Only clinical-stage candidate for Huntington’s disease designed to selectively lower mutant HTT and spare wild-type HTT

Adaptive trial design to enable faster optimization of dosing and decision-making on next steps for WVE-003; data to be generated through 2022

WVE-003 preclinical data and SELECT-HD trial to be highlighted at EHDN 2021 Remote Meeting September 9-11, 2021

CAMBRIDGE, MA, USA I September 09, 2021 I Wave Life Sciences Ltd. (Nasdaq: WVE), a clinical-stage genetic medicines company committed to delivering life-changing treatments for people battling devastating diseases, today announced the initiation of dosing in the company’s Phase 1b/2a SELECT-HD clinical trial evaluating investigational WVE-003 as a treatment for Huntington’s disease (HD). WVE-003 is a stereopure antisense oligonucleotide designed to target SNP3, a single nucleotide polymorphism on the mutant huntingtin (mHTT) allele, thereby selectively lowering mHTT protein and sparing healthy, wild-type huntingtin (wtHTT) protein.

“WVE-003 reflects the significant evolution of our chemistry and the many learnings gained from our first-generation clinical programs,” said Michael Panzara, MD, MPH, Chief Medical Officer and Head of Therapeutics Discovery and Development at Wave Life Sciences. “Our enthusiasm for this program is bolstered by a compelling set of preclinical data that demonstrated selectivity, potency, and durability of WVE-003 with effects in relevant brain regions. Further, emerging data continue to indicate that a fundamental requirement for clinical success in HD treatment will be the need to preserve wild-type HTT protein, supporting our allele-selective approach to mutant HTT protein reduction.”

Wave’s approach to HD and the WVE-003 program is guided by the recognition that, in addition to a gain of function of the mHTT protein, people with this disease have lost one copy of the wtHTT allele, leaving them with a smaller protective reservoir of healthy protein than unaffected individuals. A growing body of scientific evidence suggests that preserving as much of this essential wtHTT protein as possible, when in the setting of stress from the toxic mHTT protein, may be important for favorable clinical outcomes.

WVE-003 incorporates the company’s novel PN backbone chemistry modifications (PN chemistry), which have been shown in preclinical studies to enhance potency, exposure, and durability. In preclinical studies, WVE-003 demonstrated dose-dependent and selective reduction of mHTT mRNA in vitro and potent and durable knockdown of mHTT mRNA in vivo, in both the cortex and striatum. Data from several preclinical models evaluating pharmacokinetic to pharmacodynamic relationships for WVE-003 have informed the starting dose for the SELECT-HD trial.

The SELECT-HD trial is a global, multicenter, randomized, double-blind, placebo-controlled Phase 1b/2a clinical trial to assess the safety and tolerability of single- and multiple-ascending intrathecal doses of WVE-003 in people with a confirmed diagnosis of HD who are in the early stages of the disease and carry SNP3 in association with their cytosine-adenine-guanine (CAG) expansion. It is estimated that approximately 40 percent of adults with HD carry SNP3 in association with the HD mutation. Additional objectives include assessing the plasma pharmacokinetic profile and exposure in the cerebrospinal fluid, as well as exploratory pharmacodynamic (mHTT, wtHTT and neurofilament light chain) and clinical endpoints. The SELECT-HD trial is expected to enroll approximately 36 patients. It is designed to be adaptive, with dose escalation and dosing frequency being guided by an independent committee.

The SELECT-HD trial design and WVE-003 preclinical data will be highlighted in plenary and poster sessions at the EHDN 2021 Remote Meeting, taking place September 9-11, 2021. Presentation details are as follows:

  • Friday, September 10 at 8:05 a.m. EDT (2:05 p.m. CEST)
    SELECT-HD, an adaptive first-in-human clinical trial to evaluate WVE-003, an investigational allele-selective mHTT-lowering oligonucleotide, in early manifest Huntington’s disease (Vissia Viglietta, MD, PhD, Vice President of Clinical Development and Medical Affairs at Wave Life Sciences)
    Plenary Session III: Clinical Trial Session
  • Thursday, September 9 – Saturday, September 11
    Design of an Adaptive Randomized Controlled Phase 1b/2a Trial of WVE-003 in Participants with Huntington’s Disease (Danlin Xu, PhD, Medical Director at Wave Life Sciences)
    Poster Available On Demand

About Huntington’s Disease
Huntington’s disease (HD) is a debilitating and ultimately fatal autosomal dominant neurological disorder, characterized by cognitive decline, psychiatric illness, and chorea. HD causes nerve cells in the brain to deteriorate over time, affecting thinking ability, emotions, and movement. HD is caused by an expanded cytosine-adenine-guanine (CAG) triplet repeat in the huntingtin (HTT) gene that results in production of mutant HTT (mHTT) protein. Accumulation of mHTT causes progressive loss of neurons in the brain. Wild-type, or healthy, HTT (wtHTT) protein is critical for neuronal function and suppression may have detrimental long-term consequences. Approximately 30,000 people in the United States have symptomatic HD and more than 200,000 others are at risk for developing the disease. There are currently no approved disease-modifying therapies available.

About Wave Life Sciences
Wave Life Sciences (Nasdaq: WVE) is a clinical-stage genetic medicines company committed to delivering life-changing treatments for people battling devastating diseases. Wave aspires to develop best-in-class medicines across multiple therapeutic modalities using PRISM, the company’s proprietary discovery and drug development platform that enables the precise design, optimization and production of stereopure oligonucleotides. Driven by a resolute sense of urgency, the Wave team is targeting a broad range of genetically defined diseases so that patients and families may realize a brighter future. To find out more, please visit and follow Wave on Twitter @WaveLifeSci.

SOURCE: Wave Life Sciences