WVE-120101 / Wave Life Sciences, Takeda - LARVOL DELTA

Huntington's Disease: Latest Frontiers in Therapeutics. (PubMed, Curr Neurol Neurosci Rep) - "After initial negative results with ASO molecules Tominersen and WVE-120101/ WVE-120102, the therapeutic landscape continues to expand, with various trials currently under development to document proof-of-concept and safety/tolerability. The possibility of quantifying mHTT in CSF, along with the development of an integrated biological staging system in HD are important innovations applicable to clinical trial design that enhance the drug development process. Although a future in HD with DMTs remains a hope for those living with HD, care partners and care providers, the therapeutic landscape is promising, with various drug development programs underway following a targeted approach supported by disease-specific biomarkers and staging frameworks."

Journal • Review • CNS Disorders • Genetic Disorders • Huntington's Disease • Movement Disorders • Parkinson's Disease

Wave Life Sciences Reports Fourth Quarter and Full Year 2022 Financial Results and Provides Business Update (GlobeNewswire) - “Research and development expenses were $31.1 million in the fourth quarter of 2022 as compared to $25.8 million in the same period in 2021. The increase in research and development expenses in the fourth quarter was primarily due to increased external expenses related to our AATD, C9orf72 and DMD programs and compensation-related costs, partially offset by a decrease in spending on our HD programs. Research and development expenses were $115.9 million in 2022, as compared to $121.9 million in 2021 primarily due to the previously disclosed discontinued PRECISION-HD programs, partially offset by increased spend on our other programs.”

Commercial • CNS Disorders • Huntington's Disease

"Disease-modifying Huntington Disease candidates in development include: Tominersen @roche HTT-lowering ASO WVE-120101, WVE-120102 AMT-130 @uniQure_NV VY-HTT01 @VoyagerTx PTC518 @PTCBio Branaplam @Novartis Pepinemab-semaphorin 4D-targeted antibody @Vaccinex https://t.co/wvw7UgWlzf" (@BRAINCURES)

Clinical • Genetic Disorders • Huntington's Disease • Movement Disorders

PRECISION-HD1: Safety and Tolerability of WVE-120101 in Patients With Huntington's Disease (clinicaltrials.gov) - P1b/2a; N=61; Terminated; Sponsor: Wave Life Sciences Ltd.; Active, not recruiting ➔ Terminated; Lack of Efficacy

Clinical • Trial termination • Huntington's Disease • Movement Disorders

Open-label Extension Study to Evaluate the Safety and Tolerability of WVE-120101 in Patients With Huntington's Disease (clinicaltrials.gov) - P1/2; N=27; Terminated; Sponsor: Wave Life Sciences Ltd.; Active, not recruiting ➔ Terminated; Lack of efficacy

Clinical • Trial termination • Genetic Disorders • Huntington's Disease • Movement Disorders

PRECISION-HD1: Safety and Tolerability of WVE-120101 in Patients With Huntington's Disease (clinicaltrials.gov) - P1b/2a; N=61; Active, not recruiting; Sponsor: Wave Life Sciences Ltd.; Recruiting ➔ Active, not recruiting

Enrollment closed • Huntington's Disease • Movement Disorders

Wave Life Sciences (WVE) Provides Update on Phase 1b/2a PRECISION-HD Trials (Streetinsider.com) - P1/2, N=88; PRECISION-HD2 (NCT03225846); P1/2, N=60; PRECISION-HD1 (NCT03225833); Sponsor: Wave Life Sciences; “In the PRECISION-HD2 core trial, results from all participants (n=88) showed no statistically significant change in mutant huntingtin protein (mHTT) versus placebo...PRECISION-HD2 open label extension (OLE) trial, results from all participants (n=28) showed modest reductions in mHTT after a mean of 8.1 monthly doses (range: 1-17), but effects were inconsistent over the course of the trial….Wave will also stop clinical development of WVE-120101….expects to initiate dosing in a Phase 1b/2a clinical trial for WVE-003 in 2021.”

P1/2 data • Trial status • CNS Disorders • Huntington's Disease

Open-label Extension Study to Evaluate the Safety and Tolerability of WVE-120101 in Patients With Huntington's Disease (clinicaltrials.gov) - P1/2; N=27; Active, not recruiting; Sponsor: Wave Life Sciences Ltd.; Enrolling by invitation ➔ Active, not recruiting

Enrollment closed • Genetic Disorders • Huntington's Disease • Movement Disorders

WVE Stock Price Fell Over 20% Pre-Market: Why It Happened (News Break) - “The stock price of Wave Life Sciences Ltd (NASDAQ: WVE) fell by over 20% pre-market….Investors appear to be responding to the company announcing data from the Phase 1b/2a PRECISION-HD2 and PRECISION-HD1 trials evaluating investigational treatments WVE-120102 and WVE-120101, respectively, in Huntington’s disease (HD).”

P1/2 data • Stock price • CNS Disorders • Huntington's Disease

"$WVE mHTT results from PRECISION-HD trials do not support further development of WVE-120102 and WVE-120101" (@BioStocks)

Wave Life Sciences Reports Fourth Quarter and Full Year 2020 Financial Results and Provides Business Update (GlobeNewswire) - “Wave expects to report biomarker and safety data from all cohorts of the PRECISION-HD2 trial, along with data from all completed cohorts up to and including the 16 mg cohort from the PRECISION-HD1 trial at the end of the first quarter of 2021....Data from patients who have received multiple doses of 8 or 16 mg of WVE-120101 or WVE-120102 in the OLE trials at the end of the first quarter of 2021….Expects to initiate dosing in a Phase 1b/2a clinical trial of WVE-003 for patients with HD in 2021.”

P1/2 data • Trial status • CNS Disorders • Huntington's Disease

PRECISION-HD1: Safety and Tolerability of WVE-120101 in Patients With Huntington's Disease (clinicaltrials.gov) - P1b/2a; N=60; Recruiting; Sponsor: Wave Life Sciences Ltd.; Trial completion date: Dec 2020 ➔ May 2021; Trial primary completion date: Dec 2020 ➔ May 2021

Clinical • Trial completion date • Trial primary completion date • Huntington's Disease • Movement Disorders

WVE-120101: Regulatory approval for Huntington’s disease in FY2025/FY2026 (Takeda) - Q3 FY2020 Results

Regulatory • Huntington's Disease

Wave Life Sciences Highlights Pipeline Progress and Expansion Leveraging New PN Backbone Chemistry Modifications (GlobeNewswire) - “‘We also plan to deliver comprehensive data results from the ongoing PRECISION-HD trials late in the first quarter to enable a decision regarding potential Phase 3 development for WVE-120101 and WVE-120102...' 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)…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.”

New trial • P3 data • Amyotrophic Lateral Sclerosis • CNS Disorders • Frontotemporal Lobar Degeneration • Huntington's Disease

Investigational Assay for Haplotype Phasing of the Huntingtin Gene. (PubMed, Mol Ther Methods Clin Dev) - "WVE-120101 and WVE-120102 are investigational stereopure antisense oligonucleotides that enable selective suppression of mHTT by targeting single-nucleotide polymorphisms (SNPs) that are in haplotype phase with the CAG repeat expansion. Comparison of experimentally measured CAG repeat lengths, heterozygosity, and phasing with previously determined results showed improved performance. Our methodology enables the haplotype phasing of SNPs of interest and the disease-causing, expanded CAG repeat of the huntingtin gene, enabling accurate identification of patients with HD eligible for allele-selective clinical studies."

Journal • CNS Disorders • Huntington's Disease • Movement Disorders

[VIRTUAL] A Single-Assay Diagnostic Workflow for Genotyping and Phasing SNPs with Repeat Expansions for Allele-Selective Therapy in Huntington Disease (AMP 2020) - "Up to 70% of HD patients have SNP1 and/or SNP2 only on the mHTT allele which supports clinical trials such as WVE-120101 and WVE-120102 for allele-selective ASO therapies. Current methods for SNP genotyping and phasing with the HTT repeat tract rely on multiple workstreams and/or exploratory technologies. We describe an accurate, unified PCR-based workflow on an IVD-ready CE platform using automated genotyping capabilities with potential to expedite patient selection and improve the efficiency of clinical trials. The assay also has implications for diagnostics, including companion diagnostic kits, for other allele-selective, repeat expansion therapies."

CNS Disorders • Genetic Disorders • Huntington's Disease • Movement Disorders

Open-label Extension Study to Evaluate the Safety and Tolerability of WVE-120101 in Patients With Huntington's Disease (clinicaltrials.gov) - P1/2; N=60; Enrolling by invitation; Sponsor: Wave Life Sciences Ltd.

Clinical • New P1/2 trial • Genetic Disorders • Huntington's Disease • Movement Disorders

Wave Life Sciences Reports Third Quarter 2020 Financial Results and Provides Business Update (GlobeNewswire) - “‘…on track to file clinical trial applications for WVE-003 for Huntington’s disease and WVE-004 for amyotrophic lateral sclerosis and frontotemporal dementia this quarter.’…Wave is developing a third allele-selective HD candidate, WVE-003, which is designed to selectively target an undisclosed SNP on the mHTT mRNA transcript (SNP3), while leaving wtHTT protein relatively intact….Wave expects to initiate clinical development of WVE-004 with the submission of a CTA in the fourth quarter of 2020….Wave expects to initiate clinical development of WVE-003 with the submission of a clinical trial application (CTA) in the fourth quarter of 2020.”

New trial • Amyotrophic Lateral Sclerosis • CNS Disorders • Huntington's Disease

Development of Antisense Oligonucleotide Gapmers for the Treatment of Huntington's Disease. (PubMed, Methods Mol Biol) - "Antisense-mediated knockdown of mutated huntingtin is a promising therapeutic approach for Huntington's disease (HD), a devastating disorder affecting the motor and cognitive abilities. This chapter focuses on the modified gapmer AOs for the treatment of HD."

Journal • CNS Disorders • Huntington's Disease • Movement Disorders

Development and Clinical Applications of Antisense Oligonucleotide Gapmers. (PubMed, Methods Mol Biol) - "In addition, volanesorsen was conditionally approved in the EU for the treatment of adult patients with familial chylomicronemia syndrome (FCS) in 2019. Many others are being tested in clinical trials or under preclinical development. This chapter will cover the development of mipomersen and inotersen in clinical trials, along with advancement in gapmer treatments for cancer, triglyceride-elevating genetic diseases, Huntington's disease, myotonic dystrophy, and prion diseases."

Clinical • Journal • Amyloidosis • CNS Disorders • Dyslipidemia • Genetic Disorders • Huntington's Disease • Hypertriglyceridemia • Lipodystrophy • Metabolic Disorders • Movement Disorders • Muscular Dystrophy • Myotonic Dystrophy • Oncology

Wave Life Sciences Reports Second Quarter 2020 Financial Results and Provides Business Update (GlobeNewswire) - “Wave expects to report data from the PRECISION-HD1 and PRECISION-HD2 trials, including the 32 mg dose cohorts for each trial, in the first quarter of 2021. Open-label extension (OLE) clinical trials for patients outside of the U.S. who participated in the Phase 1b/2a PRECISION-HD trials are ongoing, and data is expected to be reported in the first quarter of 2021.”

P1/2 data • CNS Disorders • Huntington's Disease

A Multicenter, Open-label Extension Study to Evaluate the Safety, Pharmacodynamics, and Clinical Effects of WVE-120101 in Patients with Huntington’s Disease (clinicaltrialsregister.eu) - P2; N=50; Ongoing; Sponsor: Wave Life Sciences UK Limited

Clinical • New P2 trial • Huntington's Disease • Movement Disorders

WVE-120101: Regulatory approval for Huntington’s disease in FY2025/FY2026 (Takeda) - Q1 FY2020 Results

Regulatory • Huntington's Disease

Wave Life Sciences Reports First Quarter 2020 Financial Results and Provides Business Update (GlobeNewswire, Wave Life Sciences USA, Inc.) - “Our PRECISION-HD clinical trials of WVE-120101 and WVE-120102, two investigational compounds designed to selectively target mutant HTT for the treatment of Huntington’s disease, are ongoing….Wave is assessing the potential for a next higher dose cohort to be added to both PRECISION-HD trials…Wave is advancing its C9orf72 preclinical program to potentially treat amyotrophic lateral sclerosis (ALS)...and expects to initiate clinical development in the second half of 2020…Research and development expenses were $41.2 million in the first quarter of 2020…The increase in research and development expenses in the first quarter was primarily due to increased external expenses related to our clinical and preclinical activities, including our HD programs and C9orf72 program for ALS…”

Commercial • Preclinical • Trial status • Amyotrophic Lateral Sclerosis • CNS Disorders • Genetic Disorders • Huntington's Disease • Infectious Disease • Proteinopathy

PRECISION-HD1: Safety and Tolerability of WVE-120101 in Patients With Huntington's Disease (clinicaltrials.gov) - P1b/2a; N=60; Recruiting; Sponsor: Wave Life Sciences Ltd.; Trial completion date: Mar 2020 ➔ Dec 2020; Trial primary completion date: Mar 2020 ➔ Dec 2020

Clinical • Trial completion date • Trial primary completion date