Preclinical data presented at AHA 2025 show MRT-8102, an oral NEK7-directed molecular glue degrader, selectively degrades NEK7, suppresses NLRP3 inflammasome activation in vitro and in vivo, and blocks pyroptotic membrane permeabilization in human monocyte-derived macrophages while reducing multi-cytokine release. In cholesterol crystal–induced assays tied to atherosclerosis biology, NEK7 degradation was more potent than the small-molecule NLRP3 inhibitor selnoflast. In a mouse peritonitis model, MRT-8102 lowered IL-1β, IL-1α, IL-6, and TNF, and in ex vivo–stimulated whole blood from orally dosed cynomolgus monkeys, it drove near-complete suppression of IL-1β and caspase-1 activity. Initial clinical readouts from an ongoing Phase 1 study in healthy volunteers and participants with elevated cardiovascular risk are planned for the first half of 2026.
The core development is Monte Rosa’s entry of MRT-8102 into the clinic and its positioning of NEK7 degradation as an upstream inflammasome strategy for cardiovascular and cardiometabolic inflammation, including pericarditis and atherosclerosis. The company is using molecular glue chemistry to recruit NEK7 to an E3 ligase for targeted degradation, aiming to modulate the NLRP3/IL-1/IL-6 axis with a once-daily oral small molecule. The AHA poster consolidates cross-species pharmacology, mechanistic data on pyroptosis, and comparative in vitro potency relative to a representative NLRP3 inhibitor.
Strategically, this is an expansion play into cardiovascular inflammation at a time when IL-1 and IL-6 biologics and direct NLRP3 inhibitors are setting the bar. By moving upstream of cytokine blockade and beyond catalytic NLRP3 inhibition, Monte Rosa is betting that removing NEK7 can dampen both cytokine signaling and pyroptotic cell death—potentially translating into broader efficacy and more straightforward combination rules. The choice of an oral degrader also addresses the operational and payer friction associated with chronic injectable biologics in pericarditis and atherosclerosis-adjacent settings. The company’s head-to-head in vitro signal versus selnoflast is intended to frame differentiation within a crowded inflammasome pipeline where small-molecule NLRP3 inhibitors are advancing across gout, heart failure, and neuroinflammation.
For clinical operations, the near-term implications are biomarker-centric. Sites and CROs should expect protocols built around target engagement (quantified NEK7 degradation), ex vivo inflammasome stimulation assays, and downstream cytokine panels alongside standard safety, PK, and hsCRP. Cardiovascular sites without immunology lab capacity will need central-lab partnerships for caspase-1 and IL-1β readouts; imaging-based atherosclerosis endpoints, if pursued, would add MRI/CT infrastructure. If pericarditis is prioritized for early proof-of-concept, enrollment will draw from centers that have used rilonacept and anakinra, with washout and background therapy controls becoming key operational constraints. For sponsors and payers, an oral option that can address multi-cytokine biology could pressure biologic incumbents, but only if human PD and safety cleanly translate.
The next inflection is human target engagement: magnitude and durability of NEK7 degradation in blood and tissues, concordant suppression of IL-1β/caspase-1, and early tolerability in elevated-risk populations. Watch for dose-response and time-to-PD kinetics that support once-daily dosing, along with infection and hepatic signals typical of inflammasome modulation. Program risk centers on translatability from ex vivo and animal models to clinical symptoms, selection of the first patient population (recurrent pericarditis offers faster readouts; atherosclerosis requires imaging or outcomes), and competition from advancing NLRP3 inhibitors and entrenched IL-1/IL-6 biologics. Clarity on Phase 1b/2 design, biomarker gating, and comparator strategy will determine whether MRT-8102 can move quickly from mechanistic promise to a clinically credible cardiovascular anti-inflammatory profile.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
