A novel approach to target fasting and post-prandial triglycerides Dr. Joanne M. Donovan Catabasis Cambridge, MA, USA

CAT-2003: An Oral Agent that Targets Intestinal and Liver PCSK9 Chylomicron VLDL TG/Ch Apo B-100 98% TG LDL Ch Apo B-100 Apo B-48 Apo B-48 Reduces plasma/ intracellular liver PCSK9 Lower LDL-C Lower VLDL-C Activation of lipoprotein lipase (LPL) Reduces intestinal PCSK9 Lower Triglycerides Activation of LPL CAT-2003 inhibits PCSK9 production in the liver and intestine, the two major tissues that produce PCSK9

CAT 2003 CAT-2003 Inhibits Production of Active SREBP, A Central Regulator of Lipid Metabolism Cell Nucleus Inactive Immature SREBP Active SREBP PCSK9 PCSK9 Protein Secretion Gene Activation CAT-2003 inhibits production of active sterol response binding protein (SREBP) Human liver cell line HepG2 Human liver cell line HepG2 CAT-2003 reduces both protein and mRNA expression of PCSK9 by reducing nSREBP-2 the protein that regulates the PCSK9 gene

CAT-2003 Lowers Cholesterol Synergistically With a Statin PCSK9 Induces degradation of the LDL-R; Statins Activate SREBP Statins Increase PCSK9 Secretion CAT-2003 Reverses the Increase CAT-2003 in Combination with a Statin Produces Synergistic Efficacy ~50% -58% Control CAT-2003 Atorvastatin + Control CAT-2003 CAT-2003 Atorvastatin + Atorvastatin Atorvastatin Human liver cell line HepG2 apoE*3 Leiden Mice, 4 weeks CAT-2003 inhibits active SREBP (nSREBP-2) and reduces PCSK9 producing additional efficacy in combination with a statin

Summary: CAT-2003 Phase 1 Single and Multiple Ascending Dose Studies Established safety and tolerability of single and multiple doses No safety issues Tolerability acceptable in range where pharmacology demonstrated Demonstrated lack of niacin-like activity on GPR109A receptor No subjective or objective flushing No changes in free fatty acids after dosing Establish clinical exposure No detectable levels of niacin Evidence for cellular metabolism to niacin metabolites Proof of concept pharmacological effects Reductions in apo B-containing lipoproteins and PCSK9 Profound reductions in post-prandial triglycerides Reductions in fasting triglycerides in hypertriglyceridemic subjects

Acknowledgements The Catabasis Team University of Pennsylvania Medpace Richard Dunbar MD Medpace Lucasz Biernat Douglas Logan