Investigational Huntington Disease Therapy Significantly Reduces Mutant Huntingtin Protein


WVE-120102 is the first allele-selective molecule that preferentially lowers mHTT protein by targeting SNP2 in order to maintain levels of healthy or wild-type HTT protein.

Michael Panzara, MD, MPH

Michael Panzara, MD, MPH

Topline results from the phase 1b/2a PRECISION-HD2 clinical trial of Wave Life Sciences’ WVE-120102 revealed a statistically significant reduction in mutant huntingtin (mHTT) protein with the highest doses tested in adults with early manifest Huntington disease.

WVE-120102 is the first allele-selective molecule that preferentially lowers mHTT protein by targeting the single nucleotide polymorphism rs362331 (SNP2) in order to maintain levels of healthy or wild-type HTT protein.

Compared with placebo, a 12.4% reduction in mHTT in cerebrospinal fluid (CSF) was observed across all patients treated with the intrathecal therapy, dosed as 2, 4, 8, or 16 mg (P <.05). A dose-response analysis showed a statistically significant reduction in mHTT at the highest doses (P=.03), supporting the addition of 32 mg cohort in January 2020.

“This topline analysis has given us the opportunity to evaluate early data from our ongoing dose finding study. The data demonstrate a reduction in mutant HTT and a safety and tolerability profile that supports exploration of higher doses of WVE-120102, with the goal of maximizing mutant HTT reduction and avoiding a negative impact on the healthy huntingtin protein,” said Michael Panzara, MD, MPH, chief medical officer of Wave Life Sciences, in a statement. “We plan to initiate the 32 mg cohort imminently and look forward to sharing data in the second half of 2020.”

PRECISION-HD2 is an ongoing multicenter, randomized, double-blind, placebo-controlled trial that is evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of WVE-120102 in adults with early manifest Huntington disease who are carriers of SNP2. Patients were randomly assigned to dose groups of 2, 4, 8, or 16 mg of the study drug or placebo, and received up to 4 intrathecal doses. Following the first dose, patients went through a washout period of at least 8 weeks before continuing to the multidose phase of the study. Overall, 44 patients participated in the multi-dose phase (WVE-120102, n=31; placebo, n=13), and data from 39 of those participants were included in the mHTT assessment.

READ MORE: Andrew S. Feigin, MD, on New Trials for Treating Huntington Disease

Notably, there was no observed difference in total HTT protein compared with placebo, suggesting that the investigational therapy may have a differential effect on huntingtin as measured by mHTT and total HTT assays. There are currently no assays available that directly measure wild-type HTT in CSF, so Wave Life Sciences is using an assay developed to measure total HTT in order to indirectly asses the therapy’s effects on wild-type HTT. In the case of a non-allele-selective therapy, this assay would essentially show a commensurate reduction in total HTT relative to mHTT.

While the genetic medicines company will continue to work with research partners to develop ways to better assess wild-type HTT preservation, “Wave will continue to explore these potential effects with higher doses, where larger reductions of mHTT may be expected and where a more discernible impact on tHTT may be observed,” the company said in a statement.

Wave Life Sciences also disclosed that they observed no difference in neurofilament light chain in CSF between the treatment groups and placebo. Overall, the therapy was safe and well tolerated as single and multiple dosages up to 16 mg. Among those who received the study drug, 72% experienced an adverse event compared with 83% of patients who received placebo. The most common AEs were headache, procedural pain, falls, and viral upper respiratory infection. No serious AEs were reported and no study-stopping rules were met; as well, no changes in laboratory measures of liver and renal function, platelets, or immune activation were observed.

In October, the company initiated an open-label extension study open to patients outside of the US who participated in the phase 1b/2a trial. In addition, the company’s PRECISION-HD1 phase 1a/2b trial assessing WVE-120101 is also ongoing in patients with early manifest Huntington disease who carry SNP1. Given the results of the HD2 analysis, Wave announced that the HD1 study will remain blinded and they will also add a 32 mg cohort to that study, for which topline results are expected to be available in the second half of 2020.


Wave Life Sciences announces topline data and addition of higher dose cohort in ongoing phase 1b/2a PRECISION-HD2 trial in Huntington’s disease [news release]. Cambridge, MA: Wave Life Sciences. December 30, 2019. Accessed December 30, 2019.

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