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

2. 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

3. 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

4. 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

5. 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

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