An antisense oligonucleotide or ASO, WVE-120102 was being investigated as a potential disease-modifying therapy for Huntington’s. ASOs are molecules designed to target the messenger RNAs (mRNA), the intermediate molecule derived from DNA that guides protein production.
The therapy was being tested in clinical trials parallel to its companion ASO, WVE-120101, whose development also was discontinued.
How WVE-120102 works
Huntington’s is caused by a genetic mutation in the huntingtin (HTT) gene that contains the instructions for making the Huntingtin protein. The protein’s exact function is not known, but it is thought to be essential in maintaining the health of nerve cells.
The mutation causes the body to produce an abnormal form of the protein, or mutant huntingtin (mHTT), which is cut into small fragments that aggregate, or clump up, and then accumulate to toxic levels inside nerve cells. As the toxic clumps accumulate, they cause brain cells to die, leading to the cognitive, movement, and psychiatric impairment associated with Huntington’s.
People generally carry two copies of a gene, one inherited from the mother and the other from the father. Typically, Huntington’s patients have one mutated copy of HTT and a healthy copy of the gene, meaning that they produce both the normal and abnormal forms of Huntingtin.
WVE-120102 works by specifically targeting the mutant mRNA copy of the HTT gene. This specific targeting prevents the production of faulty Huntingtin protein, while leaving the production of the healthy protein untouched. This is accomplished by the recognition of a specific mutation, rs362331, present in about 40% of all Huntington’s patients, meaning that the therapy was designed to treat patients carrying that mutation.
WVE-12012 in clinical trials
Wave launched an international Phase 1/2 clinical trial, called PRECISION-HD2 (NCT03225846), in 2017. The trial evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of WVE-120102 in 88 adults, ages 25–65, with early Huntington’s due to the rs362331 mutation. Pharmacokinetics refers to the therapy’s movement into, through, and out of the body, while pharmacodynamics assesses its effects on the body.
Participants were randomly assigned to receive one of five doses of WVE-120102 — 2, 4, 8, 16, or 32 mg — or a placebo directly into the spinal canal, the cavity that encloses the spinal cord. The higher dose group (32 mg) was added at a later stage following preliminary findings suggesting the presence of dose-dependent effects with the first four doses.
In the trial’s first part, patients received a single injection into the spinal canal and underwent a washout period of at least eight weeks before entering the second part, in which they were given three monthly injections for a total of four injections.
PRECISION-HD2’s top-line results, for most participants who received one of the first four doses of WVE-120102 or a placebo, showed that the therapy was generally well-tolerated across doses. An analysis comparing all of the WVE-120102-treated patients to those given a placebo found a significant reduction of 12.4% in the levels of mHTT protein in the cerebrospinal fluid, or the liquid that surrounds the brain and spinal cord.
The researchers also found evidence suggesting a dose-dependent effect on mHTT reduction, supporting the addition of the fifth, 32 mg treatment group.
The trial’s final data, including all participants and all five doses, were announced in March 2021. The results showed that single or multiple doses of WVE-120102 were not associated with a significant drop in mHTT levels compared with a placebo. Also, there was no strong evidence of a dose response across tested doses.
The therapy was generally safe, with most adverse events being mild or moderate in intensity. Most commonly reported adverse events included headache, injection-associated pain, back pain, falls, viral upper respiratory tract infection, dizziness, and post-lumbar puncture syndrome. There was an increase in the rate of serious adverse events, some deemed related to treatment, in the 32 mg group, compared with the lower dose groups.
Participants completing PRECISION-HD2 could enter an open label extension study, in which all would receive the therapy for a longer period of time. Results from the extension trial showed modest reductions in mHTT after a mean of eight monthly doses, but effects were inconsistent during the trial. Pharmacokinetic analyses suggested that additional dose escalation was unlikely to provide the WVE-120102 exposure needed for robust depletion of mHTT.
Due to the lack of consistent and significant reductions in mHTT and the pharmacokinetic projections in these trials, Wave decided to stop the development of WVE-120102.
Last updated: May 12, 2021
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