Wave Life Sciences Ltd. · NASDAQ:WVE
Wave Life Sciences — ENCALS Meeting 2022
15 slides from Wave Life Sciences's conference presentation, Jun 3, 2022
Slide 1: Targeting pathological transcriptional variants in C9orf72-associated ALS and FTD: Initial results from FOCUS-C9
Targeting pathological transcriptional variants in C9orf72-associated amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD): Initial results from the ongoing FOCUS-C9 clinical trial Michael A. Panzara, MD, MPH Chief Medical Officer Head of Therapeutics Discovery and Development ENCAL
Slide 2: Disclosures
Disclosures Merit Cudkowicz, Jonathan D. Rohrer, Kenechi Ejebe, Ramakrishna Boyanapalli, Xiao Shelley Hu, Stephen Lake, Michael A. Panzara • Michael Panzara is a full-time employee of Wave Life Sciences and is on the Board of Directors of Athira Pharma • Merit Cudkowicz has provided consultation to
Slide 3: WVE-004 addresses each aspect of complex, but well described biology of C9orf72-associated ALS and FTD
WVE-004 addresses each aspect of complex, but well described biology of C9orf72-associated ALS and FTD RNA variants Disease drivers V1 V2 V3 C9orf72 protein C9orf72 1 Decrease in Poly(GP) biomarker Genetic mutation Loss-of- selected as preferred beneficial function Reduced protein DPR biomarker Repe
Slide 4: Including PN chemistry in WVE-004 may increase potency and decrease frequency of dosing
Including PN chemistry in WVE-004 may increase potency and decrease frequency of dosing • Stereopure oligonucleotides, which have a precisely controlled backbone stereochemistry, have been shown to outperform stereorandom oligonucleotides • New PN chemistry has demonstrated enhanced potency, tissue
Slide 5: WVE-004 potently depletes repeat-containing transcripts in patient-derived motor neurons
WVE-004 potently depletes repeat-containing transcripts in patient-derived motor neurons Comparison in C9orf72 ALS WVE-004 in C9orf72 ALS iPSC-derived motor neurons iPSC-derived motor neurons1 1.5 IC50=201.7 nM Relative expression Relative expression 1.0 C9orf72 V3 C9orf72 V3 0.5 0.0 0.001 0.01 0.1
Slide 6: Preclinical data supported the development of WVE-004 as a potential treatment for C9orf72 ALS and FTD
Preclinical data supported the development of WVE-004 as a potential treatment for C9orf72 ALS and FTD • WVE-004 treatment resulted in durable reduction of poly(GP) in spinal cord and cortex of C9 BAC mice1,2 • WVE-004 preserved expression of total C9orf72 protein in C9 BAC mice 6 months after dosin
Slide 7: Adaptive clinical trial designed to rapidly optimize dose level and frequency for WVE-004
Adaptive clinical trial designed to rapidly optimize dose level and frequency for WVE-004 Phase 1b/2a global, multicenter, randomized, double-blind, placebo-controlled trial Single dose cohorts Multidose cohorts 60 mg n=4 Follow-up ongoing 30 mg n=5 Proceed to MAD Additional cohorts Follow-up ongoin
Slide 8: Low single doses of WVE-004 resulted in dose-dependent, potent and durable CSF poly(GP) reductions
Low single doses of WVE-004 resulted in dose-dependent, potent and durable CSF poly(GP) reductions • WVE-004 reduced poly(GP) vs placebo after single 10 mg and 30 mg doses, reaching statistical significance at day 57 (p=0.05 Baseline and p=0.015, respectively) Placebo WVE-004 10 mg • Single 30 mg do
Slide 9: Adapting trial to rapidly optimize dose level, frequency and follow-up to enable discussions with regulatory authorities
Adapting trial to rapidly optimize dose level, frequency and follow-up to enable discussions with regulatory authorities later in 2022 Single dose cohorts Multidose cohorts 60 mg n=4 Follow-up ongoing 30 mg Expanded n=10 Proceed to MAD Additional cohorts Follow-up ongoing 20 mg New n=10 10 mg 10 mg
Slide 10: Predicted further reduction of CSF poly(GP) with four monthly 10 mg doses of WVE-004
Predicted further reduction of CSF poly(GP) with four monthly 10 mg doses of WVE-004 Modeling based on preclinical data and preliminary FOCUS-C9 data Spinal cord (cervical) Cortex 1.0 1.0 (Relative to control) (Relative to control) Poly(GP) remaining Poly(GP) remaining 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.
Slide 11: CSF cell counts, protein remained unchanged following treatment
CSF cell counts, protein remained unchanged following treatment NfL increased in some patients in the 30mg and 60mg cohorts Graphs show mean ± SD for pooled treated and placebo groups. NfL (pg/mL) log-transformed per Vacchiano et al., 2021 Front Aging 11 Neurosci. CSF, cerebrospinal fluid. NfL neuro
Slide 12: Adverse events balanced across treatment groups
Adverse events balanced across treatment groups • All patients (n=12) in each single dose treatment group, including with placebo, experienced at least 1 adverse event (AE) – Most AEs were mild to moderate in intensity – Four patients (one placebo) experienced severe and/or serious adverse events •
Slide 13: WVE-004 significantly reduced poly(GP) in patients with C9orf72 ALS and FTD, demonstrating target engagement
WVE-004 significantly reduced poly(GP) in patients with C9orf72 ALS and FTD, demonstrating target engagement and clinical proof of concept • Potent, durable, dose-dependent target engagement observed following single, low doses – Modeling suggests continued decline in poly(GP) with continued observa
Slide 14: Acknowledgements
Acknowledgements Study participants & families Clinical Advisory Committee • Merit Cudkowicz Investigators • Jonathan D Rohrer • Robert H Brown • Tim Anderson • Merrilee Needham • Jinsy A Andrews • Adam L Boxer • Julian Bauer • Susanne Petri • Barbara Borroni • Hanson Borjesson • Jonathan Rohrer • A
Slide 15: 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