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|Item 7.01|| |
Regulation FD Disclosure.
From time to time, Wave Life Sciences Ltd. (the “Company”) presents and/or distributes slides and presentations to the investment community to provide updates and summaries of its business. On January 11, 2021, the Company updated its corporate presentation, which is available on the “For Investors & Media” section of the Company’s website at http://ir.wavelifesciences.com/. This presentation is also furnished as Exhibit 99.1 to this Current Report on Form 8-K.
The information set forth in Exhibit 99.1 is being furnished and shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that Section, nor shall it be deemed incorporated by reference into any registration statement or other filing under the Securities Act of 1933, as amended, or the Exchange Act, except as shall be expressly set forth by specific reference in such filing.
|Item 8.01|| |
On January 11, 2021, the Company issued a press release providing key upcoming milestones for 2021, including the initiation of new clinical trials, expected data read-outs, and continued advancement of the Company’s proprietary discovery and drug development platform, PRISM. A copy of the press release is attached as Exhibit 99.2 to this Form 8-K and is incorporated by reference herein.
The information set forth in Exhibit 99.2, other than the second and third paragraphs thereof, is incorporated by reference into this Item 8.01 of this Current Report on Form 8-K.
|Item 9.01|| |
Financial Statements and Exhibits.
|99.1||Corporate Presentation of Wave Life Sciences Ltd. dated January 11, 2021|
|99.2||Press Release issued by Wave Life Sciences Ltd. dated January 11, 2021|
|104||Cover Page Interactive Data File (embedded within the Inline XBRL document)|
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
WAVE LIFE SCIENCES LTD.
Paul B. Bolno, M.D.
President and Chief Executive Officer
Date: January 11, 2021
Wave Life Sciences Corporate Presentation January 11, 2021 Exhibit 99.1
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, research and development plans, collaborations and partnerships, regulatory activities and timing thereof, competitive position, potential growth opportunities, use of proceeds and the effects of competition are forward-looking statements. These statements involve known and unknown risks, uncertainties and other important factors that may cause the actual results, performance or achievements of Wave Life Sciences Ltd. (the “Company”) to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. In some cases, you can identify forward-looking statements by terms such as “may,” “will,” “should,” “expect,” “plan,” “aim,” “anticipate,” “could,” “intend,” “target,” “project,” “contemplate,” “believe,” “estimate,” “predict,” “potential” or “continue” or the negative of these terms or other similar expressions. The forward-looking statements in this presentation are only predictions. The Company has based these forward-looking statements largely on its current expectations and projections about future events and financial trends that it believes may affect the Company’s business, financial condition and results of operations. These forward-looking statements speak only as of the date of this presentation and are subject to a number of risks, uncertainties and assumptions, including those listed under Risk Factors in the Company’s Form 10-K and other filings with the SEC, some of which cannot be predicted or quantified and some of which are beyond the Company’s control. The events and circumstances reflected in the Company’s forward-looking statements may not be achieved or occur, and actual results could differ materially from those projected in the forward-looking statements. Moreover, the Company operates in a dynamic industry and economy. New risk factors and uncertainties may emerge from time to time, and it is not possible for management to predict all risk factors and uncertainties that the Company may face. Except as required by applicable law, the Company does not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise.
Building a leading genetic medicines company ALS: Amyotrophic lateral sclerosis; FTD: Frontotemporal dementia 1stereopure oligonucleotides and novel backbone chemistry modifications Innovative platform Stereopure oligonucleotides Novel backbone modifications (PN chemistry) Allele-selectivity Multiple modalities (silencing, splicing, ADAR editing) Strong IP position1 Foundation of NEUROLOGY programs Huntington’s disease ALS / FTD Neuromuscular diseases Ataxias Parkinson’s disease Alzheimer’s disease Clinical development expertise Multiple global clinical trials ongoing across eight countries Innovative trial designs Manufacturing Established internal manufacturing capabilities to produce oligonucleotides at scale Wave’s discovery and drug development platform
PRISM has unlocked novel and proprietary advances in oligonucleotide design Backbone modifications Sugar modifications Drug approvals (FDA)2 1975 2020 2000 Mixtures of 2n molecules1 ~500,000 different molecules per dose fomivirsen pegaptanib Phosphorothioate (PS) mipomersen nusinersen PN backbone chemistry modifications Stereopure backbone 2’-4’-cEt 2’-O-methyl 2’-F 2’-4’-LNA 1n=number of chiral centers 2’-MOE Phosphorodiamidate Morpholino (PMO) eteplirsen golodirsen givosiran patisiran inotersen viltolarsen 2oligonucleotide therapies approved by the FDA across the industry
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 DMD Exon 53 100% global ADAR editing Multiple AATD (ADAR editing) SERPINA1 100% global Retinal diseases USH2A and RhoP23H 100% global NEUROLOGY HEPATIC OPTHALMOLOGY WVE-003 WVE-004 WVE-120101 WVE-120102 Innovative pipeline led by neurology programs †During a four-year term, Wave and Takeda may collaborate on up to six preclinical targets at any one time. ALS: Amyotrophic lateral sclerosis; FTD: Frontotemporal dementia; SCA3: Spinocerebellar ataxia 3; CNS: Central nervous system; DMD: Duchenne muscular dystrophy; AATD: Alpha-1 antitrypsin deficiency Stereopure PN chemistry WVE-N531
WVE-120101 WVE-120102 WVE-003 Huntington’s Disease Portfolio
Huntington’s disease: a hereditary, fatal disorder Sources: Auerbach W, et al. Hum Mol Genet. 2001;10:2515-2523. Dragatsis I, et al. Nat Genet. 2000;26:300-306. Leavitt BR, et al. J Neurochem. 2006;96:1121-1129. Nasir J, et al. Cell. 1995;81:811-823. Reiner A, et al. J Neurosci. 2001;21:7608-7619. White JK, et al. Nat Genet. 1997;17:404-410. Zeitlin S, et al. Nat Genet. 1995;11:155-163. Carroll JB, et al. Mol Ther. 2011;19:2178-2185. HDSA ‘What is Huntington’s disease?’ https://hdsa.org/what-is-hd/overview-of-huntingtons-disease/ Accessed: 11/2/18.; Becanovic, K., et al., Nat Neurosci, 2015. 18(6): p. 807-16. Van Raamsdonk, J.M., et al., Hum Mol Genet, 2005. 14(10): p. 1379-92.; Van Raamsdonk, J.M., et al., BMC Neurosci, 2006. 7: p. 80. DNA CAG Repeat RNA wild-type (healthy) allele RNA mutant allele Normal CAG Repeat Expanded CAG Repeat Healthy protein (HTT) Mutant protein (mHTT) Neuro HD 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); accumulation of mHTT causes progressive loss of neurons in the brain Wild-type (healthy) HTT protein critical for neuronal function; evidence suggests wild-type HTT loss of function plays a role in Huntington’s disease 30,000 people with Huntington’s disease in the US; another 200,000 at risk of developing the condition
Healthy CNS function Synaptic dysfunction | Cell death | Neurodegeneration mHTT toxic effects lead to neurodegeneration, loss of wtHTT functions may also contribute to HD Healthy individual Stresses wtHTT Huntington’s disease Stresses Toxic effects of mHTT + Loss of wtHTT functions ~50% decrease in wtHTT CNS, central nervous system; HD, Huntington’s disease; HTT, huntingtin protein; mHTT, mutant huntingtin protein; wtHTT, wild-type huntingtin protein. 1. Ross CA, Tabrizi SJ. Lancet Neurol. 2011;10(1):83-98. 2. Saudou F, Humbert S. Neuron. 2016;89(5):910-926. 3. Cattaneo E, et al. Nat Rev Neurosci. 2005;6(12):919-930. 4. Milnerwood AJ, Raymond LA. Trends Neurosci. 2010;33(11):513-523. Neuro HD
Plays an essential role in the transport of synaptic proteins—including neurotransmitters and receptors—to their correct location at synapses9-12 Promotes neuronal survival by protecting against stress (e.g., excitotoxicity, oxidative stress, toxic mHTT aggregates)1-8 BRAIN CIRCUITS SYNAPSE NEURON CSF circulation Supplies BDNF to the striatum to ensure neuronal survival13-16 Regulates synaptic plasticity, which underlies learning and memory17-22 Plays a critical role in formation and function of cilia—sensory organelles that control the flow of CSF—which are needed to clear catabolites and maintain homeostasis23 HD: Wild-type HTT is a critical protein for important functions in the central nervous system BDNF, brain-derived neurotrophic factor; CSF, cerebrospinal fluid; mHTT, mutant huntingtin protein. Sources: 1. Leavitt 2006 2. Cattaneo 2005 3. Kumar 2016 4. Franco-Iborra 2020 5. Hamilton 2015 6. Ochaba 2014 7. Wong 2014 8. Rui 2015 9. Caviston 2007 10. Twelvetrees 2010 11. Strehlow 2007 12. Milnerwood 2010 13. Smith-Dijak 2019 14. Tousley 2019 15. Zhang 2018 16. McAdam 2020 17. Altar 1997 18. Zuccato 2001 19. Gauthier 2004 20. Ferrer 2000 21. Baquet 2004 22. Liu 2011 23. Karam 2015 Neuro HD
Nature publication contributes to weight of evidence on importance of wild-type huntingtin Source: Poplawski et al., Nature, April 2019 Htt: Huntingtin protein Conditional knock-out of Htt in 4-month old mice (post-neuronal development) Results suggest that: Htt plays a central role in the regenerating transcriptome (potentially influencing genes such as NFKB, STAT3, BDNF) Htt is essential for regeneration Indeed, conditional gene deletion showed that Htt is required for neuronal repair. Throughout life, neuronal maintenance and repair are essential to support adequate cellular functioning Neuro HD
Utilize association between single nucleotide polymorphisms (SNPs) and genetic mutations to specifically target errors in genetic disorders, including Huntington’s disease (HD) Potential to provide treatment for up to 80% of HD population Wave approach: novel, allele-selective silencing Source: Kay, et al. Personalized gene silencing therapeutics for Huntington disease. Clin Genet. 2014;86:29–36. Neuro HD Aims to lower mHTT transcript while leaving healthy wild-type HTT relatively intact Allele-selectivity possible by targeting SNPs associated with expanded long CAG repeat in HTT gene RNase H and ASO:RNA RNA mutant allele
WVE-120101: Selective reduction of mHTT mRNA and protein Reporter Cell Line* Neuro HD Source: Meena, Zboray L, Svrzikapa N, et al. Selectivity and biodistribution of WVE-120101, a potential antisense oligonucleotide therapy for the treatment of Huntington’s disease. Paper presented at: 69th Annual Meeting of the American Academy of Neurology; April 28, 2017; Boston, MA.
Demonstrated delivery to brain tissue WVE-120101 and WVE-120102 distribution in cynomolgus non-human primate brain following intrathecal bolus injection In Situ Hybridization ViewRNA stained tissue Red dots are WVE-120102 oligonucleotide Arrow points to nuclear and perinuclear distribution of WVE-120102 in caudate nucleus Red dots are WVE-120101 oligonucleotide Arrow points to nuclear and perinuclear distribution of WVE- 120101 in cingulate cortex CIC = cingulate cortex In Situ Hybridization ViewRNA stained tissue Neuro HD CN = caudate nucleus Source: Meena, Zboray L, Svrzikapa N, et al. Selectivity and biodistribution of WVE-120101, a potential antisense oligonucleotide therapy for the treatment of Huntington’s disease. Paper presented at: 69th Annual Meeting of the American Academy of Neurology; April 28, 2017; Boston, MA.
PRECISION-HD clinical trials Single Dose Multidose 196 1 Washout CSF sample Dose 28 56 84 112 Study Day* 140 OLE 2 mg 4 mg 8 mg 16 mg 32 mg Multidose Cohorts (N = 12 per cohort) OLE: Open label extension; CSF: cerebrospinal fluid; mHTT: mutant huntingtin; wtHTT: wild-type HTT; tHTT: total HTT *Study day may vary depending on patient washout period Results Two Phase 1b/2a clinical trials for WVE-120101 and WVE-120102 ongoing Patients are migrated to highest dose tested Neuro HD Safety and tolerability Biomarkers mHTT Assay development work to measure wtHTT in CSF ongoing tHTT PRECISION-HD1 and OLE (including complete 16 mg cohort) PRECISION-HD2 and OLE (including complete 32 mg cohort) NfL Trial results expected by end of 1Q 2021
WVE-003 (SNP3) demonstrates selective, potent, and durable reduction of mHTT in preclinical models Selectively reduces mHTT mRNA in HD iPSC neurons in vitro Results from ND50036 iPSC-derived medium spiny neurons. Total HTT knockdown quantified by qPCR and normalized to HPRT1 Oligonucleotide or PBS [100 μg ICV injections through a cannula on days 1, 3, and 5] delivered to BACHD transgenic. Mean ± SD (n=8, *P<0.0332, ***P<0.0002, ****P<0.0001 versus PBS unless otherwise noted). HPRT1, hypoxanthine-guanine phosphoribosyl transferase; iPSC, induced pluripotent stem cell; ICV, intracerebroventricular; PBS, phosphate-buffered saline Similar results in cortex Pan-silencing reference compound WVE-003 PBS Weeks *** **** **** **** **** **** Clinical trial dosing expected to begin in 2021 Pan-silencing reference compound WVE-003 Percentage HTT mRNA Remaining Durable striatal mHTT knockdown for 12 weeks in BACHD mouse model Neuro HD Incorporates PN backbone chemistry modifications
Three allele-selective HD programs Intend to explore efficacy in early manifest and pre-manifest HD patient populations Neuro HD Potential to address ~80% of HD patient population % Huntington’s Disease Patient Population with SNP SNP1 WVE-120101 SNP2 WVE-120102 SNP3 WVE-003 SNP1 SNP2 SNP1 SNP2 SNP3 ~50% ~50% ~40% ~70%1 ~80%2 +10% of HD patients vs. SNP1 + SNP2 1 Percentage of patient population with SNP1 and/or SNP2 2 Percentage of patient population with SNP1, SNP2 and/or SNP3
WVE-004 Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (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 hexanucleotide repeat expansions (GGGGCC) are one of the most common genetic causes of the sporadic and inherited forms of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) The C9orf72 repeat expansions also lead to accumulation of repeat-containing transcripts, nuclear sequestration of RNA binding proteins and synthesis of toxic dipeptide-repeat (DPR) proteins The C9orf72 repeat expansions lead to reduced expression of wild-type C9orf72 and to cellular changes that reduce neuronal viability Neuro C9orf72
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 therapies in US C9-FTD Progressive neuronal atrophy in frontal/temporal cortices Personality and behavioral changes, gradual impairment of language skills ~10,000 6.4 years No approved disease modifying therapies Two devastating diseases with a shared genetic basis ALS: Amyotrophic lateral sclerosis; FTD: Frontotemporal dementia Sources: Cammack et al, Neurology, October 2019. Moore et al, Lancet Neurology, February 2020 Neuro C9orf72
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 protein exacerbates DPR-dependent toxicity Sources: Gitler et al, Brain Research, September 2016. Zhu et al, Nature Neuroscience, May 2020 Targeted by Wave ASOs Variant-selective targeting could address multiple potential drivers of toxicity Neuro C9orf72
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 WVE-004 targets only V1 and V3 transcripts, sparing V2 transcripts and healthy C9orf72 protein pre-mRNA variants Pathological mRNA products V1 V2 Mis-spliced V1/V3 Stabilized intron1 V3 Disease-causing factors RNA foci Dipeptide repeat proteins (DPRs) GGGGCC expansion Accessible target for variant selectivity WVE-004 reduces Repeat-containing transcripts Neuro C9orf72
PN backbone chemistry modifications: 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 cortex quantified by PCR (Taqman assay) 8 weeks later. Oligonucleotide concentrations quantified by hybridization ELISA. Graphs show robust best fit lines with 95% confidence intervals (shading) for PK-PD analysis. Spinal Cord Neuro C9orf72
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 treated with C9orf72 candidate and NTC under gymnotic conditions up to 10uM. Taqman qPCR assays were used to evaluating V3 and all V transcripts. NTC- non-targeting control. Relative fold change C9orf72 V3/HPRT1 1.5 1.0 0.5 0.0 0.001 0.01 0.1 1 10 Relative fold change C9orf72 V3/HPRT1 0.016 0.08 0.4 2 10 0.016 0.08 0.4 2 10 0.016 0.08 0.4 2 10 0.016 0.08 0.4 2 10 1.5 1.0 0.5 0.0 1.5 1.0 0.5 0.0 Relative fold change C9orf72/HPRT1 Neuro C9orf72
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 description: 2 x 50 ug on day 0 and day 7 dosed ICV; mRNA Samples were analyzed using quantitative PCR (Taqman assay) p≤0.0001 p≤0.0001 Neuro C9orf72
WVE-004 demonstrates durable reduction 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 7 dosed ICV; DPRs were measured by Poly-GP MSD assay. *: p≤ 0.05 **: P ≤ 0.01, ***: P ≤ 0.001 ICV: intracerebroventricular; Dipeptide repeat proteins: DPRs p≤0.0001 * *** ** Relative Poly-GP levels (normalized to PBS) Neuro C9orf72
Healthy C9 protein relatively unchanged ~6 months after WVE-004 administration ns ns C9 BAC transgenic mice were administered PBS or 50 ug WVE-004, ICV, on day 0 and again on day 7. Relative fold change of total human C9orf72 to mouse Hprt1 protein in the spinal cord (left) and cortex (right) shown at 24 weeks after first administration. Data show mean ± SD (n=7). ns, not significant; PBS, phosphate-buffered saline; ICV: intracerebroventricular Spinal cord Cortex Relative fold change C9orf72/HPRT1 Relative fold change C9orf72/HPRT1 WVE-004 PBS WVE-004 PBS Neuro C9orf72
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 exploratory clinical outcome measures ALSFRS-R and CDR-FTLD Clinical trial dosing expected to begin in 2021 CTA: clinical trial application; NfL: neurofilament light chain; ALSFRS-R: Amyotrophic Lateral Sclerosis Functional Rating Scale; CDRFTLD: Clinical Dementia Scale – frontotemporal lobar degeneration Neuro C9orf72
WVE-N531 Duchenne muscular dystrophy
WVE-N531 in vitro dose-dependent dystrophin restoration WVE-N531 contains novel PN backbone chemistry modifications Free uptake for 6 days in differentiation media with no transfection agent and no peptide conjugated to the oligonucleotide Demonstrated a dose-dependent increase in dystrophin restoration in DMD patient-derived myoblasts Experimental conditions: Δ45-52 (D45-52) patient myoblasts were treated with oligonucleotide for 6d under free-uptake conditions in differentiation media. Protein harvested in RIPA buffer and dystrophin restoration analyzed by Western Blot. Signal normalized to vinculin loading control and to primary healthy human myotube lysate (pooled from four donors) forming a standard curve in Δ45-52 cell lysate. Western Blot normalized to primary healthy human myoblast lysate Dystrophin protein restoration of up to 71% Neuro DMD
Substantial increase in survival observed in DKO model using PN chemistry (study ongoing) Double knock-out (DKO) mice lack dystrophin and utrophin protein and have a severe phenotype. Mdx/utr-/- mice received weekly subcutaneous (SC) 150 mg/kg dose of PS/PO or bi-weekly SC 75 mg/kg PS/PO/PN stereopure oligonucleotide beginning at postnatal day 10. Age-matched mdx/utr-/- littermates were treated with PBS, and mdx mice were not treated. Mice with severe disease were euthanized. DKO: PS/PO/PN 75 mg/kg n=9; PS/PO n=9, PBS n=12 PBS PS/PO, QW 150 mg/kg weekly PS/PO/PN, Q2W 75 mg/kg bi-weekly DKO Survival Neuro DMD
Planning underway for clinical trial investigating WVE-N531 in DMD DKO data and previously generated preclinical data support advancing WVE-N531 to the clinic Unmet need in DMD remains high Support from DMD advocacy community to explore possibility to improve efficiency of exon skipping with novel therapeutic approaches such as PN chemistry Planned clinical trial adequately powered to evaluate change in dystrophin production, drug concentration in muscle, and initial safety Open-label study; targeting every-other-week administration in up to 15 boys with DMD Trial planned to be conducted in Europe Potential to apply PN chemistry to other exons if successful CTA submission expected by end of 1Q 2021 Neuro DMD
Wave’s discovery and drug development platform
Through iterative analysis of in vitro and in vivo outcomes and machine learning-driven predictive modeling, Wave continues to define design principles that are deployed across programs to rapidly develop and manufacture clinical candidates that meet pre-defined product profiles Multiple modalities Silencing | Splicing | ADAR editing DESIGN Unique ability to construct stereopure oligonucleotides with one defined and consistent profile Enables Wave to target genetically defined diseases with stereopure oligonucleotides across multiple therapeutic modalities OPTIMIZE A deep understanding of how the interplay among oligonucleotide sequence, chemistry, and backbone stereochemistry impacts key pharmacological properties SEQUENCE STEREOCHEMISTRY CHEMISTRY Sequence Stereochemistry Chemistry
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), Phosphoramidate diester (PN) Sequence B: bases A, T, C, mC, G, U, other modified bases Stereochemistry Chiral control of any stereocenter 5’ modifications, backbone modifications
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 illustrative of backbone modification patterns Backbone linkages PS PO PN PO/PS PO/PS/PN Phosphoryl guanidine x-ray structure Stereorandom PS backbone Rp PS backbone Sp PN backbone Sp PN backbone Rp PN backbone Stereorandom
Silencing Splicing In vitro knockdown of PS/PO containing compounds compared to PS/PN compounds with same sequence and PS stereochemistry Rational design using PN backbone chemistry modifications increases in vitro potency in most cases Presented at Analyst & Investor Research Webcast on August 25, 2020; Left: 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; Right: DMD patient-derived myoblasts treated with PS/PO or PS/PO/PN stereopure oligonucleotide under free-uptake conditions. Exon-skipping efficiency evaluated by qPCR. PS/PO compounds are rank-ordered on X-axis. PS/PO reference compound PS/PN modified compound In vitro skipping efficiency of PS/PO containing compounds compared to PS/PO/PN compounds with same sequence and PS stereochemistry PS/PO reference compound PS/PO/PN modified compound Ranked by potency of reference PS/PO compound Ranked by potency of reference PS/PO compound Target knockdown (% remaining) Improved knockdown Improved skipping % skipping
Lead program in Takeda collaboration reinforces potential of PN chemistry in the CNS Single IT dose of 12 mg (n=3) Therapeutic candidate widely distributed across brain and spinal cord ~90% mRNA knockdown one-month following single dose Substantial and widespread target mRNA reduction following single intrathecal dose in NHPs NHPs: Non-human primates; IT: intrathecal NHPs were administered 12 mg on day 1 via IT bolus injection; tissue samples were collected from 3 NHPs at 28 days post-dose. Target mRNA knockdown 28 days post-dose
PRISM enables optimal placement of backbone stereochemistry Crystal structure confirms phosphate-binding pocket of RNase H binds 3’-SSR-5’ motif in stereopure oligonucleotide – supports design strategy for Wave oligonucleotides ASO/RNA duplex Yellow spheres represent ‘S’ atoms Phosphate binding pocket RNA cleavage site Target RNA Stereopure Oligonucleotide (C9orf72 compound) RNase H + +
Importance of controlling stereochemistry (Rp) (Sp) Top view Side view Yellow spheres represent ‘S’ atomsPS: Phosphorothioate Number of PS linkages in oligonucleotide backbone No. diastereomers 80T 60T 40T 20T 30B 22M 12M 2M 1M 500K 0 0 10 20 30 40 50 Antisense, exon skipping, ssRNAi ADAR oligonucleotide CRISPR guide Stereochemical diversity Exponential diversity arises from uncontrolled stereochemistry
ADAR editing Platform capability and Alpha-1 antitrypsin deficiency
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 Modification Delivery A: adenosine; I: inosine; G: guanosine; Nishikura, K. A-to-I editing of coding and non-coding RNAs by ADARs. Nat. Rev. Mol. Cell Biol. 2016; Picardi, E. et al. Profiling RNA editing in human tissues: towards the inosinome Atlas. Scientific reports 5, 14941, doi:10.1038/srep14941 (2015). ADAR editing
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 Exogenous ADAR or other base editors Edited RNA Protein release/ expression Delivery vehicles Alternative Base-Editing Systems Edited RNA Genetic construct or foreign protein ADAR editing
Wave platform Fully chemically modified to increase stability in vivo Chirally-controlled backbone to maximize in vitro activity PN backbone chemistry modification improves editing efficiency No requirement for AAV / nanoparticles GalNAc-conjugated for targeted delivery into liver Avoids permanent off-target DNA edits No immunogenicity from exogenous proteins Reduced off-target effects Advantages of Wave ADAR editing platform Sources: Chen Biochemistry 2019 Chemically modified Simplified delivery Endogenous ADAR ADAR editing
ADAR amenable diseases represent a sizeable opportunity Nearly half of known human SNPs associated with disease are G-to-A mutations A-to-I(G) editing could target tens of thousands of potential disease variants1 ~48% C-to-T C-to-G A-to-T C-to-A A-to-C A-to-G Potentially pathogenic human SNPs by base pair corrections >32,000 potentially pathogenic human SNPs2 SNP: single nucleotide polymorphism A: Adenosine I: Inosine G: Guanosine 1ClinVar database 2Gaudeli NM et al. Nature (2017). ADAR editing
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 pathways miRNA target site modification Modifying upstream ORFs Modification of ubiquitination sites Restore protein function Recessive or dominant genetically defined diseases Modify protein function Ion channel permeability Protein upregulation Haploinsufficient diseases Examples: Examples: Examples: ADAR editing
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 chemistry modifications increased both potency and editing efficiency in vitro ACTB editing in primary human hepatocytes using GalNAc-mediated uptake ADAR editing
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. In vitro dose-response human hepatocytes In vitro dose-response NHP hepatocytes % Editing % Editing ACTB 1 ACTB 2 ACTB 3 ACTB 1 ACTB 2 ACTB 3 ACTB GalNAc-conjugated oligonucleotides with stereopure PN backbone chemistry modifications ADAR editing
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 Substantial and durable editing out to at least Day 50, 45 days post last dose In vivo editing in NHP following subcutaneous administration Oligonucleotide quantification in NHP following subcutaneous administration 2 days post last dose 45 days post last dose 2 days post last dose 45 days post last dose ACTB 1 ACTB 2 ACTB 3 ACTB 1 ACTB 2 ACTB 3 Untreated (pre dose) % Editing µg of oligonucleotide per gram of tissue ADAR editing
Editing site RNA editing within ACTB transcript (human hepatocytes) RNA editing within transcriptome (human hepatocytes) Wave ADAR editing oligonucleotides are highly specific Coverage Genome coordinates ACTB C 0% T 100% C 53.8% T 46.2% ACTB Confidence (LOD score) % Editing Mock Editing oligonucleotide Human hepatocytes were dosed with 1um oligonucleotide, 48 hours later RNA was collected and sent for RNA sequencing. RNAseq conducted using strand-specific libraries to quantify on-target ACTB editing and off-target editing in primary human hepatocytes; plotted circles represent sites with LOD>3 ADAR editing
ADAR editing Advancing Wave’s first ADAR editing program in alpha-1 antitrypsin deficiency (AATD) Sources: Strnad 2020; Blanco 2017 AAT: Alpha-1 antitrypsin Most common cause is a single G-to-A point mutation on the “Z” allele ~250K people have the ZZ genotype, which is most severe Current approved therapies modestly increase circulating levels of AAT in those with lung pathology; no therapies address liver pathology Loss of function in lung Gain of function in liver Lack of functional AAT in serum: Insufficient levels to counteract protease levels, e.g., neutrophil elastase Lung damage due to unchecked proteolytic activity and inflammation Other tissues may be affected (e.g. skin) Misfolding of AAT in hepatocytes: Inability to secrete AAT AAT polymerizes in liver Liver damage/cirrhosis Wave’s approach may simultaneously address lung and liver manifestations by using ADAR editing to correct the mutation: Increase circulating levels of wild-type AAT protein Reduce aggregation in the liver Retain AAT physiological regulation
SERPINA1 RNA editing increases protein concentration in vitro Mouse primary hepatocytes that express SERPINA1-PIZ allele were transfected with 25 nanomolar (nM) of SERPINA1 (SA1-1 and SA1-2) targeting antisense oligonucleotides (ASOs) and a control non-targeting (NT) ASO. Media and RNA was collected at 5 days post transfection. SerpinA1 Protein in media was quantified by Elisa Assay, RNA editing was quantified by RT/PCR/Sanger sequencing. All samples done at N=6 replicates. In primary hepatocyte Pi*Z cell model, editing the Z transcript back to wild-type restored native protein folding and secretion from hepatocytes 3-Fold Increase SerpinA1 Protein Concentration in Media SERPINA1 mRNA Editing % SERPINA1-Pi*Z mRNA Editing SerpinA1 Protein ng/ml ADAR editing
Proprietary humanized mouse model developed to support ADAR platform Model validation and in vivo data expected 1H 2021 SERPINA1-Pi*Z/huADAR Protein ü Human ADAR Expressed in all tissues huADAR mouse Protein Pathology ü huADAR Liver pathology, lower huSERPINA1 serum ü SERPINA1 SERPINA1 mouse Protein ü huSERPINA1-Pi*Z Expressed in liver Expression of huADAR in mouse is comparable to expression in human cells Expression of huADAR restores editing of endogenous targets in primary mouse cell types to levels seen in human primary cell types huADAR mouse model can be crossed with disease specific mouse models to provide model systems for use across Wave’s ADAR editing programs ADAR editing
Multiple opportunities for ADAR editing in neurology 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: ~200-250nM Gymnotic uptake; Total RNA was harvested, reverse transcribed to generate cDNA, and the editing target site was amplified by PCR and quantified by Sanger sequencing Concentration (µM) ADAR editing hADAR: human ADAR; UGP2: Glucose Pyrophosphorylase 2; 5 mice in each group were injected with PBS or a single 100uG dose on day 0. Animals were necropsied on day 7. RNA was harvested and editing measured by Sanger sequencing. In vivo CNS editing in proprietary hADAR transgenic mouse (1 week)
Stereopure oligonucleotides for inherited retinal diseases (IRDs) Wave ophthalmology opportunity Oligonucleotides can be administered by intravitreal (IVT) injection; targeting twice per year dosing Stereopure oligonucleotides open novel strategies in both dominant and recessive IRDs; potential for potent and durable effect with low immune response Successful targeting of MALAT1 is a surrogate for an ASO mechanism of action Widely expressed in many different cell types Only expressed in the nucleus Intravitreal injection Sources: Daiger S, et al. Clin Genet. 2013;84:132-141. Wong CH, et al. Biostatistics. 2018; DOI: 10.1093/biostatistics/kxx069. Athanasiou D, et al. Prog Retin Eye Res. 2018;62:1–23. Daiger S, et al. Cold Spring Harb Perspect Med. 2015;5:a017129. Verbakel S, et al. Prog Retin Eye Res. 2018:66:157-186.; Short, B.G.; Toxicology Pathology, Jan 2008. Ophthalmology
Durable Malat1 knockdown through 9 months with PN backbone chemistry modifications 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 buffered saline; NTC= chemistry matched non-targeting control ~50% Malat1 knockdown at 36 weeks in the posterior of the eye PBS NTC PS/PO PS/PN % Malat1 expression Time (weeks) p≤0.01 Ophthalmology
Usher Syndrome Type 2A: a progressive vision loss disorder Autosomal recessive disease characterized by hearing loss at birth and progressive vision loss beginning in adolescence or adulthood Caused by mutations in USH2A gene (72 exons) that disrupt production of usherin protein in retina, leading to degeneration of the photoreceptors No approved disease-modifying therapies ~5,000 addressable patients in US Sources: Boughman et al., 1983. J Chron Dis. 36:595-603; Seyedahmadi et al., 2004. Exp Eye Res. 79:167-173; Liu et al., 2007. Proc Natl Acad Sci USA 104:4413-4418. Oligonucleotides that promote USH2A exon 13 skipping may restore production of functional usherin protein Ophthalmology
Potent USH2A exon 13 skipping with stereopure compound in vitro and ex vivo Left: Compounds were added to Y79 cells under free-uptake conditions. Exon skipping was evaluated by Taqman assays. USH2A transcripts were normalized to SRSF9. Data are mean±s.d., n=2. Reference Compound: van Diepen et al. 2018. Antisense oligonucleotides for the treatment of eye disease. W02018055134A1. Compound-1 is a stereopure antisense oligonucleotide. Right: Whole NHP and human eyes were enucleated (n=4 and n=2, respectively) and compounds (1–20 µM) were added to extracted retinas under free-uptake conditions. Exon skipping was evaluated by 48 hrs later by Taqman assays on RNA. USH2A transcript levels were normalized to SRSF9. Data presented are mean± s.e.m. Enhanced potency over a stereorandom reference compound (in vitro) Ophthalmology Target engagement in NHP and human retinas (ex vivo) PBS NTC Compound-1 20 20 10 5 1 [µM] PBS NTC Compound-1 20 20 10 [µM] NHP Human
Allele-selective reduction of SNP-containing allele for adRP associated with Rhodopsin P23H mutation Ferrari et al., Current Genomics. 2011;12:238-249.; Reporter assays on a Wave stereopure sequence as well as a sequence described in WO2016138353A1: ASO and luciferase reporter plasmids (wild-type and mutant rhodopsin) are transfected into Cos7 cells. 48-hours later, cells are harvested, and relative luminescence is measured. Stereorandom Stereopure Collaborations in place for evaluation in transgenic human Rho P23H pig model In vivo Ophthalmology Retinitis pigmentosa (RP): group of rare, genetic eye disorders resulting in progressive photoreceptor cell death and gradual functional loss; currently no cure ~10% of US autosomal dominant RP cases are caused by the P23H mutation in the rhodopsin gene (RHO) Mutant P23H rhodopsin protein is thought to misfold and co-aggregate with wild-type rhodopsin, resulting in a gain-of-function or dominant negative effect in rod photoreceptor cells
THERAPEUTIC AREA / TARGET Milestone Huntington’s disease mHTT SNP2 End of 1Q 2021: PRECISION-HD2 data, including complete 32 milligram cohort, and initial data from OLE trial Huntington’s disease mHTT SNP1 End of 1Q 2021: PRECISION-HD1 data, including complete 16 milligram cohort, and initial data from OLE trial Huntington’s disease mHTT SNP3 2021: Dosing of first patient in clinical trial of WVE-003 ALS and FTD C9orf72 2021: Dosing of first patient in clinical trial of WVE-004 Duchenne muscular dystrophy Exon 53 End of 1Q 2021: CTA submission ADAR editing Multiple 1H 2021: Humanized mouse model validation AATD (ADAR editing) SERPINA1 1H 2021: in vivo AATD data NEUROLOGY HEPATIC Expected upcoming milestones ALS: Amyotrophic lateral sclerosis; FTD: Frontotemporal dementia; SCA3: Spinocerebellar ataxia 3; AATD: Alpha-1 antitrypsin deficiency Stereopure PN chemistry First clinical compounds with PN chemistry to begin dosing in 2021
Realizing a brighter future for people affected by genetic diseases For more information: Kate Rausch, Investor Relations firstname.lastname@example.org 617.949.4827
Wave Life Sciences Highlights Pipeline Progress and Expansion Leveraging New PN Backbone Chemistry Modifications
Three clinical trials to begin in 2021 with compounds containing Waves novel PN backbone chemistry modifications
Data from ongoing PRECISION-HD and OLE clinical trials for Huntingtons disease expected by end of 1Q 2021
Potential best-in-class ADAR editing platform capability continues to advance, with validation of proprietary in vivo modeling system and delivery of in vivo alpha-1 antitrypsin deficiency data expected 1H 2021
CAMBRIDGE, Mass., January 11, 2021 Wave Life Sciences Ltd. (Nasdaq: WVE), a clinical-stage genetic medicines company committed to delivering life-changing treatments for people battling devastating diseases, today announced key upcoming milestones for 2021, including the initiation of new clinical trials, expected data readouts, and continued advancement of Waves proprietary discovery and drug development platform, PRISMTM.
2020 was a year of focused and formative progress for Wave, which culminated with submissions of clinical trial applications for two new programs. We continued to deliver on our ambitious goals despite the pandemic and are now on a course to unlock significant value from our pipeline and platform starting in 2021. Our research and clinical teams have made impressive headway across our portfolio of investigational stereopure oligonucleotides, and today we are advancing more than a dozen silencing, splicing and editing programs across various stages of development, said Paul Bolno, MD, MBA, President and Chief Executive Officer of Wave Life Sciences. This year, we plan to initiate clinical trials for three compounds containing PN backbone chemistry modifications, which have been shown preclinically to increase potency, exposure and durability across various modalities. With our three new trials, well be able to more fully assess the potential of this novel chemistry advancement for the field of genetic medicine. They also offer the opportunity to deepen our impact in Huntingtons disease and extend our research to others struggling with amyotrophic lateral sclerosis, frontotemporal dementia, and neuromuscular diseases.
We also plan to deliver comprehensive data results from the ongoing PRECISION-HD trials late in the first quarter to enable a decision regarding potential Phase 3 development for WVE-120101 and WVE-120102, our first-generation Huntingtons disease candidates. Lastly, we continue to invest in PRISM and look forward to contributing new findings in oligonucleotide design and delivery. Taken together, these advancements across our pipeline and platform are setting us up to become a leading genetic medicines company focused on delivering a new era of RNA therapeutics.
Advancing three clinical programs utilizing compounds containing Waves novel PN backbone chemistry modifications to first-in-human studies: Wave expects to initiate dosing in three proof-of-concept studies in 2021, which will assess target engagement, impact on key disease biomarkers, and initial safety for WVE-003 in Huntingtons disease (HD), WVE-004 in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), and WVE-N531 in Duchenne muscular dystrophy (DMD). All three compounds have novel designs incorporating PN backbone chemistry modifications, an advancement from Waves PRISM platform.
WVE-003 for HD: WVE-003 is Waves first HD candidate to use PN backbone chemistry modifications and is designed to selectively target the mRNA transcript produced by the mutant allele of the huntingtin (mHTT) gene, while leaving the wild-type (wtHTT) protein relatively intact. While the primary driver of HD is believed to be a dominant gain of function in mHTT protein, the concurrent loss of function of wtHTT protein may also be an important component of the
pathophysiology of HD. A growing body of scientific evidence suggests that preserving as much of the essential wtHTT protein as possible is important for favorable health outcomes over a lifetime with the disease.
In December 2020, Wave submitted a clinical trial application (CTA) for WVE-003. Wave expects to initiate dosing in HD patients with SNP3 in 2021.
The WVE-003 program is leveraging learnings and clinical expertise gained through the ongoing Phase 1b/2a PRECISION-HD studies, as well as learnings in oligonucleotide design gained through the PRISM platform.
WVE-004 for ALS and FTD: WVE-004 is an investigational variant-selective silencing candidate designed to selectively target the transcript variants containing a hexanucleotide repeat expansion (G4C2) in the C9orf72 gene, while sparing the healthy C9orf72 protein. G4C2 expansions are one of the most common genetic causes of the sporadic and inherited forms of ALS and FTD.
In December 2020, Wave submitted a CTA for WVE-004. Wave expects to initiate dosing in ALS and FTD patients with G4C2 expansions in 2021.
WVE-N531 for DMD: Based on compelling preclinical data, Wave is advancing WVE-N531 to explore exon skipping in dystrophic muscle. WVE-N531 was developed as an investigational treatment for DMD in boys amenable to exon 53 skipping and will be Waves first splicing candidate incorporating PN backbone chemistry modifications to be assessed in the clinic.
Wave expects to submit a CTA for WVE-N531 by the end of the first quarter in 2021.
PRECISION-HD clinical trials in HD: The PRECISION-HD1 and PRECISION-HD2 Phase 1b/2a and open label extension (OLE) trials evaluating WVE-120101 and WVE-120102 (respectively) in HD are ongoing. WVE-120101 and WVE-120102 are investigational stereopure oligonucleotides designed to selectively target the mHTT mRNA transcript, thereby leaving the wtHTT protein relatively intact.
The 32 mg cohorts added to both PRECISION-HD trials in 2020 are fully enrolled and dosing is underway in the multidose portions.
At the end of the first quarter, Wave expects to report data from both PRECISION-HD trials as well as available data from both ongoing OLE trials. These data are expected to enable a decision regarding potential Phase 3 development.
The analysis of PRECISION-HD2 will be comprised of biomarker and safety data from all cohorts, including all patients from the 32 mg cohort.
The analysis of PRECISION-HD1 will be comprised of biomarker and safety data from all completed cohorts, including all patients from the 16 mg cohort. Due to clinical site restrictions related to the COVID-19 pandemic, the last two patients in the PRECISION-HD1 32 mg cohort are currently scheduled to complete dosing in March 2021.
The OLE trials have been enrolling patients from PRECISION-HD2 since October 2019 and PRECISION-HD1 since February 2020. The vast majority of eligible patients from the PRECISION-HD trials have enrolled in the OLEs.
Patients in the PRECISION-HD OLEs have begun transitioning to the 32 mg doses.
PRECISION-HD2 patients have received up to 16 monthly doses of 8 or 16 mg of WVE-120102 in the OLE.
PRECISION-HD1 patients have received up to 9 monthly doses of 8 or 16 mg of WVE-120101 in the OLE.
ADAR-mediated RNA editing (ADAR editing) platform capability: Waves novel RNA editing modality also incorporates PN backbone chemistry modifications and uses endogenous ADAR (adenosine deaminases acting on RNA) enzymes via free uptake (non-viral, no nanoparticles) of A-to-I (G) RNA editing oligonucleotides. ADAR editing has the potential to unlock many new therapeutic applications, including restoration, modification or upregulation of proteins.
To support the advancement of best-in-class RNA editing candidates, Wave is developing a proprietary in vivo modeling system which crosses humanized ADAR mice with transgenic disease models. Wave expects to validate this modeling system in the first half of 2021.
SERPINA1 program for alpha-1 antitrypsin deficiency (AATD) with ADAR editing: In November 2020, Wave announced that its first ADAR editing program would be for AATD, which will target the G-to-A disease-causing mutation in mRNA coded by the SERPINA1 Z allele. By correcting the single RNA base mutation, ADAR editing may provide an ideal approach for increasing circulating levels of wild-type AAT protein and reducing aggregation in the liver, thus simultaneously addressing both the lung and liver manifestations of the disease.
In a primary hepatocyte SERPINA1 Z cell model, Wave demonstrated that editing the Z transcript back to wild-type restored native protein folding and secretion from hepatocytes. Wave expects to deliver in vivo data supporting the continued development of its AATD program in the first half of 2021.
Central nervous system (CNS) programs in collaboration with Takeda: Wave is leveraging learnings from PRISM to design additional stereopure oligonucleotides with optimized profiles for CNS indications, including in Alzheimers disease, Parkinsons disease and others, as part of its ongoing collaboration with Takeda. Wave is utilizing PN backbone chemistry modifications to produce compelling in vivo data and progress multiple preclinical programs.
About Huntingtons disease
Huntingtons disease (HD) is a debilitating and ultimately fatal autosomal dominant neurological disorder, characterized by cognitive decline, psychiatric illness and chorea. HD causes nerve cells in the brain to deteriorate over time, affecting thinking ability, emotions and movement. HD is caused by an expanded cytosine-adenine-guanine (CAG) triplet repeat in the huntingtin (HTT) gene that results in production of mutant HTT (mHTT) protein. Accumulation of mutant HTT causes progressive loss of neurons in the brain. Wild-type, or healthy, HTT (wtHTT) protein is critical for neuronal function and suppression may have detrimental long-term consequences. Approximately 30,000 people in the United States have symptomatic HD and more than 200,000 others are at risk for inheriting the disease. There are currently no approved disease-modifying therapies available. Between Waves three investigational molecules, the company has the potential to provide allele-selective therapeutic options for up to 80% of people with HD.
About amyotrophic lateral sclerosis and frontotemporal dementia
Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disease in which the progressive degeneration of motor neurons in the brain and spinal cord leads to the inability to initiate or control muscle movement. People with ALS may lose the ability to speak, eat, move and breathe. ALS affects as many as 20,000 people in the United States.
Frontotemporal dementia (FTD) is a fatal, neurodegenerative disease in which progressive nerve cell loss in the brains frontal lobes and temporal lobes leads to personality and behavioral changes, as well as the gradual impairment of language skills. It is the second most common form of early-onset dementia after Alzheimers disease in people under the age of 65. FTD affects as many as 70,000 people in the United States.
ALS and FTD can be caused by mutations in the C9orf72 gene, which provides instructions for making protein found in various tissues, including nerve cells in the cerebral cortex and motor neurons. In the U.S., mutations of the C9orf72 gene are present in approximately 40% of familial ALS cases and 8% to 10% of sporadic ALS cases. In FTD, the mutations appear in 38% of familial cases and 6% of sporadic cases.
About Duchenne muscular dystrophy (DMD)
DMD is a fatal X-linked genetic neuromuscular disorder caused predominantly by out-of-frame deletions in the dystrophin gene, resulting in absent or defective dystrophin protein. Dystrophin protein is needed for normal muscle maintenance and operation. Because of the genetic mutations in DMD, the body cannot produce functional dystrophin, which results in progressive and irreversible loss of muscle function, including the heart and lungs. Worldwide, DMD affects approximately one in 5,000 newborn boys.
PRISM is Wave Life Sciences proprietary discovery and drug development platform that enables genetically defined diseases to be targeted with stereopure oligonucleotides across multiple therapeutic modalities, including silencing, splicing and editing. PRISM combines the companys unique ability to construct stereopure oligonucleotides with a deep
understanding of how the interplay among oligonucleotide sequence, chemistry and backbone stereochemistry impacts key pharmacological properties. By exploring these interactions through iterative analysis of in vitro and in vivo outcomes and machine learning-driven predictive modeling, the company continues to define design principles that are deployed across programs to rapidly develop and manufacture clinical candidates that meet pre-defined product profiles.
About Wave Life Sciences
Wave Life Sciences (Nasdaq: WVE) is a clinical-stage genetic medicines company committed to delivering life-changing treatments for people battling devastating diseases. Wave aspires to develop best-in-class medicines across multiple therapeutic modalities using PRISM, the companys proprietary discovery and drug development platform that enables the precise design, optimization and production of stereopure oligonucleotides. Driven by a resolute sense of urgency, the Wave team is targeting a broad range of genetically defined diseases so that patients and families may realize a brighter future. To find out more, please visit www.wavelifesciences.com and follow Wave on Twitter @WaveLifeSci.
This press release contains forward-looking statements concerning our goals, beliefs, expectations, strategies, objectives and plans, and other statements that are not necessarily based on historical facts, including statements regarding the following, among others: the anticipated commencement, patient enrollment, data readouts and completion of our clinical trials, and the announcement of such events; the protocol, design and endpoints of our ongoing and planned clinical trials; the future performance and results of our programs in clinical trials; future preclinical activities and programs; regulatory submissions; the progress and potential benefits of our collaborations with partners; the potential of our in vitro and in vivo preclinical data to predict the behavior of our compounds in humans; our identification of future candidates and their therapeutic potential; the anticipated therapeutic benefits of our potential therapies, including our compounds containing PN chemistry, compared to others; our ability to design compounds using multiple modalities and the anticipated benefits of that model; the potential benefits of PRISM and our stereopure oligonucleotides compared with stereorandom oligonucleotides; the potential benefits of our novel ADAR-mediated RNA editing platform capabilities compared to others; and the benefit of nucleic acid therapeutics generally. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including the following: our ability to finance our drug discovery and development efforts and to raise additional capital when needed; the ability of our preclinical programs to produce data sufficient to support our clinical trial applications and the timing thereof; the clinical results of our programs, which may not support further development of product candidates; actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials; our effectiveness in managing future clinical trials and regulatory interactions; the effectiveness of PRISM, including PN backbone chemistry modifications and ADAR editing; the effectiveness of our novel ADAR-mediated RNA editing platform capability; the continued development and acceptance of oligonucleotides as a class of medicines; our ability to demonstrate the therapeutic benefits of our candidates in clinical trials, including our ability to develop candidates across multiple therapeutic modalities; our dependence on third parties, including contract research organizations, contract manufacturing organizations, collaborators and partners; and competition from others developing therapies for similar indications, as well as the information under the caption Risk Factors contained in our most recent Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC) and in other filings we make with the SEC from time to time. We undertake no obligation to update the information contained in this press release to reflect subsequently occurring events or circumstances.