AC Immune's brain-penetrant NLRP3 inhibitor ACI-19764 shows safety and CSF exposure in first-in-human study
核心洞察
AC Immune's oral NLRP3 (搜索) inflammasome inhibitor ACI-19764 was safe and well tolerated across single and multiple ascending dose cohorts in a first-in-human Phase I study.
Cerebrospinal fluid penetration was confirmed, supporting the molecule's intended use across neurodegenerative diseases including Alzheimer's and Parkinson's disease (搜索).
Serum half-life exceeded 30 hours, with daily doses of 10 mg or below achieving plasma concentrations above the IC90, and blinded data indicated dose-dependent inhibition of IL-1β (搜索) release.
AC Immune SA (Nasdaq: ACIU) reported that its oral NLRP3 (搜索) inflammasome inhibitor ACI-19764 was safe and well tolerated across single and multiple ascending dose cohorts in a first-in-human Phase I study, with cerebrospinal fluid (CSF) penetration confirmed — a finding that supports the molecule's intended use in neurological disease.
ACI-19764 is being developed as a brain-penetrant NLRP3 (搜索) inhibitor for potential use across neurodegenerative diseases including Alzheimer's and Parkinson's disease (搜索), rather than for a single indication at this stage. The cardiovascular-risk Phase Ib cohort provides an earlier opportunity to establish whether NLRP3 inhibition produces measurable anti-inflammatory effects in patients before the program advances into neurological efficacy studies.
Trial Design and Safety Findings
The Phase I/Ib trial (NCT07463196) is a single-center, double-blind, randomized, placebo-controlled study enrolling up to 78 healthy participants in Europe, with primary endpoints of safety, tolerability, pharmacokinetics (PK), and pharmacodynamics.
Preliminary data showed no serious adverse events and no treatment withdrawals across doses up to 20 mg per day in the single ascending dose cohorts. Serum half-life exceeded 30 hours, and daily doses of 10 mg or below achieved plasma concentrations above the IC90. A blinded review of whole blood assay data indicated dose-dependent inhibition of IL-1β (搜索) release, consistent with on-target NLRP3 (搜索) engagement, though causal attribution to treatment cannot be drawn from blinded data.
Pharmacokinetics and Brain Penetration
The Lausanne, Switzerland-based company said CSF penetration was confirmed, a prerequisite for any central nervous system application. Based on the PK profile, AC Immune said it expects the therapeutic dose to be 10 mg or below once daily.
ACI-19764 is an orally available, brain-penetrant, small molecule drug candidate that specifically inhibits the NLRP3 (搜索) inflammasome. It has shown high potency in vitro, demonstrated by downstream inhibition of IL-1β (搜索) production by human macrophages and human whole blood with an IC50 in the range of 2–20.5 nM.
Phase Ib Expansion and Upcoming Data
The trial has now expanded into a Phase Ib cohort enrolling patients with cardiovascular disease risk, defined by elevated high-sensitivity C-reactive protein (hsCRP) combined with type 2 diabetes and/or obesity. Initial hsCRP data from this cohort — intended to provide early evidence of anti-inflammatory activity in a disease-relevant population — are expected before the end of 2026, with full Phase I/Ib results anticipated in H1 2027.
Mechanism and Preclinical Evidence
ACI-19764 inhibits the NLRP3 (搜索) inflammasome, an intracellular multiprotein complex that drives production of pro-inflammatory cytokines including IL-1β (搜索) and IL-18. In preclinical models, the compound significantly reduced microglial activation and astrogliosis, including in experimental autoimmune encephalitis and chronic lipopolysaccharide-induced CNS inflammation. Specifically, ACI-19764 statistically significantly inhibited neuroinflammation in vivo through reduced activation of Iba1+ microglial cells and GFAP+ astrocytes.
Competitive Landscape
The NLRP3 (搜索) inflammasome has emerged as a drug target across neurological, cardiovascular, and inflammatory diseases, with several oral inhibitors now in clinical development. ACI-19764 is among a group of newer candidates designed for CNS exposure, reflecting growing interest in suppressing NLRP3-driven neuroinflammation in diseases including Alzheimer's and Parkinson's. No direct NLRP3 inhibitor has yet received regulatory approval.
Martin Zügel, interim CEO of AC Immune SA, commented: "This first-in-human data for ACI-19764 is encouraging, and represents not only an important milestone for this programme, but also the wider clinical momentum of our wholly-owned programmes."
AC Immune has a growing focus on its wholly owned proprietary clinical-stage programmes, including ACI-7104, an active immunotherapy targeting α-synuclein (α-syn) in Parkinson's disease (搜索), and ACI-19764, a small molecule inhibitor of the NLRP3 (搜索) inflammasome.