Slide 1: SELECT-HD: an adaptive first-in-human clinical trial to evaluate WVE-003 in early manifest HD
SELECT-HD: an adaptive first-in-human clinical trial to evaluate WVE-003, an investigational allele selective mHTT-lowering oligonucleotide, in early manifest Huntington's disease Vissia Viglietta, MD, PhD VP Clinical Development HSG: Nov 5, 2021
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: Unlocking the body's own ability to treat genetic disease
Unlocking the body’s own ability to treat genetic disease DESIGN OPTIMIZE Chemistry Unique ability to construct Provides the resolution to Sequence stereopure molecules and observe this structural control three structural features interplay and understand how of oligonucleotides to efficiently it im
Slide 4: Allele-selective approach to treating HD
Allele-selective approach to treating HD Preserve neuroprotective effects of wildtype HTT and reduce toxic mutant HTT Preserve Reduce wtHTT Stresses + mHTT wtHTT supports healthy brain function, especially in the context of stress Promotes neuronal Essential role in Supplies BDNF to Critical role in
Slide 5: Allele-selectivity achieved by targeting downstream SNPs
Allele-selectivity achieved by targeting downstream SNPs Target mHTT transcript to selectively reduce mHTT protein with antisense oligonucleotides Wildtype huntingtin RNA SNP3 Mutant huntingtin RNA C AG C AGC AGC AGC AG expanded CAG repeat Next Generation Chemistry Investigational WVE-003 targets mH
Slide 6: Introducing WVE-003, an investigational allele-selective oligonucleotide
Introducing WVE-003, an investigational allele-selective oligonucleotide Contains new chemistry with potential to address limitations of first-generation molecules Allele-selective approach designed to lower mutant HTT & preserve wildtype HTT New PN chemistry has demonstrated enhanced potency, t
Slide 7: WVE-003 contains backbone modifications with novel PN backbone chemistry
WVE-003 contains backbone modifications with novel PN backbone chemistry Backbone linkages PO PS PN Backbone Phosphodiester Phosphorothioate Phosphoramidate diester modification (X) Stereorandom PN backbone Stereorandom Stereochemistry Not chiral Chiral PS backbone Rp Chiral PN backbone Rp PS backbo
Slide 8: WVE-003 is potent and allele selective in vitro
WVE-003 is potent and allele selective in vitro Potently decreases HTT in Selectively reduces mHTT in HD motor neurons HD motor neurons Expression Percentage HTT RNA remaining 125 HTTExpression % mHTT mRNA % wtHTT mRNA 100 100 75 AllelicHTT NormalizedAllelic 50 50 WVE-003: EC50: 0.5 µM Normalized 25
Slide 9: HD mouse models
HD mouse models Evaluation of potency Evaluation of selectivity BACHD Mouse1 Hu97/18 Mouse2 HTT Key characteristics HTT Key characteristics mHTT 97 CAA-CAG repeats mHTT 97 CAA-CAG repeats (human) (human) Multiple copies Multiple copies Subset of copies contain SNP3 Subset of copies conta
Slide 10: WVE-003 has potent and durable effects in cortex and striatum
WVE-003 has potent and durable effects in cortex and striatum Maximum knockdown of 75% with ~50% knockdown persisting for at least 3 months Cortex Striatum Relative mHTT RNA expression Relative mHTT RNA expression 1.5 (mHTT/Tubb – PBS) (mHTT/Tubb – PBS) 1.5 *** * 1.0 **** 1.0 **** *** 0.5 0.5 0.0 0.
Slide 11: Allele-selective activity in CNS of Hu97/18 mice
Allele-selective activity in CNS of Hu97/18 mice Allele-selective molecule decreases mutant HTT, spares wildtype HTT; whereas pan-acting molecule uniformly decreases wildtype HTT and mutant HTT Mutant HTT Wildtype HTT Cortex Striatum Hippocampus Percentage HTT RNA expression wtHTT & mHTT *** ns ns n
Slide 12: Preclinical pharmacological modeling available to inform clinical starting dose
Preclinical pharmacological modeling available to inform clinical starting dose Human BACHD NHP (cortex, striatum) Ascending dose studies Concentrations in cortex and • PK & mHTT knockdown data Anticipated mHTT knockdown in striatum sufficient for target • IC50 determination cortex and striatum enga
Slide 13: Advancing investigational WVE-003 into a Phase 1b/2a clinical trial
Advancing investigational WVE-003 into a Phase 1b/2a clinical trial Leverage learnings from PRECISION-HD clinical trials Validated genotyping assay in CLIA setting to improve efficiency of patient identification Qualified biomarker assay to measure wildtype HTT protein in CSF Clinical experien
Slide 14: Rapid patient identification
Rapid patient identification Investigational assay enables SNP genotyping and phasing with CAG-repeat expansion SNP3 (CAG)n • CAG length, SNP zygosity and phasing HTT mRNA RT information from a single assay primer Reverse transcription • PCR-based assay using in vitro diagnostic device ready capilla
Slide 15: Assessment of wild-type HTT protein in CSF
Assessment of wild-type HTT protein in CSF Immunodepletion of mHTT to measure wtHTT protein CSF sample Add polyQ Ab magnetic beads to wt wt CSF sample wt wt wt wt Total HTT Wild-type HTT mt polyQ Ab magnetic beads Biotin polyQ Ab (MW1) Magnetic streptavidin beads wt Deplete Wild-type huntingtin prot
Slide 16: SELECT-HD: Adaptive first-in-human study for WVE-003
SELECT-HD: Adaptive first-in-human study for WVE-003 Ph 1b/2a global, multicenter, randomized, double-blind placebo-controlled trial Eligible PRECISION-HD participants can transition to this study after wash out Patients • Targeting 36 patients • ≥25 and ≤60 years of age Cohort 4 (P1) Cohort 4 (P2)
Slide 17: Wave remains committed to an allele-selective approach in HD
Wave remains committed to an allele-selective approach in HD • Advancing WVE-003 into SELECT-HD, a Phase 1b/2a clinical trial – New chemistry has potential to address limitations of first-generation molecules in PRECISION-HD – Preclinical pharmacological profile available in multiple species in vivo
Slide 18: Acknowledgements
Acknowledgements On behalf of Wave, thank you to all the patients, families, advocacy organizations, healthcare providers, and regulators with whom we have collaborated, particularly the study participants and families in PRECISION-HD and SELECT-HD • SELECT-HD Investigators • CHDI • Asuragen • SELEC