Wave Life Sciences' Antisense Oligonucleotide WVE-003 Demonstrates Ability to Lower Mutant Huntingtin in Phase 1b/2a Trial


The placebo-controlled multidose portion of the SELECT-HD trial included 23 patients with Huntington Disease in total.

Wave Life Science’s allele-selective antisense oligonucleotide (ASO) WVE-003 has demonstrated the ability to reduce levels of mutant huntingtin (mHTT) protein in the cerebrospinal fluid of patients with Huntington disease (HD) while preserving wild-type huntingtin (wtHTT) protein levels, according to data from the multidose portion of the phase 1b/2a SELECT-HD clinical trial (NCT05032196).1

SELECT-HD's multidose portion treated 16 patients with HD with 30mg doses of WVE-003 and 7 patients with placebo, with each being delivered intrathecally every 8 weeks with a follow-up period of 12 weeks. At 8 weeks after the last dose (24 weeks on-study), patients treated with WVE-003 showed a mean reduction of mHTT in the CSF of 46% compared to the placebo group (P = .0007). At 12 weeks after the last dose (28 weeks on-study), patients treated with WVE-003 showed a mean reduction of mHTT in the CSF of 44% compared to the placebo group (P = .0002). Wave noted that these results favor a quarterly or less frequent approach to dosing for WVE-003. Furthermore, Wave stated that preservation of wtHTT protein was observed in patients who received WVE-003 throughout their 28 weeks on-study and that wtHTT protein levels significantly increased among this group in comparison to the placebo group. The company additionally noted that neurofilament light protein levels in patients who received WVE-003 either remained in the range of those treated with the placebo or increased above this range and then returned to it later on. MRI assessments were also carried out and showed that the decrease in mHTT levels correlated with a slowing of caudate atrophy (R = -0.50; P = 0.047).

“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,” Ralf Reilmann, MD, founder of the George-Huntington Institute in Muenster, Germany, and the primary investigator and a member of the advisory committee for SELECT-HD, 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.”

In terms of safety, Wave characterized WVE-003 as “generally safe and well-tolerated". There were no serious adverse events among the treated patients and it was additionally noted that patients’ ventricular volume was congruent with natural history data.

“With these results, we have delivered the first-ever clinical demonstration of allele-selective silencing in any disease target,” Paul Bolno, MD, MBA, the president and CEO at Wave Life Sciences, added to the statement.1 “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. 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.”

WVE-003 is not the only advanced therapeutic currently in development for the treatment of HD. Just last month, uniQure’s AMT-130, an adeno-associated virus vector-based gene therapy that delivers an artificial micro-RNA designed to silence the huntingtin gene and therefore inhibit the production of mHTT, was granted regenerative medicine advanced therapeutic designation by the FDA.2 In December 2023, uniQure shared data from the program, which includes a phase 1/2 clinical trial (NCT04120493) being carried out in the United States and a separate phase 1/2 clinical trial (NCT05243017) being conducted in several European countries.3 Treated participants experienced some dose-dependent clinical benefits, with improvements in neurological function in the high dose cohort and preserved neurological function in the low dose cohort.

1. Wave Life Sciences Announces Positive Results from Phase 1b/2a SELECT-HD Trial with First Clinical Demonstration of Allele-Selective Mutant Huntingtin Lowering in Huntington’s Disease. News release. Wave Life Sciences Ltd. June 25, 2024. Accessed July 1, 2024. https://ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-announces-positive-results-phase-1b2a-select
2. uniQure Receives FDA Regenerative Medicine Advanced Therapy (RMAT) Designation for Investigational Gene Therapy AMT-130 in Huntington’s Disease. News release. June 3, 2024. Accessed July 1, 2024. https://www.globenewswire.com/news-release/2024/06/03/2892124/0/en/uniQure-Receives-FDA-Regenerative-Medicine-Advanced-Therapy-RMAT-Designation-for-Investigational-Gene-Therapy-AMT-130-in-Huntington-s-Disease.html
3. uniQure Announces Update on Phase I/II Clinical Trials of AMT-130 Gene Therapy for the Treatment of Huntington’s Disease. News release. UniQure. December 19, 2023. Accessed July 1, 2024. https://www.globenewswire.com/news-release/2023/12/19/2798425/0/en/uniQure-Announces-Update-on-Phase-I-II-Clinical-Trials-of-AMT-130-Gene-Therapy-for-the-Treatment-of-Huntington-s-Disease.html
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