A new analysis published in Nature Biotechnology adds an unexpected dimension to the clinical profile of rentosertib, the AI-designed TNIK inhibitor from Insilico Medicine (HKEX: 3696) now in Phase III development for idiopathic pulmonary fibrosis: six independently developed proteomic aging clocks showed a consistent shift toward lower predicted biological age in treated patients. The finding does not alter rentosertib’s regulatory trajectory, but raises two broader questions: whether its biology extends beyond pulmonary fibrosis, and whether aging biomarkers can be incorporated prospectively into conventional disease trials.
The analysis used longitudinal Olink proteomic data collected during the Phase IIa GENESIS-IPF trial (NCT05938920), which enrolled 71 IPF patients across 22 sites in China. Serum proteome profiles from 42 participants were evaluated across 2,841 proteins. The six aging clock models applied — ProtAge, OrganAge (chronological and mortality variants), PAC, ipfP3GPT, and PAOPAC — were developed independently by groups at Harvard, Oxford, Peking University, and Insilico. All six indicated a trend toward reversed biological age in the rentosertib-treated arms relative to placebo. The peak effect, approximately 3–4 years of biological age reversal and up to 6 years on one clock, was observed at Week 4 in patients receiving 30 mg twice daily. The study authors noted that the dose producing the strongest age-reversal signal differed from the dose producing the greatest lung-function improvement — the 60 mg once-daily arm, which showed a mean forced vital capacity change of +98.4 mL versus −20.3 mL for placebo in the previously published Phase IIa results — suggesting the geroprotective activity is at least partially independent of the anti-fibrotic effect.
Mechanistically, the study characterized rentosertib as acting as a senomorphic agent, suppressing proteins associated with cellular senescence including EREG, ESM1, IGFBP4, ITGA2, MMP10, MMP13, and SPP1, while downregulating RTK–PI3K and RAS–ERK growth-factor signaling pathways linked to accelerated aging. Comparison with 55,319 UK Biobank profiles indicated that rentosertib directly reversed typical age-related protein-expression trajectories. Rentosertib inhibits TNIK (TRAF2- and NCK-interacting kinase), a serine/threonine kinase that Insilico identified through its AI-powered target discovery platform as implicated in fibrosis, inflammation, and six hallmarks of aging — the rationale that originally motivated its development as a dual-purpose therapeutic.
The authors acknowledged a key limitation that Nobel laureate Michael Levitt, commenting on the study, stated plainly: the trial cannot yet separate slower aging from a treated lung. The 42-patient proteomic substudy is exploratory, and the clock models were not pre-specified primary endpoints. Whether the biological age signal reflects a genuine systemic geroprotective effect or is downstream of improved respiratory function remains unresolved. A study in healthy volunteers, Levitt said, is the experiment needed next.