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WVE-003 Demonstrates Huntington-Specific Biomarker Changes in Phase 1b/2a Study

After demonstrating a positive reduction of mutant huntingtin protein in preclinical studies, WVE-003 continued to show similar results when assessed in 30- and 60-mg doses.

Newly announced findings from the phase 1b/2a SELECT-HD trial (NCT05032196) of WVE-003 (Wave Life Sciences), an investigational agent for Huntington disease (HD), showed that the treatment reduced HD-specific mutant huntingtin (mHTT) protein in cerebrospinal fluid (CSF), as well as preserved wild-type huntingtin (wtHTT) protein.1

All told, WVE-003, a stereopure antisense oligonucleotide, was well-tolerated and safe for doses up to 90 mg. For those who received 30- and 60-mg single doses of the agent, pooled analysis showed a 22% median reduction in CSF mHTT from baseline to day 85, and an even greater difference in mean reduction (35%) when compared with placebo. Wave noted that additional single dose biomarker and safety data are expected in the first half of 2023.

"Based on these initial data, it appears that our preclinical data for WVE-003 are translating in the clinic,” Michael Panzara, MD, MPH, chief medical officer, and head, Therapeutics Discovery and Development, Wave Life Sciences, said in a statement.1 "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."

SELECT-HD, a multicenter, randomized, placebo-controlled trial, included patients with early-stage HD who carry SNP3, a single nucleotide polymorphism on the mHTT allele, in association with their cytosine-adenine guanine (CAG) expression. Since it was first initiated in September 2021, 18 participants with HD have been dosed with either 30 mg (n = 4), 60 mg (n = 4), 90 mg (n = 4) of WVE-003, or placebo (n = 6). It is expected to enroll approximately 36 patients, and is designed to be adaptive, with dose escalation and dosing frequency being guided by an independent committee.

Although biomarker analysis was only available for the 30- and 60-mg cohorts, there were no serious adverse events (AEs) nor discontinuations across all treatment groups. Additionally, AEs were similar between active drug and placebo groups, all of which were mild to moderate in intensity. From baseline to day 85, there were no dose-dependent response in CSF mHTT, and thus data from the 30- and 60-mg groups were pooled together.

"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," Ralf Reilmann, MD, founder, George-Huntington Institute, and member of the SELECT-HD Clinical Advisory and Dose Escalation Committees, said in a statement.1 "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."

He added, "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."

Findings from the analysis also showed that treatment with agent in 30- or 60-mg doses preserved wtHTT protein, which appeared consistent with allele-selectivity. Additionally, some participants showed increases in neurofilament light, which Wave noted will be monitored as the trial advances. Overall, patients showed no clinically meaningful changes in CSF white blood cell counts or protein that would indicate inflammation in the central nervous system, nor did they show meaningful changes in clinical outcome measures, although the dataset and duration were not sufficient to assess clinical effects.

"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," Paul Bolno, MD, MBA, president and CEO, Wave Life Sciences, said in a statement.1 "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."

REFERENCES
1. 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. News release. Wave Life Sciences. September 20, 2022. Accessed September 20, 2022. https://www.globenewswire.com/news-release/2022/09/20/2519092/0/en/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-Diseas.html