Adverse events were balanced across treatment and placebo groups, with no observed treatment-associated elevations in cerebrospinal fluid white blood cell counts or protein.
In an update to the ongoing phase 1b/2a FOCUS-C9 trial (NCT04931862), investigators observed potent, durable reductions of poly-GP dipeptide repeat proteins in cerebrospinal fluid (CSF) following treatment with low, single doses of investigational agent WVE-004 (Wave Life Sciences). Poly-GP is a key biomarker of C9orf72-associated amyotrophic lateral sclerosis (C9-ALS) and frontotemporal dementia (C9-FTD).1
All active treatment groups (10 mg: n = 2; 30 mg: n = 4; 60 mg: n = 3) had reductions of poly-GP, with the 30 mg group showing a statistically significant 34% reduction in poly-GP at day 85 (P = .11) compared with placebo. Notably, none of the patients in the 60-mg group had reached that time point when analysis was conducted. The company also announced there is an ongoing study of a multidose cohort at 10 mg, and additional single and multidose data are expected throughout 2022.
"ALS and FTD are serious, life-threatening disorders where advances in disease-modifying therapeutics have been extremely limited. While early, these data are encouraging and open an opportunity to target the disease at the RNA level," Merit Cudkowicz, MD, MSc, director, Sean M. Healey & AMG Center for ALS, chief of neurology, Massachusetts General Hospital, and chair of the FOCUS-C9 Clinical Advisory Committee, said in a statement.1 "Additionally, it is encouraging to see the benefits of the study’s adaptive design, where this early analysis has already helped narrow the doses being explored and enabled more precise, real-time exploration of dose response and optimization."
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Adverse events (AEs), mostly mild or moderate in severity, were balanced across treatment groups and placebo, with no treatment-associated elevations in CSF white blood cells counts or protein, and no other notable abnormalities observed. Serious AEs, documented in 4 patients, including 1 treated with placebo, were either related to ALS or administration (n = 3) or study drug (n = 1).
Because there was no plateau effect observed in poly-GP reduction in the 30-mg single-dose cohort, the company plans to extend the observation from approximately 3 to 6 months, specifically to identify the maximum reduction and duration of effect. Based on the durability and potency observed in the 30-mg cohort, the trial was adapted to include additional patients receiving 20-mg and 30-mg single doses of WVE-004.
In exploratory analyses, investigators observed no meaningful changes in clinical outcomes in the 30-mg and 60-mg single-dose cohorts despite elevated CSF neurofilament light (NfL) levels. The company did note, however, that the dataset and duration were not sufficient to assess clinical effects, and that exploratory assessments will continue throughout the single and multidose phases of the trial.
"FOCUS-C9 was designed to deliver an early indication of target engagement so that we could rapidly optimize the dose and move toward the next stage of development. Based on our preclinical PK/PD modeling, we expected that relatively low doses would engage target; however, seeing this level of poly-GP knockdown 3 months after a single 30-mg dose exceeded our expectations and we expect poly-GP to reduce further with repeat administrations," Michael Panzara, MD, MPH, chief medical officer, and head of Therapeutics and Discovery and Development, Wave Life Sciences, said in a statement. "The next step is to identify a regimen that maximizes knockdown with repeat dosing, while potentially enabling quarterly or less frequent dosing."1
Dosing initiation for FOCUS-C9 was announced in August 2021, with the trial anticipated to enroll 50 participants. WVE-004, a stereopure antisense oligonucleotide designed to target variants containing G4C2, is expected to have dose escalation and dosing frequency dependent on analysis from an independent safety monitoring board. G4C2 is a hexanucleotide repeat expansion associated with the C9orf72 gene, one of the most common genetic causes of ALS and FTD. expansion of G4C2 in C9orf72 may be the cause of increased repeat-containing RNA transcripts and abnormally translated dipeptide repeat proteins (DPRs), further leading to neurotoxicity and insufficient C9orf72 protein levels.2
In preclinical animal trials, intracerebroventricular doses of WVE-004 showed a decrease in repeat-containing RNA transcripts in the spinal cord and cortex. Specifically, investigators observed a 90% decrease in DRPs in the spinal cord and an 80% decrease of DRPs in the cortex during the preclinical phase. C9orf72 protein levels remain relatively unchanged; however, investigators found that reductions in DPRs persisted for at least 6 months.
Following the first patients being dosed, Cudkowicz sat down with NeurologyLive® to discuss the design of the trial, what makes it unique, and the potential for clinical outcomes. Watch below as she provided commentary on the trials adaptive, basket design.
1. Wave Life Sciences announces positive update to ongoing phase 1b/2a FOCUS-C9 study driven by potent, durable reductions of poly(GP) with low, single doses of WVE-004. News release. Wave Life Sciences. April 4, 2022. Accessed April 11, 2022. https://www.biospace.com/article/releases/wave-life-sciences-announces-positive-update-to-ongoing-phase-1b-2a-focus-c9-study-driven-by-potent-durable-reductions-of-poly-gp-with-low-single-doses-of-wve-004/
2. Wave Life Sciences announces initiation of dosing in phase 1b/2a FOCUS-C9 clinical trial of WVE-004 in amyotrophic lateral sclerosis and frontotemporal dementia. News release. July 20, 2021. Accessed April 11, 2022. https://www.globenewswire.com/news-release/2021/07/20/2265597/0/en/Wave-Life-Sciences-Announces-Initiation-of-Dosing-in-Phase-1b-2a-FOCUS-C9-Clinical-Trial-of-WVE-004-in-Amyotrophic-Lateral-Sclerosis-and-Frontotemporal-Dementia.html