SELECT-HD is a Phase 1b/2a global, multicenter, randomized trial to study the investigational drug (WVE-003) in up to 36 adult patients with early-manifest HD who carry a targeted single nucleotide polymorphism (SNP3). SNPs are normal variations in DNA, and the presence of SNP3 enables WVE-003 to specifically target mutant (toxic) huntingtin protein while leaving wild-type (healthy) huntingtin protein relatively intact. The study drug is given as an injection through a thin needle into the spinal canal (lumbar puncture). For every participant that receives the placebo, two participants will receive the active drug. Neither the doctor nor the participant will know whether they have received the active drug or the placebo. The study will measure safety and tolerability, as well as how the medicine moves through and impacts the body. The study uses an adaptive design, which means that there is a committee that reviews the data throughout the trial and decides what the next dose will be and how often the drug should be administered.
What is WVE-003
WVE-003 is a stereopure antisense oligonucleotide designed to target SNP3, a single nucleotide polymorphism in mutant huntingtin (mHTT), thereby selectively lowering mHTT protein and relatively sparing healthy, wild-type huntingtin protein.
What is an ASO (Antisense Oligonucleotide)
An antisense oligonucleotide is a small piece of RNA and DNA that recognizes and binds to RNA that exists in the cell and blocks it from producing protein. In our cells, DNA (our genes) must be converted into RNA to make proteins. Proteins are the work horses of our cells. In people with the mutated huntingtin gene (mHTT), the Wave ASO is designed to reduce the production of the RNA that tells cells to produce mHTT protein.
What is a SNP
SNPs, or single nucleotide polymorphisms, are a common type of genetic variation that normally occur in all humans but may also act as biological markers to aid in locating genes associated with a particular disease. Previous HD research has identified multiple SNPs that are associated with the disease-causing expanded cytosine-adenine-guanine (CAG) repeat that is present in all HD patients and results in the production of mutant huntingtin protein.
SNPs are a kind of 'genetic fingerprint' in DNA. They help recognize specific points of a gene and its RNA. It is as if the SNPs represent a pin on a map (in this case the mHTT) that allows the drug to identify and target, helping the drug eliminate the defective protein instead of the healthy one.
An allele-selective approach
Wave’s approach to HD and the WVE-003 program is guided by the recognition that, in addition to a gain of mutant HTT (toxic) protein, people with this disease have lost one copy of the wild-type HTT (healthy) allele, leaving them with a smaller protective reservoir of healthy protein than unaffected individuals. A growing body of scientific evidence suggests that preserving as much of this essential wild-type HTT protein as possible, when in the setting of stress from the toxic mHTT protein, may be important for favorable clinical outcomes.
What makes WVE-003 different from WVE-120101 and WVE-120102
WVE-003 reflects the many learnings gained from the company's first-generation clinical programs as well as the evolution of the chemistry we use to make our drugs. Wave now incorporates a novel chemistry called PN backbone chemistry, which improves the strength of the molecule, the length of time and distribution of the drug in the body in animal studies. In preclinical studies, WVE-003 had a dose-dependent effect on mutant HTT expression and selectively decreased mutant HTT RNA in cultured brain cells (neurons), as well as in the brain of animal models for HD. Data from several preclinical models evaluating how WVE-003 moves through a living animal over time and effects the expression of mutant HTT have informed the starting dose for the SELECT-HD trial.
Main inclusion criteria
• Presence of SNP3 on the mHTT mRNA (same copy as CAG repeat expansion)
• Ambulatory, male or female patients aged ≥25 to ≤60 years
• Presence of motor features of HD, defined as Unified Huntington’s Disease Rating Scale (UHDRS) Diagnostic Confidence Score = 4
• UHDRS Total Functional Capacity Scores ≥9 and ≤13
The study drug is given as an injection through a thin needle into the spinal canal (lumbar puncture). The SELECT-HD study is adaptive, so Wave will be changing the dose and the dosing frequency based on information collected during the course of the study.
Number of participants and locations
The study involves 36 participants, with sites actively recruiting in Australia, Germany, Poland and the UK. Additional sites will be added to clinicaltrials.gov when activated.
Initiated in 2021, ongoing.
The phase 1b / 2a will be completed successfully if ...
The molecule is safely tolerated by patients and leads to a decrease in the amount of mutant HTT protein detected in the CSF (cerebrospinal fluid).