Living Cells in DFU. Clinical Outcomes of Amnion Allografts with. Management. Alla Danilkovitch, PhD, RN

Transcription

1 Clinical Outcomes of Amnion Allografts with Living Cells in DFU Management Alla Danilkovitch, PhD, RN Chief Scientific Officer Osiris Therapeutics, Inc. Columbia, Maryland, USA

2 Disclosures Stockholder: Osiris Therapeutics, Inc Speaker s Bureau: Nothing to disclose Grant/Research Support: Osiris Therapeutics, Inc. Medical/Scientific Boards: Nothing to disclose Honorarium: Full time paid employee of Osiris Therapeutics, Inc. Consultant: Nothing to Disclose

3 Learning Objectives Diabetic foot ulcer (DFU) statistics and when to use advanced wound care modalities containing living cells Structure and properties of human amniotic membrane and effects of different tissue preservation methods on tissue components Benefits of preserving all components of the amniotic membrane and currently available amniotic membrane products with living cells Key living amniotic membrane clinical studies and outcomes for chronic DFU management

4 Diabetic Foot Ulcers (DFUs) In million Americans, or 9.4% of the population, had diabetes 1 DFU is one of the most common complications of diabetes 2 - Annual incidence 1% to 4% with lifetime risk of 15-25% ~15% of diabetic foot ulcers result in ~85,000/year lower extremity amputation 5,7 - ~85% of lower limb amputations in patients with diabetes are proceeded by ulceration 8-9 Annual cost of DFU management alone estimated to be between $9-13 Billion American Diabetes Association, Statistics about diabetes, Frykberg et al J Foot and Ankle Surg 2006 Suppl. 3. Reiber and Ledoux. In The Evidence Base for Diabetes Care. Williams et al, eds. Hoboken, NJ: John Wiley & Sons 2002: Boulton et al. NEJM. 2004;351: Sanders. J Am Podiatry Med Assoc. 1994;84: Boulton et al. Lancet. 2005;366: Ramsey et al. Diabetes Care 1999;22: Pecoraro et al. Diabetes Care. 1990;13: Apelqvist and Larsson. Diabetes Metab Res Rev. 2000:16:S Rice et al. Diabetes Care, 2014; 37:651

5 When and Why to Use Wound Care Modalities Containing Living Cells? When: in high-risk patients Advanced age is associated with impaired wound healing Co-morbidities negatively affect wound healing - Diabetes - Obesity - Chronic renal failure - Smoking - Blood circulation insufficiency Why: patients have low cellular activities Low number and functionality of stem cells Cell senescence and apoptosis Insufficient levels of growth factors & extracellular matrix produced by cells Decreased cell migration, proliferation and maturation Marchese CG, Davis RD, Frykberg RG, Kashevsky HE, Reyzelman AM, Samra AH and Gibbons GW. Advancing the science of wound care in the at-risk patients: Optimizing clinical outcomes by combining advances cellular therapy with standard of care. Proceedings from an expert panel meeting. WOUNDS, September 2016, Supplement

6 Amniotic Membrane Structure & Properties Amniotic membrane (amnion): Serve as a protective barrier for the developing fetus Contains - A single layer of epithelial cells attached to the basement membrane - Compact & fibroblast (with fibroblast and mesenchymal stem cells) layers - The spongy layer separate amnion from chorion, the second placental membrane Natural properties include: - Anti-inflammatory - Antimicrobial - Anti-scarring - Anti-adhesion - Angiogenic Amnion has a long history of clinical use for burns and chronic wounds From: Niknejad et al. Properties of the amniotic membrane for potential use in tissue engineering. Eur Cells Mater. 2008,15:88 Niknejad et al. Properties of the amniotic membrane for potential use in tissue engineering. Eur Cells Mater. 2008,15:88; Koizumi et al. Growth factor mrna and protein in preserved human amniotic membrane. Curr Eye Res. 2000,20:173; Mamede et al. Amniotic membrane: from structure and functions to clinical applications. Cell Tiss Res. 2012,349:447; Brantley & Verla. Use of placental membranes for the treatment of chronic diabetic foot ulcers Adv Wound Care; 2015,4:545.

7 Rodríquez-Ares et al. Acta Ophthalmol. 2009; Lim et al., Arch Ophthalmol. 2010; Niknejad et al. Cryobiol. 2011;Thomasen et al., Graefes Arch Clin Exp Ophthalmol. 2009, Dasgupta et al., Plast Reconstr Surg Glob Open 2016;4:e1065; doi: /GOX ; Published online 4 October 2016.) Effect of Preservation Methods on Amniotic Membrane Components The goal of preservation is to retain all components of fresh tissue in their native state to be able to store for long time sufficient: To complete donor & tissue testing To make tissues a point of care product PROCESSING OF FRESH TISSUE ECM Growth Factors Viable Cells Cryopreservation & Refrigeration Freezing & Cryopreservation Drying & Radiation Decellularization & Radiation ECM Growth Factors ECM Growth Factors Altered ECM Growth Factors Altered ECM ECM No Growth Factors Viable Cells Dead Cells Dead Cells No Cells

8 Cryopreserved Amnion with Living Cells (vcpm) Retains Antimicrobial Properties of Fresh Tissue Fresh placental membranes (amnion and chorion) have an antimicrobial effect against a diverse panel of bacteria vcpm inhibits growth of ESKAPE bacteria associated with chronic wounds Devitalized CPM shows reduced antimicrobial activity ESKAPE Bacteria Gram stain Growth reduction compared with control (Log) Enterococcus faecium Positive Staphylococcus aureus Positive Klebsiella pneumonia Negative Acinetobacter baumannii Negative Pseudomonas aeruginosa Negative Enterobacter aerogenes Negative Medium vcpm Devitalized jaergaard, et al. Eur J Obstet & Gynecol Reprod Biol. 2001; 94 (2): ; Mao, et al. J Diabetic Foot Complications. 2016; 8(2): 23-30; Mao et al., Scientific Reports, 2017; :13722; Mao et al., J Funct Biomater, 2018; 9:3.

9 Currently Available Amnion Products with Living Cells Information resources: company s websites ( product s inserts and marketing materials; Pubmed; Product Feature HSAM vhama vcpm Description Storage & Shelf Life Cell Viability testing for lot release Hypothermically stored amniotic membrane 3 weeks (42 days from the manufacturing date) at 1-10 o C No Viable human amnion membrane allograft Cryopreserved placental membrane with living cells 2 years at -70 o C or below 3 years at o C Yes, no acceptance criterion for cell viability disclosed Graft sizes 2 (1.5x1.5 & 2.5x2.5 cm) 6 (14 & 18 mm disks, 2x2, 2x4, 3x4 & 5x5 cm) Yes, >70% HCPCS codes Q4159 Q4151 Q (16 mm disks, 1.5x2, 2x3, 3x4 & 5x5 cm) Regulatory class Tissue allograft, HCT/P 361 Tissue allograft, HCT/P 361 Tissue allograft, HCT/P 361 Published DFU data No publications identified 1: Regulski M. WOUNDS, 2018, 30(3):E36-E40 (2 cases) DFU trials at clinicaltrials.gov 3 registered: NCT , active, not recruiting; NCT , recruiting; NCT , recruiting None identified 10+ publications including multicenter randomized trials 3 completed

10 Key vcpm DFU Clinical Studies Level I prospective multicenter randomized controlled clinical trial Lavery LA, Fulmer J, Shebetka KA, Regulski M, Vayser D, Fried D, et al. The efficacy and safety of Grafix for the treatment of chronic diabetic foot ulcers: results of a multi-centre, controlled, randomised, blinded, clinical trial. Int Wound J. 2014;11(5): Lavery LA, Fulmer J, Shebetka KA, Regulski M, Vayser D, Fried D, et al. The Open-label Extension Phase of a Chronic Diabetic Foot Ulcer Multicenter, Controlled, Randomized Clinical Trial Using Cryopreserved Placental Membrane. WOUNDS, 2018; Sep issue: Confirmation of level I trial results in real world setting Raspovic KM, Wukich DK, Naiman DQ, Lavery LA, Kirsner RS, Kim PJ, Steinberg JS, Attinger CE, Danilkovitch A. Effectiveness of viable cryopreserved placental membranes for management of diabetic foot ulcers in a real world setting. Wound Repair Regen. 2018; Apr 23. doi: /wrr Comparative prospective multicenter randomized clinical trial vs a bioengineered skin substitute Ananian C, Dhillon Y, Van Gils C, Lindsey D, Otto R, Dove C, Pierce J, Saunders M. A multicenter, randomized, single-blind trial comparing the efficacy of viable cryopreserved placental membrane to human fibroblastderived dermal substitute for the treatment of chronic diabetic foot ulcers. Wound Repair Regen. 2018; Aug 11.

11 avery LA, Fulmer J, Shebetka KA, Regulski M, Vayser D, Fried D, et al. The efficacy and safety of Grafix for the treatment of chronic diabetic foot ulcers: results of a multi-centre, ontrolled, randomised, blinded, clinical trial. Int Wound J. 2014;11(5): Guidance for Industry, Chronic, Cutaneous Ulcer and Burn Wounds; Developing Products for Treatment Cryopreserved Amnion Level I Multicenter RCT for Chronic DFUs: Study Design Level I multicenter RCT Based on 2006 FDA Guidelines* Independent Academic Research Organization (ARO) Oversight and monitoring clinical sites Wound closure was confirmed by a third party blinded image verification Cross-over arm The only DFU RCT that was stopped for overwhelming efficacy by an independent safety committee based on results of the pre-defined interim analysis at 50% enrollment

12 Cryopreserved Amnion Level I Multicenter RCT for Chronic DFUs: Key Study Outcomes Fewer Adverse Events, More & Faster Wound Closure and Lower Cost with vcpm Use for Chronic DFUs Patients with Complete Closure (%) Patients with a Wound Related Infection (%) 60% 40% 20% 0% 62% vcpm n=97 p= % SOC 40% 30% 20% 10% 0% 18% vcpm 36% SOC n=97 p=0.044 The cost of care for vcpm-treated patients (n=50) was approximately $14,000 lower when compared to control patients (n=47), based on associated adverse events (AEs) and serious adverse events (SAEs). The lower costs for vcpm-treated patients were driven by faster wound closure, fewer AEs, SAEs, and hospitalizations.

13 Cryopreserved Amnion Level I Multicenter RCT for Chronic DFUs: Open Label Phase Outcomes Open-Label Extension Phase of the Chronic DFUs Multicenter RCT Confirms Benefits of vcpm for Wound Closure and Reduction of Adverse Events Clinical outcomes for 26 patient cohort treated with SWC in the blinded phase and with vcpm in the extension phase of the trial SWC (n=26), blinded phase vcpm (n=26), open label phase p-value* Wound closure, n (%) 0 (0%) 17 (65.4%) N/A Time to closure in days (median) N/A** 34 N/A Study visits (median) 12*** 3 N/A Subjects with at least one AE, n (%) 18 (69.2%) 11 (42.3%) AEs, n Index wound infections, n *- Fisher s exact one-sided test and Wilcoxon test; ** - Wounds were not closed during the blinded phase; ***- Each patient in the blinded phase had 12 study visits AE - adberse event; vcpm viable cryopreserved placental membrane; N/A not applicable; SWC standard wound care Lavery et al. WOUNDS, 2018

14 Confirmation of Clinical Outcomes in Real World Setting vcpm Wound Closure Rate in Real World Mirrors RCT Closure Rates Comparison Between EHR Real World Study & Randomized, Controlled Trial Study Type Raspovic et al. Real World Study 1 Retrospective, multicenter, nonrandomized Centers Lavery et al. RCT 2 Prospective, multicenter RCT Wounds (50 Grafix, 47 Control) Wounds Excluded 0.25 cm 2 < 1 cm 2, > 15 cm 2 Complex Wounds Allowed Excluded Wound Closure at End of Treatment 59.4% 62.0% Time to Closure (median) 42.0 days 42.0 days Grafts to Close (median) 4 6 aspovic KM, Wukich DK, Naiman DQ, Lavery LA, Kirsner RS, Kim PJ, Steinberg JS, Attinger CE, Danilkovitch A. Effectiveness of viable cryopreserved placental membranes for anagement of diabetic foot ulcers in a real world setting. Wound Repair Regen Apr 23. doi: /wrr avery LA, Fulmer J, Shebetka KA, et al. The efficacy and safety of Grafix for the treatment of chronic diabetic foot ulcers: results of a multi centre, controlled, randomised,

15 Comparative Multicenter Randomized Clinical Trial for Chronic DFUs: vcpm vs hfds Ananian C, Dhillon Y, Van Gils C, Lindsey D, Otto R, Dove C, Pierce J, Saunders M. A multicenter, randomized, single-blind trial comparing the efficacy of viable cryopreserved placental membrane to human fibroblast-derived dermal substitute for the treatment of chronic diabetic foot ulcers. Wound Repair Regen. 2018; U.S. Department of Health and Human Services; Food and Drug Administration; Center for Drug Evaluation and Research; Center for Biologics Evaluation and Research. Guidance for industry: non-inferiority clinical trials to establish effectiveness November. Accessed Oct 3, 2017; Wilcox, J, Carter M, Covington S. Frequency of debridements and time to heal: a retrospective cohort study of wounds. JAMA Dermatol. 2013;149(9): Study Design Prospective, randomized, single-blind, multi-center, non-inferiority trial 1,2 comparing clinical outcomes between vcpm (cryopreserved placental membrane with living cells) and hfds (human fibroblast dermal substitute) for the treatment of chronic DFUs Weekly applications up to 8 weeks with either vcpm or hfds plus SOC Intent-to-Treat (ITT): 75 patients (38 in vcpm arm, 37 in hfds arm) Per Protocol (PP): 62 patients (31 in vcpm arm, 31 in hfds arm) Study Endpoints Primary: Proportion of patients with complete wound closure Wounds 5 cm 2 were specifically evaluated since this represents >75% of DFUs in real-world practice 3 Patient Demographics & Baseline Wound Characteristics (ITT) vcpm (n = 38) hfds (n = 37) p-value Age (mean, years) Age>65 (%) Male (%) BMI (mean, Kg/m 2 ) Heart Disease (%) Prior Amputation (%) HbA1C (%) Wound Size (cm 2 ) Wound Duration (days) Patients with Prior Advanced Therapy (%)

16 Comparative Multicenter Randomized Clinical Trial for Chronic DFUs: vcpm vs hfds nanian C, Dhillon Y, Van Gils C, Lindsey D, Otto R, Dove C, Pierce J, Saunders M. A multicenter, randomized, single-blind trial comparing the efficacy of viable cryopreserved placental embrane to human fibroblast-derived dermal substitute for the treatment of chronic diabetic foot ulcers. Wound Repair Regen Complete Wound Closure (%) Product Cost per Patient Key Study Outcomes vcpm was not inferior to hfds for the proportion of patients achieving complete wound closure: 48.4% (15/31) for vcpm vs 38.7% (12/31) for hfds (90% CI: -10.6%, 28.9%) Fewer adverse events for vcpm (17 AEs, 4 SAEs) vs hfds (24 AEs, 7 SAEs) No adverse events were attributed to vcpm For typical DFUs ( 5 cm 2 ), patients treated with vcpm had a significantly higher rate of complete wound closure (81.3% vs 37.5%) and the per patient product cost was significantly lower ($3,846 vs $7,969) vcpm Sizes hfds Size ,000 8,000 7,000 6,000 5,000 4,000 3,000 2,000 1,000 0 Complete Closure for DFUs <5 cm 2 81% Product Cost for DFUs <5 cm 2 $3,846 vcpm n=32 p< n=32 p= % $7,969 hfds

17 Summary Three amniotic membrane products (HSAM, vhama and vcpm) containing living cells are currently available, however, only one product has clinical evidence in DFU treatment vcpm, a cryopreserved amniotic membrane that retains all components of fresh tissue including viable cells is an appropriate advanced wound care modality for chronic DFU management Results of clinical trials show high rate of wound closure and reduction of woundrelated infection, which is a costly complication often leading to hospitalization and amputation