7/27/2018 Introducing a Peptide enhanced bone graft with a unique mechanism of action Current Solutions in Spine Surgery, May 2018 Jeffrey G. Marx, Ph.D. CONFIDENTIAL 0 Faculty Disclosure I am President and COO of Cerapedics. CONFIDENTIAL 1 i-FACTOR peptide enhanced bone graft A clinically proven, advanced drug-device combination bone graft • PMA approved, backed by Level 1 Human clinical data • Statistical superiority to autograft • Improved safety & cost effectiveness vs. BMP’s CONFIDENTIAL 1
7/27/2018 Synthetic Collagen Fragment (P-15) • Synthetic peptide of a 15 Amino Acid sequence from type 1 Collagen • Functional domain of collagen responsible for the attachment of cells CONFIDENTIAL 3 i-FACTOR™ Peptide Enhanced Bone Graft Mechanism of Action: “Attract - Attach - Activate” • Osteogenic cells in the surrounding tissues have an affinity for and are Osteogenic Cell naturally attracted to P-15 • Osteogenic cells attached via cellular surface receptors to P-15 the P-15 • Osteogenic cells are naturally attachment activated ABM P-15 has been shown to enhance bone formation by facilitating cellular attraction and attachment which activates natural signaling, creating a micro-environment conducive to new bone formation CONFIDENTIAL Mechanism of Action • i-FACTOR attracts osteogenic precursor cells by making an abundance of P-15 binding sites ATTRACT available for cellular adhesion • Cell binding between P-15 integrins activates natural mechanical and chemical signalling pathways within the cell ATTACH stimulating the release of specific growth factors, cytokines and Bone Morphogenic Proteins (BMPs) • The cascade of events leads to cell ACTIVATE proliferation and natural bone healing CONFIDENTIAL 2
7/27/2018 ATTRACT CONFIDENTIAL Enhances Cell Attraction & Attachment P15 bound to ABM increases the number of bound human fibroblasts and stimulates cellular activation and spreading. ABM Alone ABM / P-15 Qian JJ., Bhatnager RS., JBMR (1996) 31:545 CONFIDENTIAL ATTACH CONFIDENTIAL 3
7/27/2018 Proven to Enhance Cell Proliferation P15 bound to surface increases the number of bound pre- osteoblastic cells and stimulates cellular activity Lui Q., Lemthongkul W., et. al. Journal of Orthopedic Research (2012) 10:1526 CONFIDENTIAL Cell Attachment & Activation P15 bound to surface increases the number of bound pre- osteoblastic cells and stimulates cellular activation and spreading * * * * 100 25000 * 80 * 20000 Number of cell bound Area (pixels 2 ) 60 15000 40 10000 20 5000 0 0 15 30 60 15 30 60 *p<0.05 Time (min) Time (min) -Uncoated surface -P15-coated surface Lui Q. et. al. Journal of Orthopedic Research (2012) 10 :1526 CONFIDENTIAL *p<0.05 ACTIVATE CONFIDENTIAL 4
7/27/2018 Cell Activation: Gene Expression P15 bound to ABM stimulates upregulation of Alkaline Phosphatase at the gene expression and protein synthesis levels Histochemical Staining for Alkaline Phosphatase Expression of Alkaline Phosphatase mRNA * 5 4 Relative Expression of ALP 3 ABM * 2 * 1 0 1 5 10 *p<0.05 Time (days) -ABM only P15/ABM -P15-coated ABM Yang XB., Rajendra S. et. al. Tissue Engineering (2004) 10:1148 CONFIDENTIAL *p<0.05 Cell Activation: Gene Expression P15 bound to ABM stimulates upregulation of BMP-2 at the gene level and onset of calcificati on Histochemical Staining for Alizarin Red Expression of BMP-2 mRNA * 3 * Relative Expression of BMP-2 2 ABM 1 0 1 5 10 *p<0.05 Time (days) -ABM only P15/ABM -P15-coated ABM Yang XB., Rajendra S. et. al. Tissue Engineering (2004) 10:1148 CONFIDENTIAL *p<0.05 i-FACTOR Bone Graft: Clinical Track Record • CE Mark / TGA approved since 2008 • Putty & Strip form factors • No special handling requirements • Over 25,000 cases performed • Multiple studies / peer-reviewed (PLIF, ALIF) • i-FACTOR Putty: U.S. PMA approval Nov’15 CONFIDENTIAL 5
7/27/2018 i-FACTOR Cervical Study - FDA IDE Trial Single-level Anterior Cervical Discectomy & Fusion (ACDF) Procedure Allograft ring with anterior plate Patients 319 patients enrolled at 24 clinical sites in US and Canada Study arms 1:1 randomization i-FACTOR P-15 Putty versus Autograft Primary : Efficacy (Fusion, NDI, Neurological Outcomes) and Safety (Complications) at 12 months. Non-inferiority statistical plan. Endpoints Secondary : Pain, Kyphosis, SF-36, Modified Odom’s Criteria Extended study 18, 24, 36, 48 and 60 months Follow-Up CONFIDENTIAL Overall Success Outcomes CONFIDENTIAL Overview • In Level-I IDE study, i-FACTOR demonstrated superior to autograft in overall clinical success • Accelerates & enhances bone growth • Only second PMA approved drug-device combination product in $2.5B U.S. Spine market, and first & only bone graft approved for U.S. Cervical Spine • > 40,000 procedures with multiple Peer-reviewed publications • Very positive clinician response and rapid commercial uptake • Preparing to initiate IDE trial in TLIF with next-generation version of the product CONFIDENTIAL 6
7/27/2018 Thank You! CONFIDENTIAL 18 Mechanism of Action Evidence • Increases the number of cells available – Bhatnagar et al , Design of Biomimetic Habitats for Tissue Engineering with P-15…………., Tissue Engineering, Vol 5, Number 1, 1999 • Leads to cell differentiation – Qian & Bhatnagar, Enhanced Cell Attachment to anorganic bone……., J of Biomedical Materials Research, Vol. 31, 1996 • Produces increases in BMP2 and ALP – Yang, Bhatnagar, et al., Biomimetic Collagen Scaffolds for Human Bone Cell Growth and Differentiation, Tissue Engineering, Vol. 10, 2004 • Early bone laid down (& increased ALP, BMP2 and BMP7) – Thorwarth, et al, Bioactivation of anorganic bone Matrix by P-15 peptide for promotion of early bone formation, Biomaterials, Vol. 26, 2005 • Enhances cell viability (& increased cells on surface) – Hanks and Atkinson, Comparison of cell viability on aBM with or without P-15 cell binding peptide, Biomaterials, Vol. 25, 2004 CONFIDENTIAL 7
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