Disease-Modifying Activity in a Model of Rheumatoid Arthritis with an Orally Available Inhibitor of Methionine Aminopeptidase Type-2,
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1 Disease-Modifying Activity in a Model of Rheumatoid Arthritis with an rally Available Inhibitor of Methionine Aminopeptidase Type-2, PPI-2458 William Westlin, Ph.D. Praecis Pharmaceuticals Waltham, Massachusetts
2 PPI-2458 is a Methionine Aminopeptidase-2 2 Inhibitor of the Fumagillin Class Fumagillin Fungal Metabolite Anti-proliferative to EC H TNP-470 Potency > fumagillin Dose limiting CNS Tox Poor PK profile H N Cl H N NH2 PPI-2458 Equipotent to TNP-470 Improved Stability Improved toxicity profile rally Active PPI-2458 is structurally related to fumagillin and TNP-470 PPI-2458 was designed to overcome the clinical limitations of TNP-470 PPI-2458 is an irreversible inhibitor of MetAP-2 Inhibits angiogenesis and proliferation of sensitive cell types PPI-2458 is in Phase 1 Clinical Development in NHL & Solid Tumor
3 PPI-2458 Growth Inhibition of Sensitive Cells Important in Arthritis Disease Progression Correlates with Inhibition of Target MetAP Primary Human Endothelial cells (HUVEC) 120 Primary Synovial Fibroblasts from RA patient (HFLS) % relative to vehicle control cell growth free MetAP-2 % relative to vehicle control cell growth free MetAP Concentration (nm) 100 Primary Normal Human Dermal Fibroblasts (NHDF-Ad) Concentration (nm) PNAS 20: 10768, 2004 % relative to vehicle control cell growth free MetAP PPI-2458 inhibits the growth of both endothelial cells, important in angiogenesis, and synovial fibroblasts that contribute to the formation of the erosive pannus responsible for the destructive effects in rheumatoid arthritis Concentration (nm)
4 PPI-2458 Inhibits Disease Progression in the Rat PG-PS PS Model of Arthritis 3 Average Paw Volume (ml) , no PGPS PGPS + vehicle PPI-2458, 5mg/kg treatment start PG-PS model of arthritis Biphasic mode of progression: Early acute phase (days 1-7) Inflammatory cell infiltration and generation of inflammatory mediators Chronic phase (evident: day 12) T cell dependent phase with severe synovitis and joint destruction Day Prophylactic dosing (prior to onset of chronic disease) oral, qod
5 PPI-2458 is Efficacious in the PGPS Model of Arthritis with Therapeutic Dosing , no PGPS PGPS + vehicle PPI-2458, 0.25mg/kg PPI-2458, 1mg/kg PPI-2458, 5mg/kg DEX, 1mg/kg Day treatment start ral, QD dosing
6 PGPS Arthritis Disease-Modifying Activity Normal PPI-2458
7 PPI-2458 Demonstrates Disease-Modifying Activity in PGPS-Induced Arthritis in Rats 15 4 Pathological Processes Cell infiltration Pannus formation Cartilage erosion Bone resorption Score = 0-4 each process Maximum Score = 16 Total Histology Score (± SEM) vehicle 1 mg/kg Dex mg/kg PPI mg/kg PPI mg/kg PPI-2458 Scoring system from Byrne et al., Agents and Actions, 1991
8 PPI-2458 Inhibits the Differentiation of Human steoclast Precursor Cells in vitro M-CSF/RANKL + M-CSF/RANKL nm PPI-2458 M-CSF/RANKL nm PPI-2458 M-CSF/RANKL nm PPI-2458 M-CSF/RANKL + 10 nm PPI-2458 M-CSF + 7 days (TRAP stain)
9 PPI-2458 Inhibits Bone Resorption by Activated Human steoclasts Measurement of collagen type I helical peptide (a1 chain residues ) in cell culture supernatants by ELISA 75 Collagen type I peptide (ng/ml) Control Control (M-CSF/RANKL) Rapamycin (10ng/ml) E-64 (100 nm) PPI nm 0.1 nm 1 nm 10 nm Primary human osteoclasts M-CSF/RANKL
10 Rat PG-PS PS Arthritis Study Designed to Address Bone and Cartilage Protective Effects of PPI-2458 in vivo Average paw volume (ml) No PG-PS/ PG-PS/ PG-PS/Dex (1mg/kg) PG-PS/2458 (1 mg/kg) PG-PS/2458 (5 mg/kg) PG-PS/2458 (10 mg/kg) Time (days) Treatment start * * ral, qod
11 Protection from PG-PS PS Arthritis in Rats is Associated with Inhibition of the Molecular Target, MetAP-2, in vivo 100 Percent Free MetAP-2 (relative to diseased control) Dex (1 mg/kg) 1 mg/kg 5 mg/kg PPI mg/kg MetAP-2 inhibition in white blood cells 24 hours after the last dose PG-PS
12 PPI-2458 Preserves the Intact Joint Architecture and Normal Bone Surface Arthritis Arthritis + Dex (1 mg/kg, P, QD) Arthritis + PPI-2458 (10 mg/kg, P, QD) Micro-CT 3-D surface reconstruction
13 PPI-2458 Inhibits Bone Resorption in vivo in the Rat PG-PS PS Arthritis Model 600 CTX-I (ng/ml) ** * * ** Systemic levels of CTX-I peptides serve as a biochemical marker of bone destruction to monitor tissue involvement and to assess therapeutic interventions 0 Dex (1 mg/kg) 1 mg/kg 5 mg/kg 10 mg/kg PPI mg/kg PG-PS Collagen Type I helical Peptide (CTX-I) ELISA (urine, normalized for creatinine excretion)
14 PPI-2458 Inhibits Cartilage Erosion in vivo in the Rat PG-PS PS Arthritis Model 6 CMP (U/L) 4 2 ** * * ** ** ** Systemic levels of CMP serve as a biochemical marker of cartilage degradation to monitor tissue involvement and to assess therapeutic interventions 0 Dex (1 mg/kg) 1 mg/kg 5 mg/kg 10 mg/kg PPI mg/kg PG-PS Cartilage ligomeric Matrix Protein (CMP) ELISA (serum)
15 PPI-2458 for Rheumatoid Arthritis PPI-2458 is an orally available MetAP-2 inhibitor currently in a Phase 1 oncology clinical trial Development of PPI-2458 is guided by the availability of a sensitive pharmacodynamic marker The potent anti-angiogenic activity of PPI-2458 and its anti-proliferative activity on human RA synoviocytes inhibits synovial hyperplasia and chronic joint inflammation PPI-2458 potently inhibits the in vitro differentiation of human osteoclast progenitor cells and reduces the bone degrading activity of human osteoclasts in vitro and in vivo PPI-2458 has oral disease-modifying activity in 4 distinct animal models of arthritis Inhibitors of MetAP-2 2 provide a novel molecularly targeted therapy with disease-modifying potential for rheumatoid arthritis
16 Acknowledgements Preclinical Research Molecular & Cellular Pharmacology: Gerhard Hannig Sylvie Bernier In Vivo Pharmacology: Doug Lazarus Beth Doyle Jeanine Lorusso Russ Karp Analytical Pharmacology: Chuck Thompson Matt Labenski Jen Hoyt Nazbeh Taghizadeh Jim Wakefield Toxicology Ed Clark Jim Little Mike Murray Adaline Smith Chemistry Chris Arico-Muendel Jenn Svendson Steve Skinner Biochemistry Kerry White Patricia Medeiros Program Management Heather Lounsbury Clinical Kathryn Stiede
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