Wave Life Sciences Ltd. announced key upcoming milestones for 2021, including the initiation of new clinical trials, expected data readouts, and continued advancement of Wave’s proprietary discovery and drug development platform, PRISMTM. Advancing three clinical programs utilizing compounds containing Wave’s novel PN backbone chemistry modifications to first-in-human studies: Wave expects to initiate dosing in three proof-of-concept studies in 2021, which will assess target engagement, impact on key disease biomarkers, and initial safety for WVE-003 in Huntington’s disease (HD), WVE-004 in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), and WVE-N531 in Duchenne muscular dystrophy (DMD). All three compounds have novel designs incorporating PN backbone chemistry modifications, an advancement from Wave’s PRISM platform. WVE-003 for HD: WVE-003 is Wave’s first HD candidate to use PN backbone chemistry modifications and is designed to selectively target the mRNA transcript produced by the mutant allele of the huntingtin (mHTT) gene, while leaving the wild-type (wtHTT) protein relatively intact. While the primary driver of HD is believed to be a dominant gain of function in mHTT protein, the concurrent loss of function of wtHTT protein may also be an important component of the pathophysiology of HD. WVE-004 for ALS and FTD: WVE-004 is an investigational variant-selective silencing candidate designed to selectively target the transcript variants containing a hexanucleotide repeat expansion (G4C2) in the C9orf72 gene, while sparing the healthy C9orf72 protein. G4C2 expansions are one of the most common genetic causes of the sporadic and inherited forms of ALS and FTD. In December 2020, Wave submitted a CTA for WVE-004. Wave expects to initiate dosing in ALS and FTD patients with G4C2 expansions in 2021. WVE-N531 for DMD: Based on compelling preclinical data, Wave is advancing WVE-N531 to explore exon skipping in dystrophic muscle. WVE-N531 was developed as an investigational treatment for DMD in boys amenable to exon 53 skipping and will be Wave’s first splicing candidate incorporating PN backbone chemistry modifications to be assessed in the clinic. Wave expects to submit a CTA for WVE-N531 by the end of the first quarter in 2021. PRECISION-HD clinical trials in HD: The PRECISION-HD1 and PRECISION-HD2 Phase 1b/2a and open label extension (OLE) trials evaluating WVE-120101 and WVE-120102 (respectively) in HD are ongoing. WVE-120101 and WVE-120102 are investigational stereopure oligonucleotides designed to selectively target the mHTT mRNA transcript, thereby leaving the wtHTT protein relatively intact. The 32 mg cohorts added to both PRECISION-HD trials in 2020 are fully enrolled and dosing is underway in the multidose portions. At the end of the first quarter, Wave expects to report data from both PRECISION-HD trials as well as available data from both ongoing OLE trials. These data are expected to enable a decision regarding potential Phase 3 development. The analysis of PRECISION-HD2 will be comprised of biomarker and safety data from all cohorts, including all patients from the 32 mg cohort. The analysis of PRECISION-HD1 will be comprised of biomarker and safety data from all completed cohorts, including all patients from the 16 mg cohort. Due to clinical site restrictions related to the COVID-19 pandemic, the last two patients in the PRECISION-HD1 32 mg cohort are currently scheduled to complete dosing in March 2021. The OLE trials have been enrolling patients from PRECISION-HD2 since October 2019 and PRECISION-HD1 since February 2020. The vast majority of eligible patients from the PRECISION-HD trials have enrolled in the OLEs. Patients in the PRECISION-HD OLEs have begun transitioning to the 32 mg doses. PRECISION-HD2 patients have received up to 16 monthly doses of 8 or 16 mg of WVE-120102 in the OLE. PRECISION-HD1 patients have received up to 9 monthly doses of 8 or 16 mg of WVE-120101 in the OLE. ADAR-mediated RNA editing (ADAR editing) platform capability: Wave’s novel RNA editing modality also incorporates PN backbone chemistry modifications and uses endogenous ADAR (adenosine deaminases acting on RNA) enzymes via free uptake (non-viral, no nanoparticles) of A-to-I (G) RNA editing oligonucleotides. ADAR editing has the potential to unlock many new therapeutic applications, including restoration, modification or upregulation of proteins. To support the advancement of best-in-class RNA editing candidates, Wave is developing a proprietary in vivo modeling system which crosses humanized ADAR mice with transgenic disease models. Wave expects to validate this modeling system in the first half of 2021. SERPINA1 program for alpha-1 antitrypsin deficiency (AATD) with ADAR editing: In November 2020, Wave announced that its first ADAR editing program would be for AATD, which will target the G-to-A disease-causing mutation in mRNA coded by the SERPINA1 Z allele. By correcting the single RNA base mutation, ADAR editing may provide an ideal approach for increasing circulating levels of wild-type AAT protein and reducing aggregation in the liver, thus simultaneously addressing both the lung and liver manifestations of the disease. In a primary hepatocyte SERPINA1 Z cell model, Wave demonstrated that editing the Z transcript back to wild-type restored native protein folding and secretion from hepatocytes. Wave expects to deliver in vivo data supporting the continued development of its AATD program in the first half of 2021. Central nervous system (CNS) programs in collaboration with Takeda: Wave is leveraging learnings from PRISM to design additional stereopure oligonucleotides with optimized profiles for CNS indications, including in Alzheimer’s disease, Parkinson’s disease and others, as part of its ongoing collaboration with Takeda. Wave is utilizing PN backbone chemistry modifications to produce compelling in vivo data and progress multiple preclinical programs.