Wave Life Sciences Ltd. · NASDAQ:WVE
Wave Life Sciences — Investor Presentation (April 2018)
50 slides from Wave Life Sciences's investor presentation, Apr 2, 2018
Slide 1: Wave Life Sciences Corporate Presentation
Wave Life Sciences Corporate Presentation April 2, 2018 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: Biotechnology company focused on transformational therapies for genetically defined diseases
Biotechnology company focused on delivering transformational therapies for patients with serious, genetically defined diseases Rationally designed stereopure nucleic acid therapeutics Utilizing multiple modalities including antisense, exon skipping and RNAi 6 neurology development programs by the en
Slide 4: Paving the way to potentially safer, more effective medicines
Paving the way to potentially safer, more effective medicines 1 first to design and bring stereopure and allele-specific medicines to clinic 6 neurology development programs by end of 2018 3 clinical studies initiated in 2017 5 nucleic acid modalities being advanced with Wave stereopure chemistry 12
Slide 5: Pipeline spanning multiple modalities, novel targets
MUSCLE Pipeline spanning multiple modalities, novel targets CLINICAL NEXT ANTICIPATED MILESTONES CANDIDATE DISCOVERY ESTIMATED U.S. PREVALENCE* TARGET BIOMARKER MECHANISM PARTNER WAVE’S COMMERCIAL RIGHTS CNS A Huntington’s disease ~10k / ~35k mHTT SNP1 mHTT Phase 1b/2a Top line data H1 2019 Takeda 5
Slide 6: Broad platform relevance across therapeutic areas
CNS Muscle Broad platform relevance across therapeutic areas
Slide 7: Wave rational design: building the optimal, stereopure medicine
WAVE RATIONAL DESIGN Stereochemistry enables precise control, ability to optimize critical constructs into one defined and consistent profile Building the optimal, stereopure medicine STANDARD OLIGONUCLEOTIDE APPROACHES Pharmacologic properties include >500,000 permutations in every dose Impact: Unr
Slide 8: Creating a new class of oligonucleotides
Source: Iwamoto N, et al. Control of phosphorothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides. Nature Biotechnology. 2017. Creating a new class of oligonucleotides WAVE RATIONAL DESIGN
Slide 9: Chemistry may optimize medicines across multiple dimensions
Chemistry may optimize medicines across multiple dimensions Stability of stereopure molecules with reduced PS content (liver homogenate) Oligonucleotide exposure (spinal cord) Human TLR9 activation assay with 5mC modified CpG containing MOE gapmer IL-6 MIP-1β Cytokine induction in human PBMC assay S
Slide 10: Stereochemistry is applicable across modalities
Stereochemistry is applicable across modalities Antisense RNAi Exon skipping Stereochemistry allows for novel approaches to previously difficult diseases and inaccessible targets *
Slide 11: Unlocking the platform: transforming nucleic acid therapeutics
SUPERIOR PHARMACOLOGY + SCALABLE SYNTHESIS MULTI- MODALITY BROAD IMPACT UNLOCKING THE PLATFORM Antisense RNAi Splice Correction Exon skipping Gene editing CNS Muscle Eye Liver Skin Broad addressable patient population across multiple therapeutic areas Transforming nucleic acid therapeutics
Slide 12: Neurology
Neurology STEREOCHEMISTRY
Slide 13: Huntington's Disease
Huntington’s Disease
Slide 14: Huntington's Disease: a hereditary, fatal disorder
Huntington’s Disease: a hereditary, fatal disorder Autosomal dominant disease, characterized by cognitive decline, psychiatric illness and chorea; fatal No approved disease-modifying therapies Expanded CAG triplet repeat in HTT gene results in production of mutant huntingtin protein (mHTT); accumula
Slide 15: Allele-specific silencing of expanded CAG repeat
Utilize association between single nucleotide polymorphisms (SNPs) and genetic mutations to specifically target errors in genetic disorders, including HD. Allele-specificity possible by targeting SNPs associated with expanded long CAG repeat in mHTT gene Approach aims to lower mHTT transcript while
Slide 16: Two parallel global placebo-controlled multi-ascending-dose trials
Two parallel global placebo-controlled multi-ascending-dose trials for WVE-120101, WVE-120102 Primary objective: assess safety and tolerability of intrathecal doses in early manifest HD patients Additional objectives: exploratory pharmacokinetic, pharmacodynamic, clinical and MRI endpoints Two simul
Slide 17: Mutant huntingtin: a powerful, novel biomarker
Novel immunoassay allows for quantification of mutant huntingtin, the cause of HD Level of mHTT detected is associated with time to onset, increased with disease progression, and predicts diminished cognitive and motor dysfunction Assay currently being utilized in clinical studies Mutant huntingtin:
Slide 18: Selective reduction of mHTT mRNA & protein
Selective reduction of mHTT mRNA & protein Reporter Cell Line* Neuro HD
Slide 19: Demonstrated delivery to brain tissue
Demonstrated delivery to brain tissue WVE-120101 and WVE-120102 distribution in cynomolgus non-human primate brain following intrathecal bolus injection Demonstrated delivery to brain tissue CIC = cingulate cortex. CN = caudate nucleus. In Situ Hybridization ViewRNA stained tissue Red dots are WVE-1
Slide 20: Duchenne Muscular Dystrophy (DMD)
Duchenne Muscular Dystrophy (DMD)
Slide 21: DMD: a progressive, fatal childhood disorder
DMD: a progressive, fatal childhood disorder Fatal, X-linked genetic neuromuscular disorder characterized by progressive, irreversible loss of muscle function, including heart and lung Genetic mutation in dystrophin gene prevents the production of dystrophin protein, a critical component of healthy
Slide 22: Restoration of dystrophin production through exon skipping
Wave approach: meaningful restoration of dystrophin production through exon skipping Neuro DMD Meaningful restoration of dystrophin production is expected to result in therapeutic benefit Exon-skipping antisense approaches may enable production of functional dystrophin protein Initial patient popula
Slide 23: WVE-210201 Phase 1 clinical trial
WVE-210201 Phase 1 clinical trial initiated November 2017 Design: Multicenter, double-blind, placebo-controlled, single ascending dose study with I.V. administration Primary endpoint: Safety and tolerability Inclusion criteria: ages 5 to 18, amenable to exon 51 skipping Ambulatory and non-ambulatory
Slide 24: Exon 51: improved skipping efficiency
Exon 51: improved skipping efficiency RNA skipping determined by quantitative RT-PCR Wave isomers demonstrated a dose-dependent increase in skipping efficiency Free uptake at 10uM concentration of each compound with no transfection agent Same foundational stereopure chemistry for Wave isomers; indiv
Slide 25: Exon 51: increased dystrophin restoration
Dystrophin protein restoration in vitro was quantified to be between 50-100% of normal skeletal muscle tissue lysates, as compared to about 1% by drisapersen and eteplirsen analogs Exon 51: increased dystrophin restoration *Analogs dystrophin (400-427 kDa) vinculin (120 kDa) Marker Mock Drisapersen*
Slide 26: Exon 51: in vivo target engagement in non-human primate
Exon 51: in vivo target engagement of WVE-210201 in healthy non-human primate 5 doses @ 30 mg/kg /week for 4 weeks healthy NHP by subcutaneous dosing Nested PCR Assay Neuro DMD Experimental conditions: Muscle tissues were collected 2 days after the last dose and fresh frozen. Total RNAs were extract
Slide 27: Exon 51: no apparent tissue accumulation observed
Exon 51: no apparent tissue accumulation observed Standard oligonucleotides tend to accumulate in liver and kidney Wave rationally designed oligonucleotides optimized to allow compound to clear more effectively WVE-210201 demonstrated wide tissue distribution in dose dependent fashion No apparent ac
Slide 28: Exon 53: stereopure lead molecules advancing toward candidate
RNA skipping determined by quantitative RT-PCR Free uptake at 10uM and 3uM concentration of each compound with no transfection agent Current published clinical dystrophin levels achieved for Exon 53 are ~1% Early Exon 53 data suggests initial skipping efficiency around 20% pre-optimization Exon 53:
Slide 29: C9orf72 ALS and FTD
C9orf72 Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (FTD)
Slide 30: C9orf72: a critical genetic risk factor
C9orf72: a critical genetic risk factor C9orf72 gene provides instructions for making protein found in various tissues, with abundance in nerve cells in the cerebral cortex and motor neurons C9orf72 genetic mutations are the strongest genetic risk factor found to date for the more common, non-inheri
Slide 31: Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis Neurodegenerative disease characterized by the progressive degeneration of motor neurons in the brain and spinal cord Affects approximately 15,000-20,000 people in the US with a median survival of 3 years C9orf72 is present in approximately 40% of familial ALS and 8-10%
Slide 32: Frontotemporal dementia
Frontotemporal dementia Progressive neuronal atrophy with loss in the frontal and temporal cortices characterized by personality and behavioral changes, as well as gradual impairment of language skills Affects approximately 55,000 people in the US Second most common form of early-onset dementia afte
Slide 33: Selective silencing in vivo of expanded C9orf72 repeat transcripts
Selective silencing in vivo of expanded C9orf72 repeat transcripts Wave has developed a series of highly optimized antisense compounds which selectively silence the repeat containing transcript in C9orf72 transgenic mice These compounds show target engagement across cell types and regions of the ner
Slide 34: Durable reduction of dipeptides and RNA foci in vivo
Durable reduction of dipeptides and RNA foci in vivo Wave’s candidate (WVE-3972-01) demonstrates durable reduction of dipeptides and reductions in RNA foci Data is consistent across blinded studies in independent laboratories (collaboration with Professor Bob Brown, U. Mass) Neuro C9orf72 2-weeks 4-
Slide 35: In vivo distribution of WVE-3972-01 weeks after treatment
In vivo distribution of WVE-3972-01 8 weeks after treatment Neuro C9orf72 Experimental description: C9-BAC mice were administered 50mg of WVE-3972-01 ICV on day 1 and day 8; detection using ViewRNA. Widespread and sustained distribution in nuclei of motor neurons in the spinal cord
Slide 36: Spinocerebellar ataxia type 3
Spinocerebellar ataxia type 3
Slide 37: Spinocerebellar ataxia type 3
Neuro SCA3 Source: Paulson H. Machado-Joseph disease/spinocerebellar ataxia type 3. Handb Clin Neurol 103, 437—449 (2012). National Institute of Health. Spinocerebellar ataxia 3. Accessed at: https://ghr.nlm.nih.gov/condition/spinocerebellar-ataxia-type-3 on February 15, 2018 Also known as Machado-J
Slide 38: Emerging areas
Emerging areas STEREOCHEMISTRY LiFe SCIENCES
Slide 39: Stereopure oligonucleotides: improved in vivo potency, extended duration
Stereopure oligonucleotides: improved in vivo potency, extended duration Potency equivalent to state-of-the-art GalNAc conjugated double strand RNAi (ED50 0.3 mg/kg) Demonstrated increase in durability over GalNAc conjugated stereorandom oligonucleotide ED50 ~2.0 mg/kg ED50 0.3 mg//kg Liver Experime
Slide 40: Improved in vivo potency, extended duration (back of the eye)
Experimental description: Single intravitreal injection to mouse eye on day 1. Improved in vivo potency, extended duration Back of the eye 1 week 1 month 3 months Eye 10X lower dose of stereopure oligonucleotide is more potent than stereorandom oligonucleotide
Slide 41: Improved in vivo potency, extended duration (front of the eye)
Improved in vivo potency, extended duration Front of the eye 1 week 1 month 3 months Experimental description: Single intravitreal injection to mouse eye on day 1. Eye 10X lower dose of stereopure oligonucleotide is more potent than stereorandom oligonucleotide
Slide 42: Distribution and target engagement
Distribution and target engagement Skin In vivo distribution of oligonucleotide to key cellular compartments following intravitreal injection in murine eye Target engagement following topical administration on human skin explant model Ophthalmology Dermatology Red dots = Oligonucleotides PBS Control
Slide 43: Partnerships
Partnerships
Slide 44: $230+ million in committed cash; CNS collaboration with Takeda
$230+ million in committed cash; eligible for milestones and royalties in excess of $2 billion* Expected to fund Wave operations to end of 2020, through multiple data readouts Committed capital CNS collaboration with Takeda Takeda option on global 50:50 share of CNS programs in HD, ALS, FTD and SCA3
Slide 45: Hepatic collaboration with Pfizer
Hepatic collaboration with Pfizer Initiated May 2016 Exploring targets across modalities, including ASO and ssRNAi Up to 5 hepatic-metabolic programs 3 targets declared; APOC3 and 2 undisclosed Option to declare 2 additional targets Access to Pfizer’s hepatic targeting technology Potentially increas
Slide 46: Enabling technologies: enhancing stereopure platform
Enabling technologies: enhancing stereopure platform Collaboration leverages ReadCoor’s proprietary FISSEQ (Florescent In-Situ Sequencing) platform designed to provide critical spatial data by combining next generation sequencing and three-dimensional imaging Imaging allows for target engagement ass
Slide 47: Manufacturing strength: scalable nucleic acid synthesis
Oligonucleotide synthesis capacity ranging from high throughput to large scale GMP production 90,000 square foot facility Ability to continue to meet synthesis demands of growing portfolio and increase control and visibility of product supply chain Comparable yield and cost-of-goods to standard ster
Slide 48: Intellectual property strength: breadth and depth of patent portfolio
Intellectual property strength: breadth and depth of patent portfolio Programs HTT candidates DMD candidates Platform Designs Compositions Stereochemistry Process development Improved activity, stability, specificity, immunogenicity Oligonucleotide compositions Monomers, key reagents Methods of synt
Slide 49: Wave catalysts
Wave catalysts Q3 2018: safety data expected in DMD from Phase 1 trial for WVE-210201 Initiated clinical trial in DMD (Exon 51) November 2017 WVE-210201 is the first stereopure oligonucleotide targeting Exon 51 with potential to be best-in-class Interim dystrophin readout from planned efficacy and o
Slide 50: Realizing the potential of nucleic acid therapeutics
Realizing the potential of nucleic acid therapeutics
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