A Promise Kept — Phase 1 Data for a 7-KC-Clearing Drug (Oki O'Connor, Cyclarity Tx)

Matthew "Oki" O'Connor is the CEO of Scientific Affairs at Cyclarity Therapeutics, a clinical-stage biotech building a new class of medicines designed not to slow the accumulation of vascular damage but to reverse it. Oki and Chris first crossed paths as postdocs at Lawrence Berkeley National Lab in the mid-2000s — Oki was in Irina Conboy's lab, not far from the late Judy Campisi's group, where Chris was then working on cellular senescence. After Berkeley, Oki spent nearly a decade running the research program at the SENS Research Foundation, the organization most identified with the "damage repair" framing of aging biology, before co-founding Cyclarity (then known as Underdog Pharmaceuticals) in 2019 to translate one of SENS's most drug-tractable ideas into an actual molecule.

When Oki was last on the show in March of 2023 (Episode 36), Cyclarity was deep in IND-enabling work and its lead asset, UDP-003, had only ever seen the inside of a mouse artery. At the end of that conversation, Chris asked what Oki hoped to be discussing the next time he visited. He answered, bluntly, that he wanted to be presenting human data. Last month, at the AHA Vascular Discovery Sessions, Cyclarity reported the results of their first-in-human Phase 1 trial of UDP-003 — a designed cyclodextrin that selectively binds 7-ketocholesterol, the oxidized cholesterol species that drives foam cell formation and arterial plaque. He's back to discuss what the drug actually did when it went hunting for 7KC inside a living human being.

In this episode, Chris and Oki cover the unmet need that lipid-lowering drugs — statins, PCSK9 inhibitors, the coming Lp(a) agents — still don't address: none of them remove the damage already sitting in an artery wall. Oki explains the basic chemistry of 7-ketocholesterol and why macrophages, lacking the machinery to recycle it, collapse into foam cells and seed the necrotic core of advanced plaque. They walk through the engineering of UDP-003 as a dimeric beta-cyclodextrin "double cone" tuned for a single oxidized cholesterol species, the design of the 72-volunteer Australian Phase 1, and the exploratory pharmacodynamic readout that has the field's attention: dose-dependent urinary excretion of 7KC, stoichiometric with drug, cleared within a day. The conversation then turns to the 150-patient Phase 2 plan in coronary artery disease patients with plaque imaging as the primary biological readout, the funding math that stands between Cyclarity and that trial