WVE-120102 is a new medication designed to treat Huntington’s disease. It is being developed by Wave Life Sciences and is being tested in clinical trials together with its companion compound, WVE-120101.

Both compounds belong to a new class of medication called antisense oligonucleotides (ASO). These are designed to target molecules called messenger RNAs (mRNA), or copies of a gene that will be read by the protein-making machinery of the cell.

WVE-120102 is a stereo-pure nucleic acid therapeutic, meaning that similar but distinct forms of the ASO produced as byproducts in the manufacturing process are eliminated.

How does WVE-120102 work?

Huntington’s disease is caused by a mutation or defect in the huntingtin (HTT) gene, which contains the instructions for cells to produce the Huntingtin protein. It is not yet known what this protein normally does in the body, but it is thought to play an important role in the proper function of nerve cells.

The mutation that is seen in Huntington’s disease results in the production of a longer than normal Huntingtin protein. Parts of this longer protein may be cut into smaller pieces that accumulate and bind together inside nerve cells and form toxic aggregates. It is thought that this disrupts the normal function of the nerve cells and eventually causes their death, leading to the symptoms of Huntington’s disease.

WVE-120102 is designed to prevent the production of faulty Huntingtin protein by stopping its corresponding mRNA from being read. It specifically targets the mRNA produced from the mutant HTT gene, but not the mRNA produced from the normal HTT gene.

Roughly two-thirds of people with Huntington’s disease carry either one of two markers, called a single nucleotide polymorphism (SNP), that can be used to identify the mutant HTT gene. WVE-120101 is designed to treat people with SNP1 (rs362307) and WVE-120102 is designed to treat people with SNP2 (rs362331).

WVE-120102 in clinical trials

A Phase 1b/2a clinical trial (NCT03225846) called PRECISION-HD2 is testing the safety and tolerability of WVE-120102 in an estimated 60 patients with Huntington’s disease, ages 25 to 65. The trial, which is still recruiting participants in Canada, Australia, and Europe, is testing the effect of five different doses of WVE-120102 injected into the space around the spinal cord (intrathecal) against a placebo. Patients are given an initial injection, then after at least an eight-week washout period, they are given three monthly injections for a total of four injections. The compound’s pharmacokinetics (movement in the body ), and pharmacodynamics (effect on the body) are being assessed. Clinical improvement are being evaluated using the unified Huntington’s disease rating scale (UHDRS). The clinical features and course of the disease are assessed using the short problems behavior assessment (PBA-s) and a psychiatric assessment, as well as magnetic resonance imaging (MRI) of the brain.

Topline results from the study showed that WVE-120102 was generally well tolerated. Compared to placebo, patients treated with WVE-120102 also showed a 12.4% decrease in the faulty form of the huntingtin protein in their cerebrospinal fluid while not showing a reduction in total huntingtin protein. Based on the results, which indicated a dose-response at the higher concentrations, the company has added a fifth, 32 mg treatment group to the four (2, 4, 8, or 16 mg) groups that were studied in the topline analysis. By the end of December 2019, 44 patients (31 treated with WVE-120102 and 13 with placebo) had received the four injections but only data from 39 (27 treated with WVE-120102 and 12 with placebo) was available by the cutoff period for the topline results. The study is expected to be completed in December 2020.

 

Last updated: Jan. 16, 2020

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