After back-to-back failures in 2021, Wave Life Sciences has finally aced a Phase Ib/IIa Huntington’s disease trial and is looking to a potential accelerated approval for its investigational antisense oligonucleotide.
Wave Life Sciences on Tuesday announced that its investigational antisense oligonucleotide WVE-003 significantly and selectively reduced levels of the mutant huntingtin protein in a Phase Ib/IIa trial of Huntington’s disease.
At 24 weeks, which corresponds to eight weeks after the final dose, WVE-003 led to a 46% drop in mutant huntingtin (HTT) levels in patients’ cerebrospinal fluid (CSF) versus placebo. This effect persisted until 28 weeks or 12 weeks after the last dose, with the investigational treatment lowering mutant HTT levels by 44% compared with placebo.
Meanwhile, WVE-003 preserved wildtype HTT levels throughout the 28-week assessment period, validating its allele-selective silencing action. Wave also detected statistically significant increases in wildtype HTT protein levels versus placebo.
In Huntington’s disease, mutant versions of the HTT protein accumulate in the brain, triggering the progressive loss of neurons and in turn compromising patients’ emotion, movement and cognition. By contrast, wildtype HTT is important for brain health as it supports the normal function of neurons and is crucial to ensure CSF flow in the ventricles, according to Wave.
“With these results, we have delivered the first-ever clinical demonstration of allele-selective silencing in any disease target,” CEO Paul Bolno said in a statement. Selectively targeting the mutant protein could also boost the function of wildtype HTT, which is typically disrupted by the mutant protein.
The Cambridge, Massachusetts-based biotech is now eyeing accelerated approval for WVE-003 and is preparing to discuss the application with regulators.
WVE-003 is a potentially first-in-class allele-selective antisense oligonucleotide that targets single nucleotide polymorphism found on the mutant HTT mRNA. Because this subtle change in mRNA sequence is absent in wildtype HTT, WVE-003 only reduces levels of the mutant protein.
Wave’s Phase Ib/IIa study, dubbed SELECT-HD, also showed that the reduction in mutant HTT was significantly correlated with the slowing of caudate atrophy—or the degradation of a particular region of the brain. Caudate atrophy is a known imaging biomarker of clinical outcomes.
SELECT-HD also found that WVE-003 nominally slowed the decline of motor function in patients, as quantified by the Total Motor Score. However, the study was not powered to assess clinical outcomes.
Huntington’s disease has been a tough target for Wave, which in March 2021 discontinued the development of its two lead antisense candidates after back-to-back Phase Ib/IIa disappointments. Both investigational treatments elicited modest but inconsistent reductions in the mutant HTT protein, while pharmacokinetic modeling suggested that further testing would be moot.
Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.
