Huntington Disease Trial of New Antisense Oligonucleotide Therapy Begins Dosing 

The first participant has been treated in the phase 1b/2a SELECT-HD clinical trial evaluating an investigational stereopure antisense oligonucleotide (ASO) (WVE-003; Wave Life Sciences, Cambridge, MA) as a treatment for Huntington disease (HD). The ASO is designed to target a single nucleotide polymorphism on the mutant huntingtin (mHTT) allele, thereby selectively lowering mHTT protein and leaving healthy, wild-type huntingtin (wtHTT) protein functionally available. A growing collection of scientific evidence suggests that preserving as much wtHTT protein function as possible may be important for attaining favorable clinical outcomes.

“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.”

The SELECT-HD trial is a global multicenter randomized double-blind placebo-controlled phase 1b/2a clinical trial of single- and multiple-ascending intrathecal doses of the ASO in approximately 36 participants. All participants have confirmed HD with the polymorphism targeted by the ASO and are in the early stages of  HD. Pharmacokinetics of the ASO in blood and cerebrospinal fluid and clinical endpoints will be assessed. 

In contrast to other ASOs investigated for HD, WVE-003 has novel phosphoramidate diester backbone chemistry modifications. In preclinical studies, these modifications have been shown to enhance potency, exposure, and durability compared with first-generation ASOs targeting HD.

The SELECT-HD trial design and the ASO preclinical data will be displayed during poster sessions at the European Huntington Disease Network (EHDN) 2021 remote meeting, taking place September 9-11, 2021.