Slide 1: Innovations that led to SELECT-HD, a phase 1b/2a clinical trial in Huntington's Disease
Innovations that led to SELECT-HD, a phase 1b/2a clinical trial of an allele- selective therapy for Huntington’s Disease Michael A. Panzara, MD, MPH Chief Medical Officer, Head of Therapeutics Discovery and Development March 3, 2022
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: Wave Life Sciences
Wave Life Sciences We are a genetic medicines company focused on delivering transformational therapies for people with serious, genetically-defined diseases THERAPEUTIC AREA / TARGET MODALITY DISCOVERY PRECLINICAL CLINICAL RIGHTS NEUROLOGY NEUROLOGY ALS and FTD WVE-004 (FOCUS-C9) C9orf72 Takeda Hunt
Slide 4: Leveraging learnings from PRECISION-HD studies
Leveraging learnings from PRECISION-HD studies • mHTT results from PRECISION-HD trials did not support further development of WVE-120102 or WVE-120101 • No worsening of disease progression in treated participants versus expected based on natural history Genotyping assay to improve efficiency of pa
Slide 5: WVE-003 contains novel PN backbone chemistry
WVE-003 contains novel PN backbone chemistry PRISMTM backbone linkages PO PS PN (Sp) (Rp) -O -S N … … … … … … Phosphoryl guanidine Chirality Chirality Chirality x-ray structure None PS backbone Rp PN backbone Rp PS backbone Sp PN backbone Sp Negative Negative Neutral charge charge charge example PO:
Slide 6: PN chemistry substantially improves oligonucleotide pharmacology in preclinical studies
PN chemistry substantially improves oligonucleotide pharmacology in preclinical studies Benefits of PN chemistry in CNS Increased potency in neurons Well-tolerated in multiple in vitro & in vivo assays Increased potency & extended durability of silencing in mice Enhanced tissue exposure in m
Slide 7: WVE-003 has potent and durable effects in mouse cortex and striatum
WVE-003 has potent and durable effects in mouse cortex and striatum Maximum knockdown of 75% with ~50% knockdown persisting for at least 3 months Cortex Striatum 1.5 Relative mHTT RNA expression 1.5 *** * 1.0 **** 1.0 **** *** 0.5 0.5 0.0 0.0 2 4 12 2 4 12 2 4 12 2 4 12 2 4 12 2 4 12 weeks weeks PBS
Slide 8: Allele-selective activity in CNS of Hu97/18 mice
Allele-selective activity in CNS of Hu97/18 mice Allele-selective molecule decreases mHTT, spares wtHTT, whereas pan-acting molecule uniformly decreases wtHTT and mHTT mHTT wtHTT Cortex Striatum 150 150 **** * *** Percentage HTT RNA expression **** *** **** **** **** (mHTT/Tubb - PBS) 100 100 50 50
Slide 9: 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 striatum sufficient for target Anticipated mHTT knockdown in • IC50 determination engagement (administrati
Slide 10: SELECT-HD: Adaptive trial design enables data-driven refinement of dosing regimen
SELECT-HD: Adaptive trial design enables data- driven refinement of dosing regimen Additional cohorts Dose Level Additional cohorts Dose level and dosing Cohort 1 frequency determined by Cohort 1 independent committee Proceed to MAD Single ascending dose Multi-ascending dose Day 1-3 15 29 57 85 Mo
Slide 11: Innovations facilitate enrollment of genetically defined patient population
Innovations facilitate enrollment of genetically defined patient population wtHTT Normal Allele selectivity by SNP targeting Repeat long mRNA: ~9.6kb SNP located far from CAG repeat distance DNA: ~160kb SNP SNP Confirm presence of SNP variant mHTT Mutant Confirm location of SNP variant only on
Slide 12: 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 13: Assessment of wtHTT protein in CSF
Assessment of wtHTT protein in CSF Improvements to tHTT assay & depletion of mHTT key to quantification of wtHTT Step 1: Step 2: Step 3: Parameters Initial Improved • Quantify tHTT Immunodeplete mHTT • Re-test sample with (improved 2B7-D7F7 with polyQ Ab tHTT assay LLoQ 1.3 fM (floating) 7.3 fM assa
Slide 14: wtHTT quantification method performs reliably
wtHTT quantification method performs reliably • Evaluated precision, spike recoveries, 30 assay range and sensitivity in CSF n Mean ± SD LLOQ 75 44 ± 39 fM 20 fM 25 • Free MW1 Ab dilution of ≥1:200 minimizes interference with tHTT assay 20 Sample count • Depletion with MW1 has an acceptable level of
Slide 15: Wave remains committed to an allele-selective approach in HD
Wave remains committed to an allele-selective approach in HD • Innovations led to SELECT-HD, a Phase 1b/2a clinical trial – Advances in oligonucleotide chemistry & design: Wave’s novel PN backbone chemistry – Preclinical pharmacological modeling: informed clinical starting dose – Rapid patient ident
Slide 16: 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