Antisense Oligonucleotide Reduces Mutant Huntingtin Protein in Phase 1b/2a Trial

  • Huntington disease

New data from an ongoing phase 1b/2a PRECISION-HD2 trial (NCT03225846) show that an antisense oligonucleotide therapy (ASO)(WVE-120102; Wave Life Sciences, Cambridge, MA), reduced levels of the toxic huntintin protein produced in Huntington disease (HD). This ASO was designed to be the first allele-selective approach to treating HD. In an analysis comparing all participants treated with multiple intrathecal doses of ASO vs placebo, a statistically significant reduction of 12.4% in mutant huntingtin (mHTT) protein was observed in cerebrospinal fluid (CSF) (P<.05). An analysis to assess a dose-response across treatment groups (2 mg, 4 mg, 8 mg or 16 mg) suggested a statistically significant response in mHTT reduction at the highest doses tested (P=0.03). These data support the addition of higher dose cohorts and a cohort to be treated with 32-mg doses is expected to be added to the trial in January 2020.

The ASO was generally safe and well-tolerated among participants receiving doses up to 16 mg in both single and multidose portions of the study. Of those treated with ASO,  72% experienced an adverse event (AE) compared with 83% of those treated with placebo. Most AEs were mild to moderate in intensity. The most common AEs (those occurring in at least 10% of participants treated with ASO) were headache, procedural pain, falls, and viral upper respiratory infection. There were no serious adverse events (SAEs) related to treatment with the ASO and no study stopping rules were met, allowing dose escalation to continue. There were no notable changes in laboratory tests including liver or renal function tests, platelets, or markers of immune activation. The topline analysis also assessed the presence of neurofilament light chain (NfL) in the CSF, and there was no difference in NfL between those treated with ASO vs placebo. 

“This topline analysis has given us the opportunity to evaluate early data from our ongoing dose-finding study. The data demonstrate a reduction in mHTT and a safety and tolerability profile that supports exploration of higher doses of WVE-120102, with the goal of maximizing mHTT reduction and avoiding a negative impact on the healthy huntingtin protein,” said Michael Panzara, MD, MPH, chief medical officer of Wave Life Sciences. “We plan to initiate the 32 mg cohort imminently and look forward to sharing data in the second half of 2020.”
This ASO was designed to preferentially lower mHTT protein by targeting single nucleotide polymorphism (SNP) rs362331 (SNP2) in order to keep the level of healthy or wild-type HTT (wtHTT) protein relatively intact. The wtHTT protein is important for neuronal function and may be neuroprotective in an adult brain. There is currently no assay available to directly measure wtHTT in the CSF. With this assay, a nonallele selective, pan-silencing approach would be expected to lead to a commensurate reduction in tHTT relative to mHTT.

Although there was a statistically significant reduction in mHTT with ASO vs placebo in the topline analysis, there was no difference in tHTT compared to placebo, suggesting WVE-120102 may have a potentially differential effect on huntingtin as measured by the mHTT and tHTT assays. Higher doses will be explored for potential efficacy. 

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