WVE-003 Shows Allele-Selective Mutant Huntingtin Reduction in Phase 1b/2a SELECT-HD Trial

Positive results from the phase 1b/2a SELECT-HD trial (NCT05032196) assessing WVE-003 (Wave Life Sciences), an investigational first-in-class, allele-selective antisense oligonucleotide (ASO) for Huntington disease (HD), showed a significant reduction in mutant huntingtin protein (mHTT) and preserved healthy protein huntingtin protein (wtHTT) in patients with HD, with no serious adverse events (AEs).¹

Throughout the 28-week assessment period, investigators observed a significant mHTT protein lowering among patients with HD. At 24 weeks, 8 weeks following the last dose, researchers reported a mean mHTT lowering in cerebrospinal fluid (CSF) of 46% compared with the placebo (P = .0007). At 28 weeks, 12 weeks after last dose, the mean mHTT lowering in CSF was 44% in comparison with placebo (P = .0002), suggesting that quarterly or less frequent dosing may still be an effective approach. Furthermore, researchers also observed that wtHTT protein was preserved in the 28-week assessment period, further validating WVE-003’s impact on allele-selective silencing. The company also reported statistically significant increases in wtHTT protein versus the placebo.

“We are very proud to have demonstrated mHTT lowering of 46%, with preservation of wtHTT, and are encouraged to see these reductions in mHTT significantly correlating with a slowing in caudate atrophy after just 28 weeks. These results represent a significant achievement for Wave, for the oligonucleotide field, and most importantly, for the HD community,” Anne-Marie Li-Kwai-Cheung, MChem, MTOPRA, RAPS, the chief development officer at Wave Life Sciences, said in a statement.¹“Alongside the HD community, we have been working diligently to establish caudate volume as a biomarker for clinical development because of its association with clinical outcomes. We believe these strong data compel a case for accelerated approval for WVE-003, which we plan to discuss with regulators. We would like to express our immense gratitude to the HD community, the study participants, their families, and study site staff for their trust, support, and engagement that have helped us reach this important milestone.”

SELECT-HD is a multicenter, randomized, placebo-controlled clinical trial investigating the safety and tolerability of single and multiple-ascending intrathecal doses of WVE-003 in patients with early-stage HD who carry SNP3 in association with their CAG expansion. In the multidose portion of the 28-week study (n = 23), patients with HD received either every-8-week (Q8W) intrathecal doses of 30 mg WVE-003 (n = 16) or placebo (n = 7), with 12 weeks of follow up.

Top Clinical Takeaways

The SELECT-HD trial demonstrated a significant reduction in mHTT levels in patients treated with WVE-003.
The preservation of healthy wtHTT protein validates the allele-selective silencing approach of WVE-003.
WVE-003 was found to be generally safe and well-tolerated, with no serious adverse events reported.

“Wild-type huntingtin plays such a critical role in the central nervous system, and it’s very exciting to finally have an opportunity to evaluate mHTT lowering in the context of allele-selectivity and to see positive signals emerging,” primary investigator Ralf Reilmann, MD, founder of the George-Huntington Institute, in Muenster, Germany, said in a statement.¹ “Additionally, these data have arrived at an opportune time when the HD community is coalescing around rapid, efficient registrational trial design utilizing sensitive clinical endpoints to detect early treatment effects, and Wave is well positioned to take advantage of this momentum with WVE-003. These data provide hope and a compelling path forward as the community continues to drive toward a long-awaited therapy to treat this devastating disease.”

Additional findings showed that a majority of the WVE-003-treated patients with HD displayed neurofilament light protein (NfL) levels in the placebo range or had NfL levels that increased and returned to the range of the placebo. At 24 weeks, otherwise considered the last MRI assessment, researchers noted that mHTT reduction correlated with the slowing of caudate atrophy (R = -0.50; P = .047), an imaging biomarker predictive of clinical outcomes. Although not powered for clinical outcomes, a slowing of decline in Total Motor Score was reported by investigators for WVE-003 compared with placebo (4.25 mean difference at 24 weeks, P = not significant). Overall, the company noted that WVE-003 was generally safe and well-tolerated among the participants, with no serious AEs. In addition, ventricular volume in treated patients was in line with natural history.

“With these results, we have delivered the first-ever clinical demonstration of allele-selective silencing in any disease target. This was only possible due to the specificity, potency and durability enabled through our PRISM platform and it is validating of more than 10 years of chemistry innovation pioneered at Wave, including PN chemistry and stereochemistry,” Paul Bolno, MD, MBA, the president and chief executive officer at Wave Life Sciences, said in a statement.¹ “The translation of genetic insights and preclinical data in the clinic is also highly encouraging and reinforces the broader value of our pipeline. We are looking forward to our Duchenne muscular dystrophy and Alpha-1 antitrypsin deficiency data this year, the continued advancement of our INHBE program for obesity, and new targets to be shared at R&D Day this Fall, which together will open up a substantial total addressable market for Wave. We are at a very exciting point in Wave’s history as we advance our mission to unlock the broad potential of RNA medicines.”