Editing Openai/692df380-fd64-8008-b788-94e93ef3ff89 (section)

==== 4. Human data: what do we actually know? ====

===== 4.1 Observational human data (pathway level) =====
* Older adults with higher KYN/TRP ratios and higher KMO-branch metabolites (3-HK, QUIN) have higher frailty scores, more disability, and higher mortality in several cohorts. ScienceDirect<ref>{{cite web|title=ScienceDirect|url=https://www.sciencedirect.com/science/article/abs/pii/S0531556519305704|publisher=sciencedirect.com|access-date=2025-12-28}}</ref>
* These associations persist after adjustment for classical risk factors, suggesting KP activation is a marker—and possibly mediator—of biological aging and inflammaging.

Caveat: This is correlation. It implicates the pathway, not specifically “KMO inhibitor” as a therapy.

===== 4.2 Interventional human data: KMO inhibitors =====

The only clear clinical-stage KMO inhibitor with public data is KNS366 (Kynos Therapeutics):
* Phase I, randomized, double-blind, placebo-controlled dose-escalation trial in healthy adults (single and 7-day multiple dosing).
* Reported outcomes: - Good safety and tolerability at all tested doses - Dose-dependent and sustained inhibition of KMO, evidenced by substantial reduction in plasma 3-HK and modulation of downstream metabolites. drfalkpharma.com<ref>{{cite web|title=drfalkpharma.com|url=https://www.ipgroupplc.com/news-and-events/portfolio-news/2024/2024-04-22|publisher=ipgroupplc.com|date=2024-04-22|access-date=2025-12-28}}</ref>
* No clinical efficacy endpoints (cognition, frailty, inflammatory outcomes, etc.) have been reported yet; the trial was purely PK/PD and safety.

Earlier clinical exploration of KMO inhibitors in neurodegeneration was contemplated (e.g., Ro-family inhibitors for AD/PD), but there are no positive phase II/III trials showing hard benefits on cognition, function, or mortality. Cell<ref>{{cite web|title=Cell|url=https://www.cell.com/fulltext/S0092-8674%2811%2900592-7|publisher=cell.com|access-date=2025-12-28}}</ref>

Bottom line (clinical):
'' There is currently ''zero* published evidence that KMO inhibitors improve human healthspan or lifespan.
* We only have: (1) pathway-level associations with aging/frailty and (2) one phase-I molecule with demonstrated target engagement and good short-term safety in healthy volunteers.