Alnylam Pharmaceuticals, Inc. · NASDAQ:ALNY
Alnylam Pharmaceuticals — Technical Presentation (September 2026)
55 slides from Alnylam Pharmaceuticals's technical presentation, Sep 17, 2026
Slide 1: Zilebesiran
ZILEBESIRAN An Investigational RNAi Therapeutic for Patients with Hypertension and High Cardiovascular Risk September 17, 2026 © 2026 Alnylam Pharmaceuticals, Inc.
Slide 2: 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 efficacy or safety of zilebesiran for
Slide 3: Agenda
Agenda Pushkal Garg, M.D. 01 Introduction Chief Research & Development Officer 02 Hypertension: The Akshay S Desai, M.D., MPH Harvard Medical School Threat Beyond the Office Mass General Brigham 03 The Potential for Continuous Ishir Bhan, M.D., MPH Control with Zilebesiran Executive Director, ZENITH
Slide 4: Agenda
Agenda Pushkal Garg, M.D. 01 Introduction Chief Research & Development Officer 02 Hypertension: The Akshay S Desai, M.D., MPH Harvard Medical School Threat Beyond the Office Mass General Brigham 03 The Potential for Continuous Ishir Bhan, M.D., MPH Control with Zilebesiran Executive Director, ZENITH
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: 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 7: 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 8: Expect Significant Clinical Milestones Over the Next Two Years
Expect Significant Clinical Milestones Over the 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
Slide 9: Extending Our RNAi Leadership Across Major Drivers of Cardiovascular Disease
Extending Our RNAi Leadership Across Major Drivers of Cardiovascular Disease Addressing Major Determinants of Cardiovascular Morbidity and Mortality Cardiovascular Metabolic TTR Early Development Late-Stage Development Commercial Obesity & Weight Management Hypertension ATTR Cardiomyopathy ALN-2232
Slide 10: Cardiovascular Deaths Will Rise Through 2050 – Hypertension Remains the Leading Risk Factor
Cardiovascular Deaths Will Rise Through 2050 – Hypertension Remains the Leading Risk Factor Cardiovascular Disease Burden Attributable to High Systolic Blood Pressure is Projected to Exceed that of Obesity, Diabetes, and High LDL Cholesterol by 2050 CV MORTALITY1 CVD BURDEN BY RISK FACTOR in 20502 4
Slide 11: Agenda
Agenda Pushkal Garg, M.D. 01 Introduction Chief Research & Development Officer 02 Hypertension: The Akshay S Desai, M.D., MPH Harvard Medical School Threat Beyond the Office Mass General Brigham 03 The Potential for Continuous Ishir Bhan, M.D., MPH Control with Zilebesiran Executive Director, ZENITH
Slide 12: Hypertension: The Threat Beyond the Office
Hypertension: The Threat Beyond the Office Akshay S. Desai MD, MPH Director, HF Population Health Mass General Brigham Professor of Medicine Harvard Medical School Boston, MA
Slide 13: Hypertension Remains a Global Health Priority
Hypertension Remains a Global Health Priority Global burden of Hypertension, 1990-2015 • > 1 billion with SBP>140 mm Hg 875M • Prevalence rising with aging, obesity 440M • Leading risk factor for CVD and DALY worldwide • 10% of global health care expenditure Fourouzanfar MD, et al. JAMA. 2017;317(2)
Slide 14: Disability-Adjusted Life Years by SBP and Cause
Disability-Adjusted Life Years by SBP and Cause 29% of DALYs 71% of DALYs Estimated $100B global savings from control of BP *1 DALY = 1 year of healthy life lost Fourouzanfar MD, et al. JAMA. 2017;317(2):165-182
Slide 15: CV Risk is Lower With Effective BP Reduction
CV Risk is Lower With Effective BP Reduction Risk reduction per 10 mm Hg decrease in SBP Major CV Events 20% CHD 17% Stroke 27% HF 28% Renal Failure 5% All cause 13% mortality Meta-analysis of 123 studies, 613815 patients Ettehad D, et al. Lancet 2016; 387: 957–67
Slide 16: A Large Implementation Gap
A Large Implementation Gap BP Treatment BP Control (~40%) (~20%) Zhou B, et al. Lancet. 2021; 398:957–980.
Slide 17: A Large Implementation Gap
A Large Implementation Gap BP Treatment BP Control (~40%) (~20%) Residual Risk Zhou B, et al. Lancet. 2021; 398:957– 980.
Slide 18: SPRINT: Intensive vs. Standard BP Control
SPRINT: Intensive vs. Standard BP Control EFFICACY SAFETY Primary Mortality Hypotension AKI Outcome** 5.2% 3.3% 3.4% 4.4% 6.8% 4.5% 2.0% 2.6% • Terminated early for overwhelming HR 0.75* HR 0.73* HR 1.7* HR 1.7* benefit at median follow up of 3.26 yrs *p<0.001 **MI, ACS, Stroke, HF, or CV Death • Me
Slide 19: 2025 Hypertension Guideline Set Even Lower Targets for BP
2025 Hypertension Guideline Set Even Lower Targets for BP Blood Pressure Category SBP DBP Normal < 120 mmHg and < 80 mmHg Elevated 120 to 129 mmHg and < 80 mmHg Overarching blood pressure Stage 1 Hypertension 130 to 139 mmHg or 80 to 89 mmHg treatment goal is <130/80 mm Hg Stage 2 Hypertension ≥ 140
Slide 20: Therapeutic Options for Hypertension are Expanding
Therapeutic Options for Hypertension are Expanding Desai AS. J Am Coll Cardiol 2025 Nov, 86 (18) 1514–1516.
Slide 21: Residual Barriers to Effective BP Control
Residual Barriers to Effective BP Control • Poor access to care • Inadequate education/awareness • Failure to diagnose hypertension • Therapeutic Inertia (providers) • Poor adherence to daily oral regimens (patients) • Resistance to antihypertensive treatment (~10%) Carey RM, et al. J Am Coll Cardio
Slide 22: Poor Adherence to Antihypertensives Enhances CV Risk
Poor Adherence to Antihypertensives Enhances CV Risk ~50% of patients discontinue prescribed medications within 1 year ~10% of daily medication doses are omitted Lee H, et al. Hypertension 2021; 77(4): 1341-49; Vrijens B, et al. 2008;336(7653):1114-7
Slide 23: Need for Continuous Control of Blood Pressure
Need for Continuous Control of Blood Pressure • Mean of office BP readings over several visits is typically utilized to direct therapy • However, BP fluctuates over both short and long-term • Episodic high values often disregarded • Emerging evidence suggests that diurnal variation and visit-to-visi
Slide 24: 24-Hour Ambulatory Blood Pressure and Cardiovascular Risk
24-Hour Ambulatory Blood Pressure and Cardiovascular Risk Nocturnal HTN is the most Potent Predictor of CV Risk LaRochelle P. J Clin Hypertens. 2002; 4: 3-8; Verdecchia P, et al. Hypertension. 2012; 60:34–42 Sega R, et al.Circulation. 2005; 111:1777–1783; Roush GC, et al. Journal of Hypertension 201
Slide 25: Excessive BP variability Increases Cardiovascular Risk
Excessive BP variability Increases Cardiovascular Risk Visit-to-Visit Variability (independent of mean) Maximum BP and Stroke Risk Risk of Stroke Risk of Coronary Events 18% ↑ CV death, 15% ↑ stroke per 1 SD increase in SBP variability ASCOT-BPLA Trial, Rothwell PM, et al. Lancet 2010; 375: 895-905;
Slide 26: Higher Time in Target Range Lowers Risk of CV and Renal Events
Higher Time in Target Range (TTR) Lowers Risk of CV and Renal Events Buckley L, et al. Hypertension. 2023;80(2):305–313
Slide 27: Hypertension Needs a New Therapeutic Approach
Hypertension Needs a New Therapeutic Approach • Despite effective therapy, many patients with hypertension remain poorly controlled • Physicians commonly fail to adapt therapy even when blood pressure is high, contributing to poor time in the therapeutic range • Adherence to daily oral antihypertens
Slide 28: Thank you
Thank you
Slide 29: Agenda
Agenda Pushkal Garg, M.D. 01 Introduction Chief Research & Development Officer 02 Hypertension: The Akshay S Desai, MD, MPH Harvard Medical School Threat Beyond the Office Mass General Brigham 03 The Potential for Continuous Ishir Bhan, M.D., MPH Control with Zilebesiran Executive Director, ZENITH C
Slide 30: Targeting AGT to Achieve Continuous Control of Blood Pressure
Targeting AGT to Achieve Continuous Control of Blood Pressure with the Potential to Improve CV Outcomes Zilebesiran Targets Angiotensinogen Zilebesiran Therapeutic Hypothesis The most upstream precursor to the RAAS, Continuous Control of BP to Improve CV Outcomes the main BP-regulating pathway 24-ho
Slide 31: Single Dose Achieved Continuous Control of Blood Pressure Throughout 24 Hours
Single Dose of Zilebesiran Achieved Continuous Control of Blood Pressure Throughout the 24-Hour Period Hourly Mean SBP Assessed by ABPM at Month 3 Change from Baseline in Hourly Mean SBP Assessed by ABPM at Month 3 Both panels show sustained 24-hour separation from placebo, including through the nig
Slide 32: Continuous Control Observed Through Month 12 with Twice-Yearly Dosing
Continuous Control of Blood Pressure Observed Through Month 12 with Twice-Yearly Dosing SBP, systolic blood pressure Data on file
Slide 33: Encouraging Safety Observed Across Phase 2
Encouraging Safety Observed Across Phase 2 KARDIA Program Evaluated Zilebesiran Across Monotherapy and Add-On Settings, Including Patients with Both Low and High Cardiovascular Risk 889 patients exposed to zilebesiran across Phase 2 studies Safety Measure zilebesiran monotherapy vs. placebo zilebesi
Slide 34: KARDIA-3 Insights Informed Target Phase 3 Patient Population
KARDIA-3 Insights Informed Target Phase 3 Patient Population A Phase 2 Trial in Patients With Uncontrolled Hypertension on 2–4 Antihypertensives and High CV Risk or Established CVD COHORT A FULL POPULATION (N=270) PRESPECIFIED ANALYSIS POST HOC ANALYSIS eGFR ≥45 mL/min/1.73 m2 (N=174) (N=108) Zilebe
Slide 35: KARDIA-3 Population Largely Reflects ZENITH-Like Population
KARDIA-3 Population Largely Reflects ZENITH-Like Population Cohort A Full Population (eGFR ≥45 mL/min/1.73 m2) Demographic/Characteristic Placebo Zilebesiran 300 + 600 mg (N=88) Pooled (N=182) Age, years, mean (SD) 66.3 (9.0) 66.4 (8.4) Female, % 37.5 48.4 Black, % 22.7 23.1 Hispanic or Latino, % 5
Slide 36: Enhanced Blood Pressure Lowering in ZENITH-Like Patients
Enhanced Blood Pressure Lowering in ZENITH-Like Patients1 Placebo Zilebesiran 300 mg Zilebesiran 600 mg Cohort CohortAA Cohort Baseline Baseline A Diuretic Diuretic CohortBaseline A Baseline Baseline CohortDiuretic ADiuretic Diureticand and Baseline Baseline Baseline Baseline Diuretic Baseline Diure
Slide 37: Single Dose Improved Nighttime Blood Pressure Control, Independent of Dipping Status
A Single Dose of Zilebesiran Improved Nighttime Blood Pressure Control, Independent of Dipping Status Zilebesiran (300 + 600 mg pooled) Non-dipping is associated with BASELINE DIPPERS BASELINE NON-DIPPERS cardiovascular risk1 Daytime Nighttime Daytime Nighttime Mean Baseline −15.3% −2.4% Systolic BP
Slide 38: Rapid, Sustained Reductions in Biomarkers of CV and Renal Risk
Rapid, Sustained Reductions in Biomarkers of CV and Renal Risk Exploratory Outcome Patients with Baseline NT-proBNP ≥12 pmol/L Patients with Baseline Proteinuria 1.6 1.6 UACR ≥20 mg/g Zilebesiran 300 mg Zilebesiran 300 mg 1.4 Zilebesiran 600 mg 1.4 Zilebesiran 600 mg NT-proBNP Placebo-Adjusted Fold-
Slide 39: Addressing Persistent Cardiovascular Risk Requires a New Approach to BP Management
Addressing Persistent Cardiovascular Risk Requires a New Approach to Blood Pressure Management 24-hour continuous control of BP with nighttime dipping maintained KARDIA-3 data in ZENITH-like patients 24-Hour support zilebesiran's potential to deliver BP Level continuous control and continued evaluat
Slide 40: Agenda
Agenda Pushkal Garg, M.D. 01 Introduction Chief Research & Development Officer 02 Hypertension: The Akshay S Desai, M.D., MPH Harvard Medical School Threat Beyond the Office Mass General Brigham 03 The Potential for Continuous Ishir Bhan, M.D., MPH Control with Zilebesiran Executive Director, ZENITH
Slide 41: Phase 3 Cardiovascular Outcomes Trial
Phase 3 Cardiovascular Outcomes Trial Randomized, Double-Blind, Event-Driven Study in High CV Risk Patients with Uncontrolled Hypertension Study Population • Adult patients with uncontrolled hypertension and established CV disease or at high risk • Office systolic BP ≥140 mmHg on stable treatment (≥
Slide 42: Global Footprint & Strong Execution
: Global Footprint & Strong Execution GLOBAL SCALE CAN AUT, BEL, BGR, CZE, >1,000 sites USA DEU, DNK, ESP, FRA, KOR GBR, GRC, HUN, ITA, 35 countries NILD, POL, PRT, ROU, JPN SRB, SVK, SWE, TUR CHN MEX TWN IND COL BRA Actively screening and enrolling in all countries ZAF AUS ARG CHL NZL EXECUTION UPD
Slide 43: Executing a Comprehensive Strategy to Realize Zilebesiran’s Full Potential
Executing a Comprehensive Strategy to Realize Zilebesiran’s Full Potential WHAT WE ARE DOING TODAY TO DELIVER TOMORROW 01 02 03 04 05 06 REAL MEDICAL siRELIS PHASE 3 LINE COMMERCIAL WORLD AFFAIRS & ENZYMATIC EXECUTION EXTENSIONS READINESS EVIDENCE EDUCATION LIGATION TO UNLOCK ZILEBESIRAN’S BROAD CLI
Slide 44: Hypertension is a Global Health Crisis
Hypertension is a Global Health Crisis Uncontrolled Hypertension is Highly Prevalent and Carries Substantial Risk of Morbidity and Mortality DESPITE MULTIPLE TREATMENT OPTIONS… Multiple oral antihypertensive classes still leave most patients uncontrolled ~219M > Daily-oral adherence limits durable,
Slide 45: The Economic Burden of Hypertension
The Economic Burden of Hypertension A Large and Growing Financial Toll on the U.S. and Global Health Systems of total cost comes from 61% $292B UNCONTROLLED HYPERTENSION Global burden projected to grow to >$500B >$500B estimated annual U.S. medical cost of hypertension1 by 20502 $160B 2020 2050 as p
Slide 46: Most High-Risk Patients Spend Very Low Time in Target Range
Real World Evidence: Most High-Risk Patients Spend a Very Low Proportion of Time in Target Range Blood Pressure DISTRIBUTION OF TIME IN TARGET RANGE BP1 (<130/80 mmHg2) Over 12 Months ~80% Cohort of patients with hypertension and high CV risk1 59% 22% 13% 6% Very low control Very low control Adequat
Slide 47: Zilebesiran: A Potential Category Creator
Zilebesiran: A Potential Category Creator Generating Cardiovascular Outcomes to Maximize Value VALUE PROPOSITION Cardiovascular Continuous Infrequent Favorable Outcomes Control Dosing Safety Clinically significant Durable control beyond Twice-yearly dosing to Generally well tolerated MACE reduction
Slide 48: Early Insights Signal Strong Adoption Intent
Early Insights Signal Strong Adoption Intent Demand is Validated Across Prescribers, Patients and Payers PROVIDERS PATIENTS PAYERS 3 in 4 EAGER OUTCOMES 1st CV risk reduction is the #1 intend to prescribe for a new option decision driver Viewed as a Drawn to twice-yearly Meaningful CV outcomes cardi
Slide 49: Need for Long-Term Continuous Control of Blood Pressure
The Reality Highlights the Importance and Need for Long-Term Continuous Control of Blood Pressure Mean Systolic Blood Pressure Time-Dependent HR for CV Death Intensive vs. Standard Treatment Intensive vs. Standard Treatment Loss of CV Risk Protection Loss of BP Control Zilebesiran offers the Potenti
Slide 50: Bringing the Need for Better Control Into Focus
Bringing the Need for Better Control Into Focus Bob, Living with Hypertension
Slide 51: For years, I felt fine and convinced myself that I had a handle on
For years, I felt fine and convinced myself that I had a handle on my high blood pressure. Looking back, that decision nearly cost me my life …
Slide 52: … At 45, I suffered a heart attack that left permanent damage to my
… At 45, I suffered a heart attack that left permanent damage to my heart. Hypertension is often called the 'silent killer' for a reason …
Slide 53: ... My experience taught me that even when you feel healthy, uncontrolled blood pressure
... My experience taught me that even when you feel healthy, uncontrolled blood pressure can have life-threatening consequences."
Slide 54: Q&A
“LAlnylam Q&A
Slide 55: Up next
Up next… Oct. 26 NEUROSCIENCE ALN-HTT02 Unique targeting strategy aiming to reduce progression of Huntington’s disease 55
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