Wave Life Sciences Ltd. · NASDAQ:WVE
Wave Life Sciences — 20th Annual HD Therapeutics Conference (February 2025)
17 slides from Wave Life Sciences's conference presentation, Feb 25, 2025
Slide 1: WVE-003: An investigational first-in-class allele-selective mutant huntingtin-lowering molecule in Huntington's Disease
WVE-003: An investigational first-in-class allele-selective mutant huntingtin-lowering molecule in Huntington’s Disease Jane Atkins, PhD SVP, HD Global Program Lead February 25, 2025 1 Presented at the 20th Annual HD Therapeutics Conference
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: Disclosures
Disclosures • Jane Atkins in an employee of Wave Life Sciences 3
Slide 4: Wave has been dedicated to HD for more than a decade
HAS BEEN DEDICATED TO HD FOR MORE THAN A DECADE Allele-selective silencing of mHTT is a promising therapeutic strategy for HD ➢ Allele-selective silencing has the potential to impact multiple pathogenic mechanisms in HD ➢ WVE-003 robustly and durably lowered mutant huntingtin (mHTT) while sparing wi
Slide 5: mHTT is toxic and can interfere with normal wtHTT function
mHTT is toxic and can interfere with normal wtHTT function Aberrant mHTT complexes induce transcriptional mHTT misfolds and forms aggregates with toxic dysregulation, impacting HTT gene expression properties, which can have a detrimental effect on wtHTT function • By activating IKK complexes, mHTT d
Slide 6: wtHTT is critical for normal brain function
wtHTT is critical for normal brain function wtHTT supports health and function of neurons wtHTT is crucial for cilia health • wtHTT (a scaffold protein) interacts with numerous • In the absence of wtHTT, cilia formation and function is protein partners, influencing various cellular processes, compro
Slide 7: WVE-003: Investigational first-in-class allele-selective mHTT lowering oligonucleotide
WVE-003: Investigational first-in-class allele-selective mHTT lowering oligonucleotide WVE-003 suppresses mHTT protein expression Recruit by promoting degradation of the transcript RNase H SNP3 mHTT transcript Expanded CAG repeat mHTT allele ‘003 Transcript degradation Reduced mHTT protein wtHTT tra
Slide 8: An allele-selective approach will address the second step of somatic expansion
An allele-selective approach will address the second step of somatic expansion by reducing levels of potential pathogenic drivers STEP 1: Length of CAG repeat STEP 2: Neurodegeneration increases over time • Somatic expansion associated with • Role for DNA repair (e.g. MSH3, PMS1), pathogenic process
Slide 9: An allele-selective approach will address the second step of somatic expansion
An allele-selective approach will address the second step of somatic expansion by reducing levels of potential pathogenic drivers STEP 1: Length of CAG repeat STEP 2: Neurodegeneration increases over time • Somatic expansion associated with • Role for DNA repair (e.g. MSH3, PMS1), pathogenic process
Slide 10: Multiple 30 mg doses of WVE-003 demonstrated a favorable safety profile and confirmed the allele-selective mechanism
Multiple 30 mg doses of WVE-003 demonstrated a favorable safety profile and confirmed the allele-selective mechanism of action • SELECT-HD was an adaptive Ph1b/2a randomized, placebo-controlled, double-blind clinical trial designed to rapidly assess WVE-003 in HD • First clinical demonstration of al
Slide 11: Slowing of caudate atrophy associated with mHTT lowering, WVE-003 exposure
Slowing of caudate atrophy associated with mHTT lowering, WVE-003 exposure Normalized caudate volume mHTT lowering associated with slowing caudate atrophy Change from baseline caudate volume -2 percent change from baseline R: -0.503 P<0.05 Slowing atrophy -3 Least-squares mean -5.10 -4.68 Slowing at
Slide 12: Preservation of caudate volume is expected to predict clinical benefit in HD
Preservation of caudate volume is expected to predict clinical benefit in HD • Medium spiny neurons, the primary neurons of the caudate and putamen, are sensitive to mHTT- HD-ISS stage probability and predicted clinical landmark induced toxicity and death in HD1 changes as a function of age IS TFC P
Slide 13: A 1% difference in rate of atrophy is associated with delayed onset of disability
Internal analysis of natural history data demonstrates a 1% difference in rate of atrophy is associated with a delayed onset of disability by ≥7.5-years Slower decline in caudate volume associated with probability of TFC preservation in HD natural history data TRACK-HD, PREDICT-HD • HD-ISS 1 + 2 p<0
Slide 14: Use of biomarkers as endpoints to support drug approval
Use of biomarkers as endpoints to support drug approval has the potential to rapidly bring disease-modifying medicines to patients Caudate • There remains a high unmet need for disease- atrophy modifying medicines for people living with HD • We need to work with urgency to design safe and efficient
Slide 15: Advancing Wave's allele-selective approach for the treatment of HD
Advancing Wave’s allele-selective approach for the treatment of HD Next steps for WVE-003: Next steps for allele-selective silencing: Ph2/3 study Targeting additional SNPs on mHTT • Planning underway, including key aspects of study design, for a global, potentially registrational Phase 2/3 study in
Slide 16: Acknowledgements
Acknowledgements THANK YOU to SELECT-HD participants and their families Clinical Advisory Committee SELECT-HD Investigators • Mayke Oosterloo • Daniel Claassen • Jamie Kulisevsky Bojarski • Tommaso Bovi • Carolyn Orr • Mary Edmondson • Ralf Reilmann • Sylvain Chouinard • Ray Dorsey • Richard Rhys Da
Slide 17: For questions contact
For questions contact: investorrelations@wavelifesci.com
Wave Life Sciences — 20th Annual HD Therapeutics Conference (February 2025) on 6ix