F39 Design of an adaptive randomized controlled phase 1B/2A trial of WVE-003 in participants with huntington’s disease

Background Huntington’s disease is caused by the expansion of CAG-repeats (≥36 repeats) in at least one copy of HTT gene that leads to the expression of mutant HTT (mHTT) protein. The unaffected copy of HTT gene encodes wild-type HTT (wtHTT) protein, which supports many processes important for the health and function of the CNS. Aims Wave has developed WVE-003, an investigational stereopure oligonucleotide designed to selectively reduce the expression of mHTT mRNA while preserving wtHTT mRNA by targeting a single nucleotide polymorphism, SNP3, in the mHTT mRNA. WVE-003 contains Wave’s new PN chemistry, which has been shown to improve the pharmacological profile of oligonucleotides in preclinical studies. We are evaluating WVE-003 in an adaptive, multicenter, randomized, double-blind, placebo-controlled, phase 1b/2a clinical trial called SELECT-HD. The study is planned to enroll approximately 36 participants who have SNP3 only on the mHTT allele. We will assess the safety and tolerability of single- and multiple-ascending doses of WVE-003 administered intrathecally (IT) by lumbar puncture. Secondary objectives include studying WVE-003 pharmacokinetics (PK) in plasma and cerebrospinal fluid (CSF). We will also evaluate biomarkers for neurodegeneration, such as neurofilament light chain (NfL) in the CSF, as well as mutant and wild-type HTT proteins in CSF, biomarkers of pharmacodynamic effect and selectivity, respectively. The trial is designed to be adaptive, so that PK, safety and tolerability results from each cohort will inform the dose and dosing frequency for subsequent cohorts in the single- and multiple-ascending dose phases of the trial. Conclusions This first-in-human study will provide proof of concept for PD effects, as well as PK, safety and tolerability of WVE-003 in early manifest Huntington’s disease.