Wave Life Sciences Announces Positive Update from Phase 1b/2a SELECT-HD Trial

September 20, 2022 at 7:30 AM EDT

Single doses of WVE-003 appear generally safe and well-tolerated CSF mutant huntingtin (mHTT) protein was reduced following single doses of 30 or 60 mg; mean mHTT reduction across both cohorts was 22% (median reduction 30%) from baseline 85 days post-single dose Wild-type huntingtin (wtHTT) protein levels through day 85 appear consistent with allele-selectivity Expanding single dose cohorts to optimize dose level with data expected in 1H 2023 Continued clinical validation of PRISM platform and PN stereochemistry


CAMBRIDGE, Mass., Sept. 20, 2022 (GLOBE NEWSWIRE) -- Wave Life Sciences Ltd. (Nasdaq: WVE), a clinical-stage genetic medicines company committed to delivering life-changing treatments for people battling devastating diseases, today announced a positive update to the ongoing Phase 1b/2a SELECT-HD clinical trial of WVE-003, the company’s clinical candidate for Huntington’s disease (HD). SELECT-HD (NCT05032196) is an adaptive trial designed to rapidly optimize dose level and frequency based on early indicators of target engagement. The trial update announced today is being driven by the observation of reductions in mutant huntingtin (mHTT) protein in cerebrospinal fluid (CSF) after study participants received either a single 30 or 60 mg dose of WVE-003. Additionally, wild-type huntingtin (wtHTT) protein was preserved, which appears consistent with allele-selectivity. “These preliminary data suggest WVE-003 is working as intended: to selectively reduce the toxic mHTT protein while avoiding targeting the healthy, wild-type huntingtin protein, thereby preserving its beneficial effects in the central nervous system,” said Ralf Reilmann, MD, founder of the George-Huntington Institute, Muenster, Germany and member of the SELECT-HD Clinical Advisory and Dose Escalation Committees. “Additionally, I am encouraged by the safety and tolerability data. Taken together, WVE-003 appears to have a unique profile with the potential to overcome prior therapeutic challenges in this field. Furthermore, as a clinician and researcher focused on HD, it is my hope that innovative adaptive trial designs like SELECT-HD become more commonplace to optimize dosing in early proof-of-concept studies. It is also exciting to finally see an assay measuring wtHTT being developed and used successfully in a clinical trial – a long awaited, big step forward for the HD research community. The availability of this assay has potential to significantly increase our understanding of how best to treat this challenging disease.” “Based on these initial data, it appears that our preclinical data for WVE-003 are translating in the clinic,” said Michael Panzara, MD, MPH, Chief Medical Officer and Head of Therapeutics Discovery and Development at Wave Life Sciences. “We are encouraged to see a mean CSF mHTT reduction from baseline of 22% at day 85 after participants received just a single dose of WVE-003, demonstrating a compelling pharmacological profile for individuals with HD. We are grateful to the HD community, including the SELECT-HD participants, study sites and advisors, for their continued partnership and support of this program. We look forward to continuing to expand this study and sharing additional data next year.” Eighteen (18) participants have been dosed in the SELECT-HD trial (30 mg, n=4; 60 mg, n=4; 90 mg, n=4; placebo, n=6). Participants enrolled at 30 mg, 60 mg and placebo had adequate follow-up to day 85 for biomarker analysis. At the time of analysis, none of the participants dosed with 90 mg had reached day 85 so this cohort is not included in the biomarker analysis. Key observations include:

  • Single doses of WVE-003 up to 90 mg appeared generally safe and well-tolerated

  • Adverse events (AEs) were balanced across treatment groups, including placebo, and all were mild to moderate in intensity

  • No serious adverse events (SAEs) were observed

  • No participants discontinued from the study


  • Among participants in the 30 and 60 mg WVE-003 cohorts, the mean reduction in CSF mHTT from baseline was 22% (median reduction 30%) at 85 days following a single dose

  • The difference in the mean reduction in CSF mHTT compared to placebo was 35% at 85 days post-single dose

  • For these analyses, the 30 and 60 mg single dose cohorts were pooled as there was no apparent dose response between these two cohorts. Wave will continue to evaluate dose response in the expanded single dose cohorts


  • In the 30 and 60 mg cohorts, wtHTT protein was preserved, which appears consistent with allele-selectivity

  • Increases in neurofilament light chain (NfL) from baseline were observed in some participants. Wave will continue to monitor trends in NfL as SELECT-HD advances

  • There were no clinically meaningful elevations in CSF white blood cell counts or protein that would indicate inflammation in the CNS

  • There were no meaningful changes in clinical outcome measures, although the dataset and duration were not sufficient to assess clinical effects

Based on these data, Wave is adapting the SELECT-HD clinical trial to expand the single dose cohorts and will also continue advancing the 90 mg cohort for biomarker analysis at day 85. Additional single dose biomarker and safety data are expected in the first half of 2023. Wave’s approach to HD is guided by the recognition that, in addition to a gain of function of the mHTT protein, people with this disease have lost one copy of the wtHTT allele, leaving them with a smaller protective reservoir of healthy protein than unaffected individuals. wtHTT protein is critical for neuronal function and suppression may have detrimental long-term consequences. WVE-003 is the only allele-selective HD candidate in clinical development. It is designed to preferentially lower mHTT by targeting a single nucleotide polymorphism (SNP3) that appears on the mHTT allele and is not present on the wtHTT allele. Based upon scientific literature, it is estimated that approximately 40 percent of adults with HD carry SNP3 in association with the HD mutation. “These SELECT-HD data are the first to support the feasibility of allele-selective mHTT knockdown in the clinic – a precision approach enabled by our PRISM discovery and drug development platform,” said Paul Bolno, MD, MBA, President and Chief Executive Officer at Wave Life Sciences. “SELECT-HD is the second clinical trial this year to demonstrate clinical translation of Wave’s PN backbone chemistry modifications, as well as the impact of rational design through control of stereochemistry, increasing our conviction in our platform. We look forward to sharing data from our splicing clinical program in muscle – WVE-N531 for exon 53 skipping in Duchenne muscular dystrophy – in the fourth quarter of 2022.” About the SELECT-HD Clinical Trial The SELECT-HD trial is a global, multicenter, randomized, double-blind, placebo-controlled Phase 1b/2a clinical trial to assess the safety and tolerability of single- and multiple-ascending intrathecal doses of WVE-003 in people with a confirmed diagnosis of HD who are in the early stages of the disease and carry SNP3 in association with their cytosine-adenine-guanine (CAG) expansion. Additional objectives include assessing the plasma pharmacokinetic profile and exposure in the cerebrospinal fluid, as well as exploratory pharmacodynamic (mHTT, wtHTT and neurofilament light chain) and clinical endpoints. The SELECT-HD trial is expected to enroll approximately 36 participants. It is designed to be adaptive, with dose escalation and dosing frequency being guided by an independent committee.

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