Wave Life Sciences Ltd. · NASDAQ:WVE
Wave Life Sciences — Technical Presentation (August 2020)
64 slides from Wave Life Sciences's technical presentation, Aug 25, 2020
Slide 1: Analyst & Investor Research Webcast
Analyst & Investor Research Webcast August 25, 2020 Exhibit 99.1
Slide 2: Forward-looking statements
Forward-looking statements This document contains forward-looking statements. All statements other than statements of historical facts contained in this document, including statements regarding possible or assumed future results of operations, preclinical and clinical studies, business strategies, r
Slide 3: Today's speakers
Paul Bolno, MD, MBA President and CEO Vision & Strategy Chandra Vargeese, PhD Chief Technology Officer PRISM Platform Update ADAR Editing Kenneth Rhodes, PhD SVP, Therapeutics Discovery Neurology Pipeline C9orf72 Program Today’s speakers Conclusion and Q&A
Slide 4: Vision and Strategy
Vision and Strategy Paul Bolno, MD, MBA President and CEO
Slide 5: Wave Life Sciences vision and mission
Wave Life Sciences VISION We envision a future in which the diagnosis of a genetically-defined disease leads to effective and available treatment, providing patients and their families the ability to realize a brighter future MISSION Apply innovative nucleic acid chemistry and deep biological insigh
Slide 6: Building a fully integrated genetic medicines company
Wave Life Sciences Building a fully integrated genetic medicines company >6,000 genetically defined diseases Increases in genetic testing Greater understanding of genetic drivers of disease and definition at molecular level Evolution of PRISM Stereochemistry New ADAR editing modality Advances in ol
Slide 7: PRISM platform designed to achieve four goals
PRISM platform designed to achieve four goals ü ü ü ü Enable multiple modalities Silencing, Splicing, ADAR editing Ability to optimize pharmacology Potency, Exposure, Durability Target engagement across key tissues Scalable and cost-effective manufacturing
Slide 8: PRISM has unlocked advances in oligonucleotide design
PRISM has unlocked novel and proprietary advances in oligonucleotide design Backbone modifications Sugar modifications Drug approvals (FDA) 1975 2020 2000 Mixtures of 2n molecules1 ~500,000 different molecules per dose fomivirsen pegaptanib Phosphorothioate (PS) mipomersen nusinersen PN backbone che
Slide 9: PRISM platform advancements
PRISM platform advancements Primary screen hit rates in neurons far above industry standard hit rates Stereorandom Chemistry & stereochemistry optimization + Machine learning Stereopure Evolution of primary screen hit rates with chemistry improvements and PRISM advancement All screens used iPSC-deri
Slide 10: Building a fully integrated genetic medicines company focused on neurology
Today: Building a fully integrated genetic medicines company focused on neurology Committed cash: at least $60M in research support over 4 years Potential additional cash inflows: Category 1 programs Six programs: HD (SNP1, SNP2, SNP3) C9-ALS, C9-FTD SCA3 Milestones, global 50:50 profit split Catego
Slide 11: Looking ahead: neurology pipeline expansion
Looking ahead: Building a fully integrated genetic medicines company focused on neurology Employing new chemistries and modalities to expand wholly-owned neurology pipeline ADAR editing to access new target classes and new pathways PRISM enables access to larger set of potential indications than oth
Slide 12: Opportunities outside of neurology
Leveraging platform discovery research to build out areas of potential new biology Hepatic diseases Ophthalmology Muscle diseases Additional therapeutic areas Opportunities outside of neurology
Slide 13: Innovative pipeline led by neurology programs
THERAPEUTIC AREA / TARGET DISCOVERY PRECLINICAL CLINICAL PARTNER Huntington’s disease mHTT SNP1 Takeda 50:50 option Huntington’s disease mHTT SNP2 Huntington’s disease mHTT SNP3 ALS and FTD C9orf72 SCA3 ATXN3 CNS diseases Multiple† Takeda milestones & royalties ADAR editing Multiple 100% global ADAR
Slide 14: Redefining the potential of RNA therapeutics in neurology
Wave Life Sciences: Redefining the potential of RNA therapeutics in neurology Continuous learning Platform engine delivering new targets Four global clinical neurology programs expected next year, with multiple data readouts by 2022 Positioned to deliver multiple clinical trial applications over the
Slide 15: PRISM platform update
PRISM platform update Chandra Vargeese, PhD Chief Technology Officer
Slide 16: PRISM platform enables rational drug design
Sequence Stereochemistry Chemistry PRISM platform enables rational drug design Chemistry R: 2’ modifications OMe, MOE, F, other modifications 5’ 2’ 3’ 5’ 3’ 2’ R X B B X: backbone chemistry Phosphodiester (PO), phosphorothioate (PS), other backbone modifications Sequence B: bases A, T, C, mC, G, U,
Slide 17: PRISM backbone modifications
Backbone modification (X) Phosphodiester Phosphorothioate Stereochemistry Not chiral Chiral Charge Negative Negative Depiction PRISM backbone modifications Focused on backbone chemistry modifications amenable to all modalities Molecule structure illustrative of backbone modification patterns Backbon
Slide 18: Expanding backbone modifications with PN chemistry
Backbone modification (X) Phosphodiester Phosphorothioate Phosphoramidate diester Stereochemistry Not chiral Chiral Chiral Charge Negative Negative Neutral Depiction PRISM backbone modifications Expanding repertoire of backbone modifications with novel PN backbone chemistry Molecule structure illust
Slide 19: PN chemistry enhances potency, exposure, and durability
Across many modalities, PN chemistry enhances potency, exposure, and durability Modality Pharmacology Potency Exposure Durability Silencing Splicing Editing Efficient engagement of RNase H or Ago2 Efficient uptake in the cell nucleus Efficient engagement of ADAR Enabling infrequent administration In
Slide 20: Screen of stereopure PS/PO molecules ranked by potency
Screen of stereopure PS/PO molecules ranked by potency Experiment was performed in iPSC-derived neurons in vitro; target mRNA levels were monitored using qPCR against a control gene (HPRT1) using a linear model equivalent of the DDCt method (referred to as "delta-delta Ct") In vitro knockdown of PS/
Slide 21: In vitro knockdown of PS/PO compared to PS/PN compounds
In vitro knockdown of PS/PO containing compounds compared to PS/PN compounds Rational design using PN chemistry backbone modification increases potency on average Experiment was performed in iPSC-derived neurons in vitro; target mRNA levels were monitored using qPCR against a control gene (HPRT1) us
Slide 22: PN chemistry increases durability across CNS tissues
PN chemistry increases durability across CNS tissues Mice received a single 100 ug ICV injection (n=3 per group). Relative fold-change in MALAT1 expression is shown for the indicated tissues 10-weeks post-dose. MALAT1 expression levels are normalized to Hprt1. PBS, phosphate buffered saline Malat1 k
Slide 23: Durable Malat1 knockdown with PN chemistry
Durable Malat1 knockdown through 9 months with PN chemistry Compound or PBS (1 x 50 ug IVT) was delivered to C57BL6 mice. Relative percentage of Malat1 RNA in the posterior of the eye (retina, choroid, sclera) to PBS-treated mice is shown at 12, 20 and 36 weeks post-single injection. PBS = phosphate
Slide 24: Improved exon skipping with PN chemistry
Improved exon skipping with PN chemistry DMD patient-derived myoblasts treated with PS/PO or PS/PO/PN stereopure oligonucleotide under free-uptake conditions. Exon-skipping efficiency evaluated by qPCR. Exon skipping plotted for compounds with same sequence In vitro skipping efficiency of PS/PO cont
Slide 25: PN chemistry improves potency and cellular uptake in myoblasts
PN chemistry improves potency and increases cellular uptake in myoblasts Left: Cultured H2K myoblasts treated with increasing concentrations of PS/PO or PS/PO/PN stereopure oligonucleotide under free-uptake conditions. Skipping efficiency evaluated by TaqMan assay. Right: Cultured H2K cells treated
Slide 26: DKO model to assess PN chemistry on survival
DKO model to assess PN chemistry on survival DKO model generation and in vivo studies were performed by our collaborator Professor Matthew Wood at the University of Oxford; DKO PS/PO/PN and DKO PS/PO oligonucleotides have same sequence Double knockout mouse (DKO) Protein Pathology ü Utrophin Mild No
Slide 27: Step-change in survival in DKO model
Study completion: DKO PS/PO/PN mice sacrificed for further analyses Step-change in survival observed in DKO model using PN chemistry Mdx/utr-/- mice received weekly subQ 150 mpk dose of PS/PO or PS/PO/PN stereopure oligonucleotide beginning at postnatal day 10. Age-matched mdx/utr-/- littermates wer
Slide 28: Similar survival trend with 75% less total dose
Similar survival trend observed with 75% less total dose PBS PS/PO, QW 150 mpk weekly PS/PO/PN, QW 150 mpk weekly PS/PO/PN, Q2W 75 mpk bi-weekly* Silencing Splicing Editing Potency Exposure Durability *Ongoing study at (50%) reduced dose and frequency (bi-weekly vs. weekly) DKO Survival Mdx/utr-/- m
Slide 29: Restoration of wild-type muscle function
Restoration of wild-type muscle function using PS/PO/PN compound DKO / PBS (6 week old) DKO PS/PO/PN, QW 150mpk (38-41 week old) Wild-type (6 week old) Specific Force (EDL) Eccentric Contraction (EDL) Silencing Splicing Editing Potency Exposure Durability Mdx/utr-/- mice received weekly subQ 150 mpk
Slide 30: PN chemistry improves exposure and target engagement
PN chemistry improves exposure and target engagement in key tissues Silencing Splicing Editing Potency Exposure Durability 6x weekly 75 mg/kg subcutaneous doses; Sample collected 2 days after last dose PS/PO PS/PO/PN p≤0.0001 p≤0.0001 p≤0.0001 p≤0.01 p≤0.0001 p≤0.0001 p≤0.0001 p≤0.0001 p≤0.0001
Slide 31: PRISM platform has unlocked ADAR editing
PRISM platform has unlocked ADAR editing A-to-I editing is one of most common post-transcriptional modifications ADAR is ubiquitously expressed across tissues, including liver and CNS ADAR Target RNA I(G) A Edited RNA Oligonucleotide establishes double-stranded RNA complex Oligonucleotide Modificati
Slide 32: RNA editing without delivery vehicle or exogenous proteins
No delivery vehicle required No exogenous proteins necessary Potential for reduced off-target effects PRISM enables practical approach to RNA editing without need for viruses or exogenous protein Intracellular Extracellular space Endogenous ADAR Unedited RNA Wave ADAR-editing oligonucleotides Exogen
Slide 33: ADAR amenable diseases represent a sizeable opportunity
ADAR amenable diseases represent a sizeable opportunity Nearly half of known human genetic pathogenic SNPs are G-to-A mutations Tens of thousands of potential disease variants A-to-I(G) editing could target1 ~48% C-to-T C-to-G A-to-T C-to-A A-to-C A-to-G Pathogenic human SNPs by base pair correction
Slide 34: RNA editing opens many new therapeutic applications
RNA editing opens many new therapeutic applications Fix nonsense and missense mutations that cannot be splice-corrected Remove stop mutations Prevent protein misfolding and aggregation Alter protein processing (e.g. protease cleavage sites) Protein-protein interactions domains Modulate signaling p
Slide 35: PN chemistry improves editing efficiency
Data from independent experiments; Total RNA was harvested, reverse transcribed to generate cDNA, and the editing target site was amplified by PCR and quantified by Sanger sequencing PN chemistry improves editing efficiency PN backbone modification increased both potency and editing efficiency in vi
Slide 36: ADAR editing in NHP and primary human hepatocytes
Significant ADAR editing demonstrated in vitro in NHP and primary human hepatocytes NHP: non-human primate; ACTB: Beta-actin; nd= not determined Total RNA was harvested, reverse transcribed to generate cDNA, and the editing target site was amplified by PCR. Silencing Splicing Editing Potency Exposur
Slide 37: Efficient ADAR editing in vivo in non-human primate
Efficient ADAR editing translated in vivo in non-human primate study NHP: non-human primate; ACTB: Beta-actin; Left: 5mg/kg SC: Day 1,2,3,4,5; Liver Biopsy for mRNA (ACTB Editing) & eASO Exposure: Day 7 Up to 50% editing efficiency observed at Day 7, 2 days post last dose Silencing Splicing Editing
Slide 38: Sustained editing in vivo in non-human primates
Sustained editing in vivo in non-human primates after 45 days NHP: non-human primate; ACTB: Beta-actin; Left: 5mg/kg SC: Day 1,2,3,4,5; Liver Biopsy for mRNA (ACTB Editing) & eASO Exposure: Day 7 Substantial and durable editing out to at least Day 50, 45 days post last dose Silencing Splicing Editin
Slide 39: Sustained editing confirmed by Sanger sequencing
Sustained editing in vivo in non-human primates after 45 days % Editing quantified from Sanger sequencing using EditR program. Efficient and potent editing of ACTB demonstrated with Sanger sequencing Silencing Splicing Editing Potency Exposure Durability T A G T G G T G G Baseline Post-treatment (2
Slide 40: ADAR editing is highly specific
Editing site RNA editing within ACTB transcript (human hepatocytes) RNA editing within transcriptome (human hepatocytes) ADAR editing is highly specific Silencing Splicing Editing Potency Exposure Durability Coverage Genome coordinates ACTB C 0% T 100% C 53.8% T 46.2% ACTB Confidence (LOD score) % E
Slide 41: Editing in neurons and astrocytes
Efficient and potent editing observed in neurons and astrocytes Silencing Splicing Editing Potency Exposure Durability ACTB editing in iCell Neurons ACTB editing in human iCell Astrocytes Concentration (µM) % Editing % Editing Compound 2 (PS / PN) Compound 1 (PS / PN) Compound 3 (PS / PN) EC50: ~200
Slide 42: Opening the door to ADAR editing in CNS
Opening the door to ADAR editing in CNS Silencing Splicing Editing Potency Exposure Durability In vivo CNS editing in proprietary hADAR transgenic mouse (1 week) Editing oligonucleotide (100 µg) PBS % Editing UGP2 Cortex Hippocampus Striatum Brain stem Cerebellum Spinal cord hADAR: human ADAR; UGP2:
Slide 43: Continued evolution of PRISM platform
Continued evolution of PRISM platform PN chemistry is a novel backbone chemistry modification Preclinical data demonstrates PN chemistry can enhance potency, durability and exposure across three modalities (silencing, splicing, editing) Platform innovations have unlocked ADAR editing modality Effici
Slide 44: Neurology pipeline & C9orf72 program
Neurology pipeline & C9orf72 program Kenneth Rhodes, PhD SVP, Therapeutics Discovery
Slide 45: Focus on neurological diseases
Focus on neurological diseases Neurological diseases represent one of the greatest medical challenges of our time PRISM can deliver oligonucleotide drug candidates that directly address the genetic drivers of neurologic diseases PRISM-derived oligonucleotides access neurons and glia without need for
Slide 46: Diverse pipeline of disease-modifying therapies
Diverse pipeline of disease-modifying therapies THERAPEUTIC AREA / TARGET DISCOVERY STAGE PRECLINICAL STAGE PHASE 1/2 CLINICAL STAGE Huntington’s disease mHTT SNP1 Huntington’s disease mHTT SNP2 Huntington’s disease mHTT SNP3 ALS and FTD C9orf72 SCA3 ATXN3 CNS diseases Multiple† ADAR editing Multipl
Slide 47: WVE-004: C9orf72 program for ALS and FTD
WVE-004: C9orf72 program for ALS and FTD THERAPEUTIC AREA / TARGET DISCOVERY STAGE PRECLINICAL STAGE PHASE 1/2 CLINICAL STAGE Huntington’s disease mHTT SNP1 Huntington’s disease mHTT SNP2 Huntington’s disease mHTT SNP3 ALS and FTD C9orf72 SCA3 ATXN3 CNS diseases Multiple† ADAR editing Multiple NEURO
Slide 48: C9-ALS and C9-FTD: clinical spectrum
C9-ALS and C9-FTD: Manifestations of a clinical spectrum Disease C9 specific US population Mean disease duration Standard of care C9-ALS Fatal neurodegenerative disease Progressive degeneration of motor neurons in brain and spinal cord ~2,000 3.1 years Significant unmet need despite two approved the
Slide 49: C9orf72 repeat expansions: genetic driver of ALS and FTD
C9orf72 repeat expansions: a critical genetic driver of ALS and FTD Normal (non-expanded) Allele < 25 GGGGCC repeats Expanded Allele Sources: DeJesus-Hernandez et al, Neuron, 2011. Renton et al, Neuron, 2011. Zhu et al, Nature Neuroscience, May 2020 Typically 100’s-1000’s of GGGGCC repeats C9orf72 h
Slide 50: C9orf72 repeat expansions: mechanisms of cellular toxicity
C9orf72 repeat expansions: mechanisms of cellular toxicity C9-ALS and C9-FTD may be caused by multiple factors: Insufficient levels of C9orf72 protein Accumulation of repeat-containing RNA transcripts Accumulation of aberrantly translated DPR proteins Recent evidence suggests lowering C9orf72 protei
Slide 51: C9orf72 targeting strategy spares C9orf72 protein
Normal C9orf72 allele produces three mRNA transcripts (~80% are V2, ~20% are V1 and V3) Pathological allele with expanded repeat leads to healthy V2 and pathological V1 and V3 transcript by-products C9orf72 targeting strategy spares C9orf72 protein Wave C9orf72 candidate targets only V1 and V3 trans
Slide 52: WVE-004: knockdown of repeat-containing transcripts in vitro
WVE-004: Potent and selective knockdown of repeat-containing transcripts in vitro V3 Dose (μM) All V WVE-004 NTC Dose (μM) In vitro activity in C9 patient-derived neurons WVE-004 NTC Dose (μM) IC50:201.7nM In vitro selectivity in C9 patient-derived neurons C9 patient-derived motor neurons were treat
Slide 53: Dose dependent knockdown of V3 mRNA and DPRs in mouse
WVE-004 shows dose dependent knockdown of V3 mRNA and DPRs in C9 transgenic mouse model Spinal Cord C9 BAC transgenic mice were administered two times with PBS, 1.5ug, 5ug, 15ug or 50ug of WVE-004 on day 0 and day 7. Mice were euthanized 6 weeks after first injection. Taqman qPCR assay used to evalu
Slide 54: Knockdown of repeat transcripts and DPRs in spinal cord
WVE-004: Potent and selective knockdown of repeat transcripts and DPRs in spinal cord 2 4 8 week 2 4 8 1.5 WVE-004 PBS 2 4 8 week 2 4 8 WVE-004 PBS Potent and durable knockdown 8 weeks WVE-004 PBS NS Repeat-containing transcripts Dipeptide repeat proteins (DPRs) Total C9orf72 protein Experimental de
Slide 55: WVE-004 reaches target brain regions and cell types
WVE-004 reaches target brain regions and cell types in vivo In situ hybridization: Red - ViewRNA for WVE-004; Blue – Hematoxylin. 40X magnification. C9 BAC transgenic mice were administered PBS or 50 ug of WVE-004, ICV, on day 0 and day 7. Mice were euthanized at 8 weeks after the first injection. S
Slide 56: PN backbone chemistry: improved potency in vivo
PN backbone chemistry: Improved potency among C9orf72-targeting oligonucleotides in vivo Exposure (µg/g) Exposure (µg/g) C9orf72 compounds Spinal cord Cortex PS/PO backbone PS/PO/PN backbone %C9orf72 V3 transcript remaining Mice received 2 x 50 ug ICV doses on days 0 & 7; mRNA from spinal cord and c
Slide 57: Durable knockdown of repeat transcripts after 6 months
4 12 18 12 18 24 4 24 Durable knockdown of repeat transcripts in vivo after 6 months in spinal cord and cortex Spinal cord Cortex 1.0 0.5 0.0 Relative fold change C9orf72 V3/mHPRT1 WVE-004 PBS week 4 12 18 12 18 24 4 24 1.0 0.5 0.0 Relative fold change C9orf72 V3/mHPRT1 WVE-004 PBS week Experimental
Slide 58: Durable knockdown of DPRs in vivo
Durable knockdown of DPRs in vivo after 6 months in spinal cord and cortex 4 12 18 12 18 24 4 24 Spinal cord Cortex 1.5 0.5 0.0 WVE-004 PBS week 4 12 18 12 18 24 4 24 WVE-004 PBS week 1.0 Relative Poly-GP levels (normalized to PBS) 1.5 0.5 0.0 1.0 Experimental description: 2 x 50 ug on day 0 and day
Slide 59: WVE-004 proof-of-concept study design
WVE-004 proof-of-concept study to include both ALS and FTD patients Patients with documented C9orf72 expansion and confirmed ALS or FTD diagnosis Single and multiple ascending doses to be explored Safety and tolerability Pharmacodynamic effects on key biomarkers while on treatment PolyGP NfL Key exp
Slide 60: PRISM enables further pipeline expansion in neurology
PRISM platform enables further pipeline expansion in neurology PRISM modalities Silencing Editing Splicing PRISM evolution Stereochemistry PN backbone chemistry Unlocking new targets in neurological diseases Wave & Takeda CNS programs Multiple Category 2 programs ongoing† Novel PN chemistry an impor
Slide 61: Conclusion
Conclusion Paul Bolno, MD, MBA President and CEO
Slide 62: Redefining the potential of RNA therapeutics in neurology
Wave Life Sciences: Redefining the potential of RNA therapeutics in neurology Continuous learning Platform engine delivering new targets Four global clinical neurology programs expected next year, with multiple data readouts by 2022 Positioned to deliver multiple clinical trial applications over the
Slide 63: Q&A
Q&A
Slide 64: Analyst & Investor Research Webcast
Analyst & Investor Research Webcast August 25, 2020
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