Robust, sustained reductions in key pharmacodynamic biomarker were observed; however, this did not lead to functional benefits on any of the scales used in the trial.
Despite hitting its target engagement, newly announced topline findings from the phase 1b/2a FOCUS-C9 study (NCT04931862) showed that treatment with WVE-004 (Wave Life Sciences) did not result in clinical benefit after 24 weeks, prompting Wave to discontinue its development. The company remains on track to share data later this year from its phase 1b/2a SELECT-HD study (NCT05032196) assessing its investigational agent WVE-003 in patients with Huntington disease.
FOCUS-C9 was a global, double-blind, placebo-controlled trial that assessed the safety and tolerability of single- and multiple-ascending doses of WVE-004, an antisense oligonucleotide, in patients with C9orf72-associated amyotrophic lateral sclerosis (C9-ALS) and frontotemporal dementia (FTD). Over a 24-week treatment period, investigators observed maximal mean reductions of 48% (P <.0001) and 50% (P = .0001) in poly(GP), a pharmacodynamic biomarker, in the WVE-004 groups dosed every 12 (Q12W; n = 8) or 4 weeks (Q4W; n = 5).
Poly(GP) is a biomarker that indicates lowering of C9orf72 hexanucleotide repeat expansion (G4C2) transcripts, which are hypothesized to contribute to pathogenesis in C9-ALS and FTD. Although target engagement was reached, this was not associated with stabilization or improvement in functional outcomes. In fact, in comparison with placebo, there was no benefit observed on ALS Functional Rating Scale-Revised, a common measure used in ALS clinical trials.
"Following our initial positive single dose data last year, we advanced WVE-004 with the hope that its potency and differentiated pharmacology may deliver a better result than C9orf72-targeting oligonucleotides discontinued by others in the field. While we again saw substantial reductions of poly(GP) with multiple doses, we are deeply disappointed that we were not able to see any evidence of potential benefits that would be expected to drive meaningful outcomes for these patients," Paul Bolno, MD, MBA, president and chief executive officer, Wave Life Sciences, said in a statement.
The trial originally included single doses of 10, 30, or 60 mg of WVE-004 or placebo, and was further expanded to include a 20 mg single dose cohort based on potency and durability assessed in the single dose cohorts. Additionally, those findings led to the 10 mg dose being advanced as the dose used for the repeat dose phase, administered every 12 or 4 weeks. In the 20 mg single dose cohort, the mean maximal poly(GP) reduction from baseline was 51% (95% CI, 0.29-0.67; P = .0006) at week 24.
Throughout the study, WVE-004 was generally safe and well-tolerated, with documented adverse events (AEs) that were related to disease progression and intrathecal administration. Among WVE-004-treated individuals, all serious AEs were associated with disease progression except for 1 that was procedure related and another in the 60 mg dose cohort that was considered related to the study drug. Notably, there were no AEs indicative of antisense oligonucleotide class effects, and no evidence of inflammation in the cerebrospinal fluid (CSF), as indicated by no clinically meaningful changes in CSF white blood cell count or protein.
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"C9-ALS/FTD is complex and made all the more challenging by the absence of a clinically validated biomarker. Our hope is that these data can help advance future research, and we are committed to sharing results with the community at an upcoming medical congress. On behalf of everyone at Wave, I wish to sincerely thank the participants, their families, the clinical sites, and our study advisory committees for their participation and support."
On exploratory biomarker analyses, neurofilament light (NfL) elevations were observed in the WVE-004 20 mg single dose cohort and the 10 mg Q4W cohort, while the 10 mg Q12W and placebo cohorts had overlapping confidence intervals. Additionally, investigators observed no correlation between CSF NfL increases and ALSFRS-R change. In the Q12W cohort, there was no statistically significant difference in ALSFRS-R mean change between WVE-004 and placebo at any time point.
For patients with FTD, WVE-004 continued to show a lack of functional benefit, as explained through the Dementia Staging Instrument plus National Alzheimer’s Coordinating Center (NACC) frontotemporal lobar degeneration Behavior and Language domains (CDR plus NACC FTLD). Furthermore, the significant reductions seen in poly(GP) did not associate with improvement on ALSFRS-R and CDR plus NACC FTLD.
"These data do reinforce that our preclinical data on target engagement and pharmacology are translating in the clinic," Bolno added. "Looking forward, our lead programs in Huntington’s disease, Duchenne muscular dystrophy and Alpha-1 antitrypsin deficiency are designed to leverage biomarkers correlated with functional outcomes, making us more confident in the future of these programs and our emerging preclinical pipeline."