An antisense oligonucleotide or ASO, WVE-120101 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.
WVE-120101 was being tested in clinical trials parallel to its companion ASO, WVE-120102, whose development was also discontinued.
How WVE-120101 works
Huntington’s disease is caused by mutations in the huntingtin (HTT) gene, which provides the instructions for making the Huntingtin protein. While Huntingtin’s function remains largely unclear, the protein is thought to play an important role in the proper function of nerve cells.
HTT mutations result in the production of an abnormal, longer-than-normal Huntingtin protein, or mutant huntingtin (mHTT), which is cut into small pieces that accumulate and bind together inside nerve cells and form toxic aggregates. It is thought that these toxic clumps disrupt the function of nerve cells and eventually cause their death, leading to the symptoms of Huntington’s disease.
Every person carries 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-120101 was designed to prevent the production of faulty Huntingtin protein by specifically targeting the mutant mRNA copy of the HTT gene, while not affecting HTT’s healthy mRNA molecule. This was accomplished by the recognition of a specific mutation, rs362307, present in about half of all Huntington’s patients, meaning that the therapy was designed to treat patients carrying that mutation.
WVE-120101 in clinical trials
A Wave-sponsored Phase 1/2 clinical trial, called PRECISION-HD1 (NCT03225833), evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of WVE-120101 in 61 adults, 25 to 65 years old, with early manifest Huntington’s due to the rs362307 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-120101 (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 evidence suggesting dose-dependent effects with the first four similar doses of WVE-120102 in a separate Phase 1/2 trial (NCT03225846) called PRECISION-HD2.
In the first part of PRECISION-HD1, 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.
Participants completing the trial could enter an open label extension study, in which all would receive the therapy for a longer period of time.
PRECISION-HD1’s data, for 51 participants who received one of the first four doses of WVE-120101 or a placebo, were announced in March 2021. They showed that the treatment did not result in a significant drop in the levels of mHTT protein in patients’ cerebrospinal fluid, compared with a placebo. The cerebrospinal fluid is the liquid that surrounds the brain and spinal cord. In addition, no dose-dependent effect was observed.
The therapy was generally well-tolerated, with most adverse events being mild or moderate in intensity. The most commonly reported adverse events included headache, procedure-related pain, dizziness, back pain, falls, and viral upper respiratory infection. No serious adverse events were deemed related to treatment across all doses.
Dosing in the group of patients assigned to receive 32 mg of WVE-120101 is complete, and Wave expects to conclude the analysis of these data by mid-2021.
Similar disappointing results were reported for WVE-120102, up to and including the 32 mg dose, in PRECISION-HD2, as well as evidence that additional dose escalation was unlikely to provide treatment exposure needed for robust depletion of mHTT.
As such, Wave decided to stop the development of WVE-120101 and WVE-120102.
Last updated: May 17, 2021
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