295: Neither Small Molecule nor Biologic: The Cyclodextrin Dimer CMC Challenge with Matthew O'Connor - Part 1

Why does CMC development still expect every drug to be one molecule with one peak, when new therapeutics don't always fit neatly into existing regulatory or chemical categories?
Matthew O'Connor, CEO of Scientific Affairs at Cyclarity Therapeutics, is developing a drug that sits between a small molecule and a biologic. On the Smart Biotech Scientist Podcast, Matthew shared how his team engineered a cyclodextrin dimer that binds and removes 7-ketocholesterol, an oxidized form of cholesterol that builds up in artery plaque and is linked to a higher risk of heart attack and stroke.
Topics discussed:
• Matthew O'Connor's motivation for focusing on aging and molecular damage (03:39)
• The biological problem of oxidized cholesterol buildup and its role in atherosclerosis (04:42)
• Mechanism of action: how the cyclodextrin binds and removes 7-ketocholesterol (06:23)
• Approaches to designing a highly specific cyclodextrin therapeutic (09:14)
• The "medium-sized molecule" characteristics and the question of regulatory classification (12:16)
• Why cyclodextrin starting material is cheap and not a manufacturing bottleneck (15:37)
• Manufacturing strategies and the role of specialist CDMOs in complex carbohydrate chemistry (17:04)
• Methods for demonstrating identity and consistency in isomeric mixtures (18:43)
• Drug formulation considerations and why an injectable route is necessary (21:46)
Smart insight: Matthew O'Connor's work shows what happens when you start with the problem rather than the drug format. His team's cyclodextrin dimer doesn't fit neatly as a small molecule or a biologic, and that makes manufacturing, analytics and regulatory work harder. But if it can remove oxidized cholesterol from the body, it could help reverse plaque instead of just slowing it down.
When a drug is too big to be a small molecule and too small to be a biologic, every CMC decision gets harder. These episodes look at what it takes to develop, characterize and manufacture a modality that doesn't fit an existing box.
• Episodes 281 - 282: When Your Delivery Vehicle Contains a Membrane Protein: CMC Decisions With No Regulatory Precedent with Jitendra Kumar
• Episodes 207 - 208: Cryogenic Infrared Ion Spectroscopy: From Mass Spec Limitations to Molecular Precision with Tom Rizzo
• Episodes 197 - 198: Mastering ADC Development: CDMO Strategies for Analytics and Scale-Up with Amanda Hoertz
• Episodes 231 - 232: From IND to BLA: The Biologics CMC Decisions That Determine Regulatory Success with Henri Kornmann
Connect with Matthew O'Connor:
Website: www.cyclaritytx.com (cyclaritytx.com)
LinkedIn: www.linkedin.com/in/droki (linkedin.com/in/droki)
Email: matthew.oconnor@cyclaritytx.com
Free 5-day email course, The CMC Failure Chain: the five recurring CMC mistakes that put your promising program at risk → Get it here (smartbiotechscientist.com/#cmc)
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