Slide 1: WVE-003 Ph1b/2a study in early manifest Huntington's disease and PRECISION-HD results
A Ph1b/2a study of WVE-003, an investigational allele-selective, mHTT–lowering oligonucleotide for the treatment of early manifest Huntington’s disease, and review of PRECISION-HD results Vissia Viglietta, MD PhD VP Clinical Development Presented at CHDI, Apr 27, 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: mHTT results from PRECISION-HD trials do not support further development of WVE-120102 or WVE-120101
mHTT results from PRECISION-HD trials do not support further development of WVE-120102 or WVE-120101 • PRECISION-HD2: Core Study – No statistically significant reductions of mHTT after single or multiple doses of WVE-120102 (doses 2-32 mg) – No dose response • PRECISION-HD2: Open Label Extension (OL
Slide 4: PRECISION-HD study design
PRECISION-HD study design Single Dose Washout Multidose OLE Dose CSF sample Single dose Cohorts* Multidose Cohorts 2 mg OLE Study: 4 mg Patients are migrated to highest dose tested 8 mg N = 12 per cohort 16 mg 32 mg PRECISION-HD2 PRECISION-HD1 WVE-003 OLE: Open label extension; CSF: cerebrospinal fl
Slide 5: PRECISION-HD2: Patient Disposition
PRECISION-HD2: Patient Disposition WVE-120102 Placebo 2 mg 4 mg 8 mg 12 mg 16 mg 32 mg Total (pooled) Number of patients 22 9 12 15 8 9 13 88 No. of doses per patient 1 6 3 4 7 8 0 6 28 2 0 0 0 0 0 0 0 0 3 3 0 3 6 0 0 3 12 4 13 6 5 2 0 9 4 26 Mean 3.0 3.0 2.8 2.2 1.0 4.0 2.4 2.5 Patients who prematu
Slide 6: PRECISION-HD2: Patient Demographics and HD Disease History
PRECISION-HD2: Patient Demographics and HD Disease History WVE-120102 Placebo 2 mg 4 mg 8 mg 12 mg 16 mg 32 mg Total (pooled) (n=9) (n=12) (n=15) (n=8) (n=9) (n=13) (active) (n=22) (n=66) Mean time since initial 6.1 9.9 3.8 5.6 3.9 3.2 5.6 5.3 diagnosis (y) Mean age at HD onset (y) 40.18 42 41.75 43
Slide 7: PRECISION-HD2 core: No statistically significant reduction of mHTT
PRECISION-HD2 core: No statistically significant reduction of mHTT detected after 3 or 4 doses of WVE-120102 Change in mHTT relative to baseline Percentage change from baseline (%) mean median Placebo 2 mg 4 mg 8 mg 16 mg 32 mg PRECISION-HD2 PRECISION-HD1 mHTT, mutant HTT WVE-003 7
Slide 8: PRECISION-HD2 core: No statistically significant changes in NfL
PRECISION-HD2 core: No statistically significant changes in NfL detected after 3 or 4 doses of WVE-120102 Change in NfL relative to baseline Percentage change from baseline (%) mean median Placebo 2 mg 4 mg 8 mg 16 mg 32 mg PRECISION-HD2 PRECISION-HD1 NfL, neurofilament light chain WVE-003 8
Slide 9: PRECISION-HD2 OLE: Modest reductions of mHTT at some timepoints
PRECISION-HD2 OLE: Modest reductions of mHTT at some timepoints Multiple prespecified and ad hoc sensitivity analyses confirmed no consistent effects Measured mHTT in CSF mHTT relative to baseline Percentage change from baseline mHTT (fM) in CSF Baseline N Week Week PRECISION-HD2 PRECISION-HD1 In PR
Slide 10: 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 11: PRECISION-HD2 OLE: No reductions in wtHTT over time
PRECISION-HD2 OLE: No reductions in wtHTT over time No correlation between greater than 20% reduction in mHTT and wtHTT change suggests allele-selectivity (correlation coefficient = 0.4, 95% CI: -0.22-0.19) Measured wtHTT in CSF wtHTT relative to baseline Percentage change from baseline wtHTT (fM) i
Slide 12: PRECISION-HD2 OLE: No changes in NfL over time
PRECISION-HD2 OLE: No changes in NfL over time Change in NfL relative to baseline Percentage change from baseline Baseline Week N PRECISION-HD2 PRECISION-HD1 NfL, neurofilament light chain; OLE, open label extension Data are represented as mean ± SD and median WVE-003 12
Slide 13: Progression on UHDRS-based endpoints matched natural history studies
Progression on UHDRS-based endpoints matched that expected from natural history studies (NHS) cUHDRS relative to baseline cUHDRS relative to baseline (OLE) (Core & OLE) Change from baseline Change from baseline Week Years N PRECISION-HD2 PRECISION-HD1 CHDI provided data from Track-HD, Predict-HD, En
Slide 14: PRECISION-HD2 Core and OLE Safety
PRECISION-HD2 Core and OLE Safety Core • AEs reported in 83% of WVE-120102-treated participants versus 90% on placebo, most mild to moderate in intensity – Most common (reported in ≥10% receiving WVE-120102): Headache, procedural pain, back pain, falls, viral upper respiratory tract infection, dizzi
Slide 15: PRECISION-HD1: No change in mHTT in core or OLE; generally safe and well tolerated
PRECISION-HD1: No change in mHTT in core or OLE; generally safe and well tolerated mHTT relative to baseline • Patient disposition & demographics matched PRECISION-HD2 Percentage change from (core) with fewer discontinuations • No statistically significant changes in mHTT, wtHTT, or NfL in mean base
Slide 16: Allele-selective approach to treating HD
Allele-selective approach to treating HD Reduce mHTT & preserve wtHTT, which supports brain function at multiple levels Preserve Reduce Neuron Synapse Promotes neuronal Supports transport survival by of synaptic proteins protecting against and vesicles; stresses prevalent in Regulates synaptic neuro
Slide 17: Introducing WVE-003, an investigational oligonucleotide
Introducing WVE-003, an investigational oligonucleotide Allele-selective approach for lowering mHTT Designed to preserve wtHTT protein Contains Wave’s new chemistry PN chemistry has demonstrated enhanced potency, tissue WVE-003 exposure & durability in CNS SNP3 Clinical starting dose informed by
Slide 18: WVE-003 is potent and selective in vitro
WVE-003 is potent and selective in vitro Potently decreases mHTT in Selectively reduces mHTT in HD motor neurons HD motor neurons Percentage HTT RNA remaining Percentage HTT RNA Remaining WVE-003: EC50: 0.5 mM Pan-silencing control Concentration (mM) Pan-silencing WVE-003 reference control PRECISION
Slide 19: WVE-003 has potent and durable effects in cortex and striatum of BACHD mice
WVE-003 has potent and durable effects in cortex and striatum of BACHD mice Maximum knockdown of 70-75% 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 **** *
Slide 20: 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 21: WVE-003: Clinical trial to leverage experience and learnings in HD
WVE-003: Clinical trial to leverage experience and learnings in HD Leveraging learnings from PRECISION HD SAD (Period 1) MAD (Period 2) • Starting dose informed by 2:1 3:1 preclinical in vivo models (active:placebo) (active:placebo) • Genotyping assay to improve efficiency of patient identification
Slide 22: Adaptive SAD/MAD Ph1b/2a study for WVE-003
Adaptive SAD/MAD Ph1b/2a study for WVE-003 Multicenter, randomized, double-blind, placebo-controlled trial Eligible PRECISION-HD participants can transition to this study after wash out Patients Secondary objectives • Targeting 36 patients • Plasma PK profile • ≥18 and ≤60 years of age at screening
Slide 23: Wave remains committed to an allele-selective approach in HD
Wave remains committed to an allele-selective approach in HD • Results from PRECISION-HD trials do not support further development of WVE-120102 and WVE-120101 • Advancing WVE-003 into Phase 1b/2a clinical trial – New chemistry has potential to address limitations of first-generation molecules – Pre
Slide 24: Acknowledgements
Acknowledgements PRECISION-HD study participants & Clinical Advisory Committee families • Daniel Claassen • Mary Edmondson • Ray Dorsey PRECISION-HD Investigators • Ralf Reilmann • Robert Adam • Clement Loy CHDI • Kelly Bertram • Susan Mathers Asuragen • Sylvain Chouinard • Carolyn Orr EVOTEC • Dani