Alnylam Pharmaceuticals, Inc. · NASDAQ:ALNY
Alnylam Pharmaceuticals — Technical Presentation (June 2018)
43 slides from Alnylam Pharmaceuticals's technical presentation, Jun 26, 2018
Slide 1: Platform Advances in RNAi Therapeutics
Platform Advances in RNAi Therapeutics June 26, 2018 © 2018 Alnylam Pharmaceuticals, Inc. 1
Slide 2: Agenda
Agenda Welcome • Christine Lindenboom, Vice President, Investor Relations & Corporate Communications Introduction • Martin Maier, Ph.D., Vice President, Research Platform Advances in RNAi Therapeutics • Advances in ESC+ Design for Improved Specificity and Therapeutic Index • Mark Schlegel, Ph.D., Se
Slide 3: Reminders
Reminders Event will run for approximately 60-75 minutes Q&A session at end of presentation • Questions may be submitted at any time via the ‘Ask a Question’ field on the webcast screen Replay, slides and transcript available at www.alnylam.com/capella 3
Slide 4: 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. There are a number of important factors that could cause actual results to differ material
Slide 5: Agenda
Agenda Welcome • Christine Lindenboom, Vice President, Investor Relations & Corporate Communications Introduction • Martin Maier, Ph.D., Vice President, Research Platform Advances in RNAi Therapeutics • Advances in ESC+ Design for Improved Specificity and Therapeutic Index • Mark Schlegel, Ph.D., Se
Slide 6: RNAi Therapeutics: New Class of Innovative Medicines
RNAi Therapeutics: New Class of Innovative Medicines Clinically Proven Approach with Transformational Potential Nobel Prize-winning science Silence any gene in genome Potent and durable mechanism of action Product engine for sustainable pipeline Now entering commercial stages 6
Slide 7: Addressing Delivery Challenge
Addressing Delivery Challenge Alnylam Platforms for Functional siRNA Delivery to Target Tissue Sense strand Antisense strand Lipid Nanoparticles (LNPs) • Multi-component lipid = formulation (~100 nm in size) GalNAc GalNAc-siRNA Conjugates • Encapsulated siRNA • Single chemical entity • Highly effici
Slide 8: Alnylam Clinical Development Pipeline
Alnylam Clinical Development Pipeline Focused in 4 Strategic Therapeutic Areas (STArs): Genetic Medicines Cardio-Metabolic Diseases Hepatic Infectious Diseases CNS Diseases HUMAN BREAKTHROUGH EARLY STAGE LATE STAGE REGISTRATION/ COMMERCIAL POC1 DESIGNATION (IND or CTA Filed-Phase 2) (Phase 2-Phase 3
Slide 9: Key Features of Alnylam Investigational RNAi Therapeutics
Key Features of Alnylam Investigational RNAi Therapeutics Potential Attributes for Differentiation and Value MAXIMUM CLAMPED KNOCKDOWN PHARMACODYNAMICS (PD) (KD) EFFICACY Up to NOT 99% UNDRUGGABLE TARGETS ROOM TEMP DURABILITY As few as 2 VS. 26 doses per year SUBCUTANEOUS or more doses per year (SC)
Slide 10: Extensive Human Safety Experience
Extensive Human Safety Experience Encouraging Results to Date Number of Number of Clinical Total Patients or Greatest Duration Programs Studies Volunteers Dosed of Exposure >10 >25 >1200 >48 months Minimal platform related findings* • Low incidence (2.9%) of generally mild, asymptomatic, reversible
Slide 11: GalNAc-Conjugate Platforms for Delivery to Liver
GalNAc-Conjugate Platforms for Delivery to Liver Next Gen ESC+ Conjugates Featuring Seed-Pairing Destabilization STC-Conjugate ESC-Conjugate ESC+ Conjugate • Standard Template Chemistry • Enhanced Stability Chemistry • Enhanced Stability Chemistry GalNAc conjugate GalNAc conjugate GalNAc conjugate,
Slide 12: Alnylam CNS Pipeline Strategy
Alnylam CNS Pipeline Strategy Expanding a Pipeline of Potentially Transformative Medicines GCCCCUGGAGGG Genetically validated, Biomarker for Definable path CNS-expressed POC in to approval and target gene Phase 1 patient access Alnylam CNS Objectives • 1st DC in 2018 • 1st IND in late ’19/early ’20
Slide 13: Agenda
Agenda Welcome • Christine Lindenboom, Vice President, Investor Relations & Corporate Communications Introduction • Martin Maier, Ph.D., Vice President, Research Platform Advances in RNAi Therapeutics • Advances in ESC+ Design for Improved Specificity and Therapeutic Index • Mark Schlegel, Ph.D., Se
Slide 14: Enhanced Stabilization Chemistry (ESC) GalNAc-siRNAs
Enhanced Stabilization Chemistry (ESC) GalNAc-siRNAs Subcutaneously-Administered Conjugate Platform for Targeted Delivery to Liver siRNA Ligand • Metabolic stability • Trivalent GalNAc • Intrinsic potency • High affinity and specificity Asialoglycoprotein Receptor (ASGPR) • Highly expressed in hepat
Slide 15: Subset of ESC Conjugates Show Rat Hepatotoxicity at Exaggerated Doses
Subset of ESC Conjugates Show Rat Hepatotoxicity at Exaggerated Doses In silico prediction & In vitro efficacy In vitro screen for predicted off-targets Rodent Knockdown Rat Tox @ >100x PD dose NHP Knockdown DC Good Actors Bad Actors No hepatotoxicity Show hepatotoxicity Single cell necrosis and/or
Slide 16: Seed-Based Off-Target Effects Are Important Drivers of Rodent Hepatotoxicity
Seed-Based Off-Target Effects Are Important Drivers of Rodent Hepatotoxicity for Subset of Conjugates 1. Non-RNAi effects 2. Competition for RISC 3. Undesired seed-based e.g. siRNA chemistry, metabolites loading with miRNAs off-target activity protein binding, drug accumulation miRNA GalNAc GalNAc G
Slide 17: Strategy to Improve Specificity and Therapeutic Index
Strategy to Improve Specificity and Therapeutic Index Utilize seed-pairing destabilization via novel chemical modifications to selectively destabilize off-target binding Off-target binding Partial sequence match Important Considerations pos. 2-8 Antisense loaded RISC 1. On-target potency must be mai
Slide 18: GNA – a Potential Solution
GNA – a Potential Solution • Glycol Nucleic Acid (GNA) in seed region generally appears to be well-suited to minimize off-target effects via seed-pairing destabilization while maintaining potency • GNA can be well accommodated within the RNA duplex despite shorter phosphate-phosphate and base-backbo
Slide 19: GNA at Positions 6-8 Demonstrates Superior Off-Target Mitigation
GNA at Positions 6-8 Demonstrates Superior Off-Target Mitigation Compared to Positions 3-5 In Vitro RNAseq GNA Walk DEGs (Differentially Expressed Genes), significant 3’UTR match, significant 3’UTR match, not significant 19
Slide 20: Sequence-Dependent Impact of GNA on Inherent Potency
Sequence-Dependent Impact of GNA on Inherent Potency 100 P a re n t A S -G N A m R N A r e m a in in g (% ) Example Screen • Screen of 47 sequences 50 against single target • Transfection, 10 nM siRNA, 24 hours, PMH 0 Sequences 200 • Differential tolerance of GNA modification m R N A r e m a in in g
Slide 21: Comparable Potency in Rodents with GNA-Containing Conjugates
Comparable Potency in Rodents with GNA-Containing Conjugates Parent ESC AS7-GNA 1 .5 ED50 ~ 0.30 mg/kg 1 .5 ED50 ~ 0.30 mg/kg P r o t e in r e m a in in g ( % ) r e l. t o p r e d o s e 1 .0 1 .0 0 .3 m g /k g 1 .0 m g /k g Mice 3 .0 m g /k g 0 .5 0 .5 0 .0 0 .0 0 10 20 30 40 50 60 70 80 90 100 0 10
Slide 22: ESC+ Demonstrates More Quiescent Off-Target Signature in Rat Liver
ESC+ Demonstrates More Quiescent Off-Target Signature Across Dose Levels in Rat Liver Dose: qw x 3 Necropsy: Day 16 ESC 3 mg/kg 10 mg/kg 30 mg/kg 60 mg/kg 120 mg/kg ESC+ DEGs (Differentially Expressed Genes), significant 3’UTR match, significant 3’UTR match, not significant 22
Slide 23: Therapeutic Index Improved Greater Than 5-fold with ESC+ Conjugates
Therapeutic Index Improved Greater Than 5-fold with ESC+ Conjugates 𝐍𝐎𝐀𝐄𝐋 (𝐪𝐰 𝐱 𝟑) Therapeutic Index = 𝐄𝐃𝟖𝟎(𝐬𝐢𝐧𝐠𝐥𝐞 𝐝𝐨𝐬𝐞) Sequence 1 Sequence 2 100 5 100 5 t t 4 4 n n e e 75 75 % Knockdow n % Knockdow n m m e e T o x g ra d e T o x g ra d e v v ro ro 3 3 p p NOAEL NOAEL Im Im…
Slide 24: ESC+ Conjugates Containing GNA Translate to NHP
ESC+ Conjugates Containing GNA Translate to NHP Seq. 1 ESC Legend Seq. 2 Seq. 3 AS5-GNA A D - 1 2 6 3 0 6 (3 m g /k g ) AS6-GNA A D -8 5 4 8 1 ( 3 m g /k g ) ESC ESC AS8-GNA A D - 1 3 3 3 6 2 (3 m g /k g ) AS7-GNA AS7-GNA P r o t e in r e m a in in g ( % ) P r o t e in r e m a in in g ( % ) P r o t
Slide 25: GalNAc-Conjugate Platforms for Delivery to Liver
GalNAc-Conjugate Platforms for Delivery to Liver Next Generation ESC+ Conjugates Featuring Seed-Pairing Destabilization STC-Conjugate ESC-Conjugate ESC+ Conjugate • Standard Template Chemistry • Enhanced Stability Chemistry • Enhanced Stability Chemistry GalNAc conjugate GalNAc conjugate GalNAc conj
Slide 26: Summary
Summary • RNAi-mediated off-target effects are important drivers of hepatotoxicity observed for subset of ESC conjugates in rodent toxicity studies ◦ No evidence for impact of chemical modifications on observed toxicity • Developed ESC+ strategy to mitigate seed-mediated off-target effects and impro
Slide 27: Agenda
Agenda Welcome • Christine Lindenboom, Vice President, Investor Relations & Corporate Communications Introduction • Martin Maier, Ph.D., Vice President, Research Platform Advances in RNAi Therapeutics • Advances in ESC+ Design for Improved Specificity and Therapeutic Index • Mark Schlegel, Ph.D., Se
Slide 28: RNAi Therapeutics for CNS Diseases
RNAi Therapeutics for CNS Diseases No Current Therapies to Prevent or Reverse Neurodegenerative Disease • Dominantly inherited neurodegenerative diseases include – Alzheimer’s disease – Parkinson’s disease – Frontotemporal dementia – Huntington’s disease – Amyotrophic lateral sclerosis (ALS) – Spino
Slide 29: Alnylam Advancements in Conjugate-Based Delivery
Alnylam Advancements in Conjugate-Based Delivery siRNA Linker Ligand design/chemistry Potency/duration/ Stability, optimal Efficient delivery specificity ligand orientation to target cells Evolution of conjugate potency (mouse, SD ED50) 100 Partially modified 10 STC ED50 (mg/kg) ESC 1 Advanced ESC E
Slide 30: CNS Target 1, an Optimal Target for CNS POC
CNS Target 1, an Optimal Target for CNS POC Target 1 is broadly expressed • Expressed ubiquitously in CNS and robustly expressed in liver ◦ Lead selection can be performed in vitro and in vivo activity confirmed in liver utilizing GalNAc conjugate chemistry prior to triggering CNS studies CNS Target
Slide 31: In vitro Results Identify Potent Duplexes for Mouse in vivo Study
In vitro Results Identify Potent Duplexes for Mouse in vivo Study In vitro efficacy screen Primary mouse hepatocytes 10 and 0.1 nM 24 hr time point Assayed by qPCR CNS Target 1 efficacy screen 120 100 80 60 40 20 0 %of Message Remaining (10nM) %of Message Remaining (0.1nM) 31
Slide 32: In vivo CNS Target Screen Identifies Potent Candidate for IT Dosing
In vivo CNS Target 1 Screen Identifies Potent Candidate for IT Dosing In vivo potency screen with GalNAc versions 7 duplexes selected for in vivo screen (target silencing in liver) Single 2 mg/kg subcutaneous dose with two time points day 7 and 21 CNS Target 1 Silencing in Liver 120.00 D7 D21 100.00
Slide 33: Intrathecal Delivery of Novel siRNA Conjugates
Intrathecal Delivery of Novel siRNA Conjugates Single Dose Time Course in Rat Two targets tested to demonstrate sequence specificity siRNA conjugate dose of 0.9 mg Day 0 2 4 7 14 28 Tissue collection Tissues: Spinal cord: Lumbar, thoracic and cervical Brain: prefrontal cortex, cerebellum and remaini
Slide 34: CNS Target siRNA Shows Significant Target Knockdown Throughout Spinal Cord
CNS Target 1 siRNA Shows Significant Target Knockdown Throughout Spinal Cord Lumbar Spinal Cord Thoracic Spinal Cord Control Control Message Remaining Message Remaining Conjugate 1 Conjugate 1 Conjugate 2 Conjugate 2 Conjugate 3 Conjugate 3 Cervical Spinal Cord Control Message Remaining Conjugate 1
Slide 35: Differing Degrees of Knockdown Observed Across Brain
Differing Degrees of Knockdown Observed Across Brain Cerebellum Frontal Cortex Control Control Conjugate 1 Message Remaining Message Remaining Conjugate 1 Conjugate 2 Conjugate 2 Conjugate 3 Conjugate 3 Remaining Brain Control Message Remaining Conjugate 1 Conjugate 2 Conjugate 3 35
Slide 36: Potent Silencing Achieved by Second, Independent siRNA Conjugate
Potent Silencing Achieved by Second, Independent siRNA Conjugate Across Spinal Cord and Brain Spinal Cord Brain Message Remaining Message Remaining • Significant knockdown observed in spinal cord and brain by a second siRNA conjugate targeting beta-catenin, which is ubiquitously expressed throughout
Slide 37: siRNA Conjugates Show Enhanced Uptake and Activity
siRNA Conjugates Show Enhanced Uptake and Activity Higher Drug Levels and Robust Silencing Observed in Brain with siRNA Conjugates • Rapid siRNA clearance from CSF • Conjugate reveals superior uptake and stability in brain over unconjugated siRNA • Increased uptake in brain results in substantial im
Slide 38: CNS Tissue Analysis Confirms Distribution of siRNA and Protein Knockdown
CNS Tissue Analysis Confirms Distribution of siRNA and Protein Knockdown Intraneuronal and Purkinje cell siRNA uptake in spinal cord, cerebellum and brain (Day 28) Purkinje cells Neurons 65% protein reduction in spinal cord detected by IHC (Day 28) Control siRNA Target 1 siRNA 38 Anti-siRNA antibody
Slide 39: Rat Intrathecal Study Conclusions
Rat Intrathecal Study Conclusions Successful Delivery of siRNA Conjugate Across CNS Rest of brain • CSF clearance is rapid following IT bolus injection Frontal Cortex • Tissue uptake was observed in all CNS tissues examined with drug levels in the low to mid single Cerebellum digit mg/g range Cervic
Slide 40: Alnylam CNS Pipeline Strategy
Alnylam CNS Pipeline Strategy Expanding a Pipeline of Potentially Transformative Medicines GCCCCUGGAGGG Genetically validated, Biomarker for CNS-expressed POC in target gene Phase 1 Alnylam CNS Objectives • 1st DC in 2018 • 1st IND in late ’19/early ’20 • 1-2 INDs/yr starting in ’20 40
Slide 41: Agenda
Agenda Welcome • Christine Lindenboom, Vice President, Investor Relations & Corporate Communications Introduction • Martin Maier, Ph.D., Vice President, Research Platform Advances in RNAi Therapeutics • Advances in ESC+ Design for Improved Specificity and Therapeutic Index • Mark Schlegel, Ph.D., Se
Slide 42: Upcoming RNAi Roundtables
Upcoming RNAi Roundtables Givosiran, in Development for the Treatment of Acute Hepatic Porphyrias • Tuesday, July 24, 10:00 am ET Lumasiran, in Development for the Treatment of Primary Hyperoxaluria Type 1 • Wednesday, August 15, 10:30 am ET Patisiran & ALN-TTRsc02, for the Treatment of Transthyreti
Slide 43: Thank You
Thank You © 2018 Alnylam Pharmaceuticals, Inc. 43
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