platform to Catalyze Long-Term Growth Expand into Tissue 10 TISSUES Delivery by 2030 Potency Access to Specificity RNAi 2 MILLION Durability lives through genetics databases Reversibility Human Platform Multiplexing Genetics Designs 6
Slide 7: Strategic Principles Driving a Differentiated Approach
Strategic Principles Driving a Differentiated Approach Pursue high conviction targets Address diseases with high strong biologic rationale, informed by human genetics morbidity & mortality Potential to halt or reverse disease; Clear clinical Encouraging market best-in-class potential proof-of-concep
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 Filings Per Year * Assuming positive phase 3 data and
Slide 10: Alnylam 2030 – Growth Through Sustainable Innovation
Alnylam 2030 – Growth Through Sustainable Innovation Delivering Therapies that Prevent, Halt, or Reverse Disease Deliver 2+ new transformative medicines beyond TTR with blockbuster potential Expand to 10 tissue types & >40 clinical programs Invest ~30% of revenues in non-GAAP R&D, including select e
Slide 11: Next Wave of Potential Transformative Medicines
Next Wave of Potential Transformative Medicines CARDIOVASCULAR HEMATOLOGY NEUROSCIENCE + METABOLIC ALN-6400 ZILEBESIRAN ALN-HTT02 Targeting Plasminogen to Address Targeting Angiotensinogen to Achieve Targeting Exon 1 of Huntington Gene to Rare Bleeding Disorders Continuous Control of Blood Pressure
Slide 12: ALN-6400 Opportunity
ALN-6400 Opportunity John Gansner, M.D., Ph.D. Executive Director, ALN-6400 Program Lead 12
Slide 13: Broad Opportunity Across Bleeding Disorders
Broad Opportunity Across Bleeding Disorders High Disease Burden Underscores Unmet need for Therapies with Durable and Safe Bleeding Protection Varying Common 5 Disease Bleeding Etiologies Phenotype ~ Disease burden associated with: MILLION Anemia, Iron Infusions, Procedures, people living with Blood
Slide 14: ALN-6400 Targets Liver-Expressed Plasminogen to Prophylactically Reduce Bleeding
ALN-6400 Targets Liver-Expressed Plasminogen (PLG) to Prophylactically Reduce Bleeding Therapeutic Hypothesis Supporting Rationale Genetically and Preclinically Validated Target Mechanism Clinically De-Risked Not Expected to Increase Thrombotic Risk Infrequent subcutaneous administration to enable e
Slide 15: Strong Evidence to Support PLG Knockdown to Reduce Bleeding
Strong Evidence to Support PLG Knockdown to Reduce Bleeding Genetic Evidence Preclinical Data Genetically-predicted lower levels of PLG PLG-siRNA reduces fibrinolysis and mucosal protein are associated with1: bleeding in Non-Human Primates2 Reduced Menstrual Bleeding Reduced GI bleeding Reduced nose
Slide 16: ALN-6400 Not Expected to Increase Thrombotic Risk
ALN-6400 Not Expected to Increase Thrombotic Risk Genetic and Natural History Pre-Clinical Proteomic Data Data Data Control PLG siRNA Thrombotic Thrombin response generation Low PLG levels not associated 107 patients with PLG deficiency had same as control1 not altered4 with increased risk of arteri
Slide 17: Indications Prioritized Based on Unmet Need and Disease Burden
Indications Prioritized Based on Unmet Need and Disease Burden – 2 Most Common Inherited Bleeding Disorders Hereditary Hemorrhagic Telangiectasia 1 (HHT) ~1.5M patients globally (1:5,000) 1 No approved treatments Current Von Willebrand Disease (VWD) 2 prophylactic treatments ~1.5-3M patients with cl
Slide 18: Hereditary Hemorrhagic Telangiectasia (HHT)
Hereditary Hemorrhagic Telangiectasia (HHT) Multi-System Bleeding Disorder with High Clinical Burden; No Approved Treatments Abnormal blood “…nosebleed…picture a faucet of a sink on full.” vessels lead to fragile, high-flow “…severely anemic and low on connections that are blood…” prone to rupture a
Slide 19: ALN-6400: Potential First-in-Class Treatment for HHT
ALN-6400: Potential First-in-Class Treatment for HHT Providing Durable and Safe Bleeding Control Durable Bleeding Control Approved Tx → Increased Diagnosis Long-acting mechanism expected to ~35% patients with HHT diagnosed; provide sustained bleeding protection expect to increase with disease with o
Slide 20: Von Willebrand Disease (VWD)
Von Willebrand Disease (VWD) Limited/Burdensome Treatment Options Leave Clinical Gap “…systemic challenges and Deficient or defective repeated dismissal, and it’s exhausting.” VWF disrupts platelet adhesion “…multiple treatments that and stability of FVIII, didn’t work. I’ve since had a hysterectomy
Slide 21: ALN-6400 Aims to Transform Prophylactic Treatment for Patients with VWD
ALN-6400 Aims to Transform Prophylactic Treatment for Patients with VWD Targeting Durable Bleeding Protection Expected Across All VWD Types and Bleed Types ✓ Type 1 VWD ✓ Type 2 VWD ✓ Type 3 VWD Simple, Quarterly Dosing Reduces Treatment Burden and is Expected to Increase Prophylaxis Use Current SOC
Slide 22: Two Unique and Sizeable Opportunities
Two Unique and Sizeable Opportunities HHT VWD No therapies available, Low treatment rates due to high Low diagnosis rates burden of current therapies1 ~70K ~1.5M ~140K ~3M U.S. patients U.S. patients Globally Globally Types 1-3 35% 25% Diagnosis Rate2 Adequately Treated Patients3 Potential Multi-Bil
Slide 23: ALN-6400: Differentiated Approach and Broad Impact Potential
ALN-6400: Investigational Therapeutic with Differentiated Approach and Broad Impact Potential Across Bleeding Disorders Targeting Durable Not Expected to Increase Reduced Treatment Bleed Protection Thrombotic Risk Burden Universal Address primary clinical Expand prophylactic use to Hemostatic Agent
Slide 24: Hereditary Hemorrhagic Telangiectasia and Von Willebrand Disease
Hereditary Hemorrhagic Telangiectasia and Von Willebrand Disease Hanny Al-Samkari, M.D. Associate Professor of Medicine Harvard Medical School The Peggy S. Blitz Endowed Chair in Hematology/Oncology Classical Hematologist and Clinical Investigator Co-Director, HHT Center of Excellence Massachusetts
Slide 25: Disclosures
Disclosures Universal Disclosures (financial): • Consultancy (Agios, Amgen, Alnylam, Sobi, Sanofi, argenx, Pharmacosmos, Novartis, Alpine, Diagonal, Vaderis, Terremoto) • Research Funding (Agios, Sobi, Amgen, Vaderis, Novartis, Alnylam, Atavistik) 25
Slide 26: The Spectrum of Inherited Bleeding Disorders
The Spectrum of Inherited Bleeding Disorders Coagulation Vascular Structural Factor Problem Problem Hemophilia Von Willebrand Hereditary Hemorrhagic Disease Telangiectasia • 1 in 10,000 people • 1 in 1,000-10,000 people • 1 in 5,000 people • Coagulation factor • Coagulation factor • No coagulation f
Slide 27: Hereditary Hemorrhagic Telangiectasia
Agenda Hereditary Hemorrhagic Telangiectasia Von Willebrand Disease
Slide 28: Case: 41-Year-Old Man with HHT, Severe Epistaxis
Case: 41-Year-Old Man with HHT, Severe Epistaxis • 41-year-old man with severe nosebleeds working in the biomedical field • Diagnosed with HHT in his 20s, sent for regular nasal and intestinal cautery procedures that each worked for a couple of months but provoked worse nosebleeding as time went on
Slide 29: HHT is a Multisystem Hereditary Bleeding Disorder
HHT is a Multisystem Hereditary Bleeding Disorder with Numerous Morbid and Potentially Fatal Manifestations • Progressive, multisystem bleeding disorder due to abnormal vessel formation – Mucocutaneous telangiectasias → chronic gastrointestinal hemorrhage and severe recurrent epistaxis – Severe iron
Slide 30: HHT is the Second-Most-Common Inherited Bleeding Disorder
HHT is the Second-Most-Common Inherited Bleeding Disorder • Autosomal dominant inheritance • Occurs in all sexes equally • Most clinically significant and morbid inherited bleeding disorder of women – More severe bleeding and visceral disease manifestations in women • Patients with HHT have reduced
Slide 31: The Pathologic Lesion of HHT is the Arteriovenous Malformation
The Pathologic Lesion of HHT is the Arteriovenous Malformation Telangiectasia is small AVM (<1 millimeter to few millimeters in diameter), usually occur in skin, GI mucosa, upper aerodigestive tract AVMs are more than a few millimeters in diameter and most commonly occur in lung (>50%), liver (~70%)
Slide 32: Mucocutaneous Telangiectasias: Skin
Mucocutaneous Telangiectasias: Skin 32 Images from Hanny Al-Samkari, MD
Slide 33: Mucocutaneous Telangiectasias: Oral Cavity
Mucocutaneous Telangiectasias: Oral Cavity 33 Images from Hanny Al-Samkari, MD
Slide 34: Mucocutaneous Telangiectasias: Gastrointestinal Tract
Mucocutaneous Telangiectasias: Gastrointestinal Tract 34 Images from https://gastrointestinalatlas.com/english/hereditary_hemorrhagic_telangi.html
Slide 35: Mucocutaneous Telangiectasias: Nasal Cavity
Mucocutaneous Telangiectasias: Nasal Cavity 35 Pagiella et al. Amer J Rhinol Allergy 2009, Folz et al. Eur Arch Otorhinolaryngology 2006
Slide 36: Incidence of Spontaneous, Recurrent Epistaxis
Incidence of Spontaneous, Recurrent Epistaxis Mild Moderate-to-Severe Epistaxis: 41% (1) Epistaxis Severity Score>4.00, Mod- (2) Systemic medical or Severe surgical intervention, and/or 59% (3) intravenous iron and/or red cell transfusion to manage anemia 95% Al-Samkari et al., Blood 2026 36
Slide 37: Incidence of Chronic Gastrointestinal Bleeding
Incidence of Chronic Gastrointestinal Bleeding Patients with GI bleeding receiving IV iron 72% Patients with GI bleeding receiving RBC 30% transfusion (Upper Endoscopy only in 40%) 48% Al-Samkari et al., Blood 2026 37
Slide 38: Incidence of Heavy Menstrual Bleeding and Other Mucocutaneous Bleeding
Incidence of Heavy Menstrual Bleeding and Other Clinically- Significant Mucocutaneous Bleeding 35% 41% Al-Samkari et al., Blood 2026 38
Slide 39: Incidence of Moderate-to-Severe HHT-Associated Mucosal Bleeding
Incidence of Moderate-to-Severe HHT-Associated Mucosal Bleeding Moderate-to-Severe HHT Mucosal Bleeding: Mild (1) Epistaxis Severity 24% Score>4.00, (2) Systemic medical or surgical intervention for Mod- epistaxis and/or GI bleeding, Severe (3) intravenous iron and/or red cell transfusion to 76% man
Slide 40: Iron Deficiency and Iron Deficiency Anemia is the Norm in HHT
Iron Deficiency and Iron Deficiency Anemia is “the Norm” in HHT 2023 N=23,524 Sex 61% (% female) Age <18 7% 18-29 7% 30-49 18% 50-64 26% ≥65 41% Insurance Medicare 40% Commercial 48% Medicaid 12% 40 Al-Samkari H. et al, Am J Hematol 2025
Slide 41: Bleeding Complications of HHT
Bleeding Complications of HHT • 3 in 4 people with HHT develop moderate-to-severe mucosal bleeding, including epistaxis, gastrointestinal, and/or heavy menstrual bleeding • 1 in 3 menstrual-age women with HHT develop heavy menstrual bleeding • 7 in 10 people with HHT develop iron deficiency and/or a
Slide 42: Standard of Care for Bleeding in HHT in 2026
Standard of Care for Bleeding in HHT in 2026 42 Hanny Al-Samkari, How I treat bleeding in hereditary hemorrhagic telangiectasia, Blood, 2024.
Slide 43: Von Willebrand Disease
Agenda Hereditary Hemorrhagic Telangiectasia Von Willebrand Disease
Slide 44: Case: 40-Year-Old Woman with Type 2B VWD Complicated by Chronic GI Bleeding
Case: 40-Year-Old Woman with Type 2B VWD Complicated by Chronic GI Bleeding • Previously managed on 3x weekly IV pdVWF, but developed infusion fatigue; switched to twice-weekly rVWF, but this only treated HMB, not GI bleeding • On endoscopy has numerous vascular malformations that intermittently ble
Slide 45: Von Willebrand Factor
Von Willebrand Factor • A protein in the blood that helps form clots to stop bleeding • Two (main) functions: – Facilitate platelet binding to subendothelial collagen (GPIb, GPIIb/IIIa), platelet-platelet interactions – Protect clotting factor VIII 45
Slide 46: VWD is a Common, Frequently Missed Cause of Excessive Bleeding
Von Willebrand Disease is a Common, Frequently Missed, Important Cause of Excessive Bleeding and Iron Deficiency • Results in mucocutaneous bleeding due to insufficient VWF for normal platelet tethering and adhesion • Results in impaired primary hemostasis and ability to form platelet plug, leading
Slide 47: VWD is the Most Common Inherited Bleeding Disorder
VWD is the Most Common Inherited Bleeding Disorder and Results in a Significant Burden of Mucocutaneous Bleeding • Heavy menstrual bleeding in women • Obstetric bleeding (labor, delivery, postpartum) • Epistaxis • Gingival bleeding • Easy bruising • Gastrointestinal bleeding • Increased surgical ble
Slide 48: Von Willebrand Disease
Von Willebrand Disease 48 2007 National Heart, Lung, and Blood Institute (NHLBI) guideline on diagnosis, evaluation, and management of von Willebrand disease.
Slide 49: Current Treatments for VWD Leave a Conspicuous Gap
Current Treatments for VWD Leave a Conspicuous Gap • Patients with mild type 1 and type 2 disease: – Desmopressin before most procedures – VWF-containing factor concentrate before major procedures – Antifibrinolytics PRN for a few days after dental procedures, certain surgeries • Patients with moder
Slide 50: What Do Physicians and Patients Need?
What Do Physicians and Patients Need? • Safe and effective medications for moderate-to-severe mucocutaneous bleeding in HHT and VWD • Ideally be convenient for patients • It should have a minimal or nil thromboembolic risk • Be a prophylactic agent administered infrequently rather than something on-
Slide 51: ALN-6400 Clinical Plans & Progress
ALN-6400 Clinical Plans & Progress Martina Slingsby, Ph.D. Senior Clinical Scientist, ALN-6400 Clinical Science Lead 51
Slide 52: From Idea to Proof of Mechanism in Under 3 Years
From Idea to Proof of Mechanism in Under 3 Years PLG identified Lead candidate Phase 1 POM HHT Phase 2 VWD Phase 2 as liver target endorsed study dosed achieved study initiated study initiated Apr 2022 Sept 2023 Dec 2024 Jan 2025 Sept 2025 May 2026 2022 2023 2024 2025 2026 Disciplined execution & ea
Slide 53: Phase 1 Study in Healthy Adult Volunteers
Phase 1 Study in Healthy Adult Volunteers Double-Blind, Placebo-Controlled tPA-ROTEM All cohorts randomized 3:1 ALN-6400:placebo ALN-6400 Dose Level 1 or placebo Primary Objective • Safety and tolerability Screening ALN-6400 Dose Level 2 or placebo TXA Benchmark Run-in & ALN-6400 Dose Level 3 or pla
Slide 54: Clinical Proof of Mechanism – Inhibition of Fibrinolysis
Clinical Proof of Mechanism – Inhibition of Fibrinolysis tPA-ROTEM traces from a healthy volunteer showing deep, sustained antifibrinolytic effect with ALN-6400 tPA-ROTEM Healthy Volunteer dosed with oral TXA* Blue trace shows whole blood clot TXA Peak TXA trough formation and fibrinolysis over time
Slide 55: HHT Phase 2 Multinational Study
HHT Phase 2 Multinational Study Patients with HHT with moderate to severe nosebleeds N=48 All cohorts randomized 2:1 ALN-6400:placebo ALN-6400 Dose Level 1 Observation Period ALN-6400 Dose Level 1 Primary Objective or placebo • Safety and tolerability Screening ALN-6400 Dose Level 2 ALN-6400 Dose Le
Slide 56: VWD Phase 2 Multinational Study
VWD Phase 2 Multinational Study Adult and adolescent female patients with VWD (all types) and heavy menstrual bleeding N=24 2 menstrual cycles via ALN-6400 Dose Level 1 ALN-6400 Dose Level 1 1:1 Randomization Primary Objective • Safety and tolerability Screening PBAC ALN-6400 Dose Level 2 ALN-6400 D
Slide 57: ALN-6400: Differentiated Approach and Broad Impact Potential
ALN-6400: Investigational Therapeutic with Differentiated Approach and Broad Impact Potential Across Bleeding Disorders Targeting Durable Not Expected to Increase Reduced Treatment Bleed Protection Thrombotic Risk Burden Universal Address primary clinical Expand prophylactic use to Hemostatic Agent
Slide 58: Austin, USA: Living with HHT
Austin, USA Living with Hereditary Hemorrhagic Telangiectasia (HHT) 58
Slide 59: Q&A Session
Q&A Session RNAi Roundtable ALN-6400: Targeting Plasminogen to Address Rare Bleeding Disorders 59
Slide 60: Upcoming RNAi Roundtables
Upcoming RNAi Roundtables Sept. Oct. 17 26 CARDIOVASCULAR NEUROSCIENCE + METABOLIC ZILEBESIRAN ALN-HTT02 Potential to reduce the risk of Unique targeting strategy aiming cardiovascular events by providing to reduce progression of continuous control of blood pressure Huntington’s disease 60
Slide 61: Silence diseased “Amplify life
Silence diseased “Amplify life ver i it ae “YAlnylam
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