Module 2 Objectives. Module 2 Current Research in Regenerative Therapy - Orthopedics - Rabbit Osteochondral Defect Repair Model

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Maximilian Richards
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Module 2 Current Research in Regenerative Therapy - Orthopedics - Module 2 Objectives Review of current research Review of equine orthopedics clinical data Review of canine orthopedics clinical data

1 Module 2 Current Research in Regenerative Therapy - Orthopedics - Module 2 Objectives Review of current research Review of equine orthopedics clinical data Review of canine orthopedics clinical data Review of quality standards and safety profile Early Report of In-Vitro Conversion to Cartilage Adult Stem Cells From Knee Fat Turned Into Cartilage, Bone, Fat Cells Science Daily DALLAS -- Duke University Medical Center researchers have "reprogrammed" adult stem cells taken from a small deposit of fat behind the kneecap into functioning cartilage, bone or fat cells that could potentially be grown into replacement tissues Rabbit Osteochondral Defect Repair Model Nathan et al, Cell-based therapy in the repair of osteochondral defects: A novel use for adipose tissue Tissue Engineering,

Goat Osteoarthritis Model Goat Osteoarthritis Model B & C excised

Protected tibial plateau Murphy et al, Stem cell therapy in a caprine

Stem cell therapy in a caprine model of osteoarthritis, Arthritis and

chronic, infected hock caused severe OA Single IA Vet-Stem Cell

injection in hock joint Now out over three years!

Horse Return to Performance Analysis* Return to full performance 66.

8% Be a Bono QH Horse of the Year 2004 Ready to retire after two

Single Injection and 9 mos later beat his own track record *A

2 Goat Osteoarthritis Model Goat Osteoarthritis Model B & C excised neo-meniscus Neo-meniscus New enthesis of insertional ligament Protected tibial plateau Murphy et al, Stem cell therapy in a caprine model of osteoarthritis, Arthritis and Rheumatism, 2003 Murphy et al, Stem cell therapy in a caprine model of osteoarthritis, Arthritis and Rheumatism, Case Study OA - Lucy Dressage Horse Over 1 year chronic, infected hock caused severe OA Single IA Vet-Stem Cell injection Case Study Joint Lucy Three months after stem cell injection in hock joint Now out over three years! 9 10 Case Study Racing QH Return to Performance Chronic OA in the Horse Return to Performance Analysis* Return to full performance 66.7% Return to lower level performance 28.6% Non-responsive 4.8% Be a Bono QH Horse of the Year 2004 Ready to retire after two arthroscopic chip surgeries (OA). Single Injection and 9 mos later beat his own track record *A RETROSPECTIVE REVIEW OF 62 CASES OF JOINT INJURY IN SPORT HORSES TREATED WITH ADIPOSE- DERIVED STEM AND REGENERATIVE CELL THERAPY. HARMAN R; COWLES B; ORAVA C; HARMAN S 11 12

Bilateral Stifle / Hips Bilateral Stifle / Hips 4 YO Rat Terrier Bilateral stifle and hip degeneration since 6

four joints 4 YO Rat Terrier Post Treatment: 2 weeks Dramatic pain reduction Now NSAID free for >24 months 13 14

Intra-articular injection Veterinary orthopedic exams at pre, 30, 60, 90, 180 13 dog study; 6 for interim 6 dogs

Osteoarthritis Pilot Study Severe, Chronic Elbow OA Annie 9 YO FS Lab mix Chronic elbow OA non-nsaid controlled

3 Bilateral Stifle / Hips Bilateral Stifle / Hips 4 YO Rat Terrier Bilateral stifle and hip degeneration since 6 months old NSAIDS for 12 months and still painful ================= Intra-articular RX with Stem cells in all four joints 4 YO Rat Terrier Post Treatment: 2 weeks Dramatic pain reduction Now NSAID free for >24 months Elbow Osteoarthritis Study Outline 180 Day Study Pilot - Unblinded Uni or Bilateral Elbow OA VSRC Intra-articular injection Veterinary orthopedic exams at pre, 30, 60, 90, dog study; 6 for interim 6 dogs completed to 30 days (9 joints-3 bilateral) 5 of those completed to 90 days (7 joints-2 bilateral) Elbow Osteoarthritis Pilot Study Severe, Chronic Elbow OA Annie 9 YO FS Lab mix Chronic elbow OA non-nsaid controlled pain IV stem cells at Day 0 and 14. Able to jump in and out of car; took 2 hour run in the woods before her 90 day study exam! 17 18

Chronic Post-Surgical Elbow 2 YO Bull Mastiff Right Elbow FCP FCP Surgery > 3 months prior to cell therapy 12/12/06 Exam. Persistent lameness and pain on manipulation.

3MM cells 1/11/07 Improvement in 4/5 orthopedic parameters. 3/15/07 3/5 Orthopedic parameters normal including no lameness at the walk or trot.

Bilateral Coxofemoral Joint Osteoarthritis Study 180 Day Study Blinded/Placebo Bilateral Hip OA 20 dogs VSRC cells - Intra-articular injection 1X Veterinary orthopedic exams at pre,

4 Chronic Post-Surgical Elbow 2 YO Bull Mastiff Right Elbow FCP FCP Surgery > 3 months prior to cell therapy 12/12/06 Exam. Persistent lameness and pain on manipulation. Radiographic severe DJD with osteophytes, sclerosis and remodeling. 12/12/06 Adipose collection and 12/14 IA treatment with 3.3MM cells 1/11/07 Improvement in 4/5 orthopedic parameters. 3/15/07 3/5 Orthopedic parameters normal including no lameness at the walk or trot. Owners assessment showed 8/10 quality of life measurements were returned to normal. Bilateral Coxofemoral Joint Osteoarthritis Study 180 Day Study Blinded/Placebo Bilateral Hip OA 20 dogs VSRC cells - Intra-articular injection 1X Veterinary orthopedic exams at pre, 30, 60, 90 then un-blinded crossover for placebo dogs at day for interim data review Chronic Post-Surgical Stifle Osteoarthritis Study 365 Day Pilot Study, 9 dogs Chronic Post-Surgical OA (>3 Mo) VSRC Intra-articular injection 1X Veterinary orthopedic exams at pre, 30, 90, 180, 365 N=9 for 90 day interim analysis 11 joints (2 dogs had bilateral chronic post surgical OA) 23 24

Chronic Post-Surgical Stifle 5 YO Vizsla- Left stifle 1/9/06 ACL Tear - TTA

RX VSRC cell therapy IA. 3/21/07- mild lameness and no pain.

Cornell Study-2004* Design: 8 Horses 4 treated / 4 controls Collagenase induced

volume of saline 6 week endpoint with weekly ultrasounds *Accepted for

5 Chronic Post-Surgical Stifle 5 YO Vizsla- Left stifle 1/9/06 ACL Tear - TTA 12/1/06 Debride/Slocum release 2/19/07 Arthroscopy w/ 3 / 4 lame. RX VSRC cell therapy IA. 3/21/07- mild lameness and no pain. 12/1/06 2/19/ Early Rabbit Tendon Repair SDF Tendon Study Horses Cornell Study-2004* Design: 8 Horses 4 treated / 4 controls Collagenase induced injury Rx 10 days later Fully blinded histology Controls were treated with same volume of saline 6 week endpoint with weekly ultrasounds *Accepted for publication, American Journal of Veterinary Research, 2008 SDF Tendon Study Horses Cornell Study-2004* Stem Cell Treated Saline Controls 29 30

Cornell Clinical Study Data SDF Tendon Horses (Cornell Study-2004) SDF

Hemorrhage reduction» Inflammatory cell infiltrate (p=0.

013)» Polarized collagen fiber crimping (p=0.

crimping -improved collagen fibers -improved linearity 31 32

Month Post Stem Cell Implant Case Study - Darius Darius Dressage Horse

6 Cornell Clinical Study Data SDF Tendon Horses (Cornell Study-2004) SDF Tendon Horses Histology showed Improved:» Cell shape» Cell density» Hemorrhage reduction» Inflammatory cell infiltrate (p=0.015)» Collagen fiber linearity» Collagen fiber uniformity (p=0.013)» Polarized collagen fiber crimping (p=0.040) Saline Control Stem Cell Treated Overall Healing Score Statistically Improved (p=0.028) H&E Stain -reduce infiltrate Polarized Light -improved collagen crimping -improved collagen fibers -improved linearity Thoroughbred Racehorse Tendon Case Study LEFT Front SDFT 3 Year Old TB Racehorse Time of Stem Cell Implant 32.7% Injury Case Study LEFT Front SDFT 3 Year Old TB Racehorse 5 Month Post Stem Cell Implant Case Study - Darius Darius Dressage Horse RH Proximal susp tear + mid-body adhesions Surgery to remove adhesions and intralesional therapy with VSRCs Within 5 months, return to prior level of performance and has continued to perform since. Left is Injured Right is Un-injured 35 36

Case Study Reiner SDF Bowed Tendon Thanks to Vet-Stem his tendon healed completely and within just ten months of his

- Tim McQuay Success Eq Suspensory Dz Veterinary Full Work- Full Work- Nonresponsive Totals Diagnosis Prior Level Lower

7%) 0 ( 0.0%) 1 (14.3%) 7 Fore Body/Branch 1 (33.3%) 1 (33.3%) 1 (33.3%) 3 Rear TOTALS 47 (75.8%) 10 (16.1%) 5 ( 8.

Nicadual 37 38 Case Study Patellar Tendon Patellar Tendon Avulsion Lab Study Bone Repair Comparison in Canine Skull

7 Case Study Reiner SDF Bowed Tendon Thanks to Vet-Stem his tendon healed completely and within just ten months of his injury we won team gold and individual silver at the FEI World Equestrian Games! - Tim McQuay Success Eq Suspensory Dz Veterinary Full Work- Full Work- Nonresponsive Totals Diagnosis Prior Level Lower Level Proximal - 15 (83.3%) 2 (11.1%) 1 ( 5.6%) 18 Fore Proximal 25 (73.5%) 7 (20.6%) 2 ( 5.9%) 34 Rear Body/Branch 6 (85.7%) 0 ( 0.0%) 1 (14.3%) 7 Fore Body/Branch 1 (33.3%) 1 (33.3%) 1 (33.3%) 3 Rear TOTALS 47 (75.8%) 10 (16.1%) 5 ( 8.1%) 62 Mr. Nicadual Case Study Patellar Tendon Patellar Tendon Avulsion Lab Study Bone Repair Comparison in Canine Skull Critical Defect Model Surgical reattachment 3 Doses over 45 days Back to full ranch work in 90 days Cui et al, 2007, Biomaterials Lab Study Bone Repair Comparison in Canine Skull Critical Defect Model Adipose Stem Cells + coral Control Coral alone Cui et al, 2007, Biomaterials 41 42

Liver Disease Example: 12 YO Doberman NSAID & Old Dog Liver Failure 1 month estimated to live Test Normals 01/03/07 01/19/07 01/26/07 02/22/07 03/22/07 05/05/07 07/21/07 Alk.

7 8 4 2 5 Bile Acids <15 231 15 Single IV Regenerative Cell Injection Wound Healing Potential Role of Adipose Stem Cells: Secretion of collagen I, fibronectin, PDGF, bfgf, IGF

Wound healing effects of adipose-derived stem cells: A critical role of secretory factors on human dermal fibroblasts J Derm Sci, 48(1); Oct 2007; 15-24 43 44 Wound Healing Potential

8 Liver Disease Example: 12 YO Doberman NSAID & Old Dog Liver Failure 1 month estimated to live Test Normals 01/03/07 01/19/07 01/26/07 02/22/07 03/22/07 05/05/07 07/21/07 Alk. Phosphatase ALT (SGPT) AST (SGOT) CK GGT Bile Acids < Single IV Regenerative Cell Injection Wound Healing Potential Role of Adipose Stem Cells: Secretion of collagen I, fibronectin, PDGF, bfgf, IGF Promotes mrna expression of ECM proteins Promotes fibroblast migration No single growth factor can reproduce this activity.. Kim et al. Wound healing effects of adipose-derived stem cells: A critical role of secretory factors on human dermal fibroblasts J Derm Sci, 48(1); Oct 2007; Wound Healing Potential Wound Healing Potential Fibroblast migration in response to micro-injury Kim et al. Wound healing effects of adipose-derived stem cells: A critical role of secretory factors on human dermal fibroblasts J Derm Sci, 48(1); Oct 2007; Wound healing in response to adipose-derived stem cell treatment (Day 7) Kim et al. Wound healing effects of adipose-derived stem cells: A critical role of secretory factors on human dermal fibroblasts J Derm Sci, 48(1); Oct 2007; Wound Healing Potential Surgical/radiation ulcers Korean Studies - HUMAN Crohn s fistula study Phase I HUMAN Rodent wound strength studies Diabetic ulcer therapy Immune-mediated (autoimmune) HUMAN TRIALS: Crohn s Disease Spain and US trials Graft-vs-Host Disease US and China trials Canine: perianal fistula, chronic wounds?? PROPOSED USE IN CANINE: Irritable Bowel Lupus-like Syndromes Immune-mediated Thrombocytopenia Autoimmune Skin Disease Engrafted MSCs in GI Tract Le Blanc et al, Lancet

Ischemic Disease Potential Cardiovascular Congestive heart failure - DCM* Cardiotoxic drugs Spinal Stroke (FCE) All of these need angiogenesis!

9 Ischemic Disease Potential Cardiovascular Congestive heart failure - DCM* Cardiotoxic drugs Spinal Stroke (FCE) All of these need angiogenesis! *Texas Heart Institute Ischemia Model Adipose Cell Therapy 14 Days post ischemia Why did we decide it was safe and effective to move to the clinic? 1. Human preclinical data in orthopedics 2. Human therapy in reconstructive surgery 3. Placebo-controlled Equine Tendon Study Cornell 4. Pilot clinical data in equine clinical cases 5. Quality control systems in our lab Quality Standards 1. Written standard operating procedures 2. Independent Quality Assurance Unit 3. Routine audits of all procedures 4. Sample release criteria 5. Formal training systems 6. Environmental monitoring ALL HANDLING DONE IN STERILE HOODS Safety Profile Horses: 1% reported adverse events. All adverse events have been local, without reported systemic sequelae. Reported: inflammation, soreness, fiber disruption. Dogs: <0.5% reported adverse events. All adverse events have been local, without reported systemic sequelae. Occasional seroma at the site of adipose collection reported. Current Indications Osteoarthritis Polyarthritis Tendonitis Desmitis Fracture 53 54

10 Compassionate Use Program Criteria for Vet-Stem Compassionate Use Program: By approval only Credentialed Veterinarian Veterinarian or another veterinarian in the same clinic must have used VSRC therapy in 10 or more orthopedic cases Detailed case history, veterinary consultation, medical records, lab reports and follow-up Cost is full price 55

Clinical Case Series Adipose Derived Stem and Regenerative Cells for the Treatment of Equine Tendon and Ligament Injuries

Clinical Case Series Adipose Derived Stem and Regenerative Cells for the Treatment of Equine Tendon and Ligament Injuries VetStem Biopharma, Inc., 12860 Danielson Court, Suite B, Poway, CA 92064 Abstract: