Wave Life Sciences Announces Positive Update from Phase 1b/2a SELECT-HD Trial with Initial Results Indicating Allele-Selective Target Engagement with WVE-003 in Huntington's Disease
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
Wave to host investor conference call and webcast at 8:30 a.m. ET today
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:
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 inthe 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.”
Investor Conference Call and Webcast
About the SELECT-HD Clinical Trial
About Huntington’s Disease
Approximately 30,000 people in the United States have symptomatic HD and more than 200,000 others are at risk for developing the disease. There are currently no approved disease-modifying therapies available.
About Wave Life Sciences
HD Community Contact: