Pro : 3D Autologous Chondrocyte Implant System - PowerPoint Presentation

1. Pro: 3D Autologous Chondrocyte Implant SystemThomas M. DeBerardino, MDProfessor of Orthopaedic Surgery, Baylor College of MedicineCo-Director, Baylor-San Antonio, Texas Sports Medicine FellowshipThe San Antonio Orthopaedic Group Medical Director, BRIO

2. Matrix Assisted Autologous Chondrocyte Implantation NOVOCART® BasicChondrocytesFGF-2N3DScaffoldCellsGrowth FactorsBiologic-Device Combination Product**Membrane3D PorousScaffold5 mos post-implantationCartilage Regeneration: NOVOCART 3D

3. Forecasted shift from “conservative” options in 2017 to “cell based” options in 2022Other includes: one-step/point-of care/intra-op tissue-derived, device only (scaffold), fresh stem cells, PRP’s and other options - 2017 - 2022Cartilage Regeneration: NOVOCART 3D

4. Cartilage repair continues to be an opportunity for growth Estimated that cartilage repair is needed in 16% of all patients presenting with knee pain.The global cartilage repair market number is expected to reach $7B by 2024, rising at a market growth of 5.6% CAGR*The number of US Patients with diagnosed knee pain was estimated at 20 M which suggests 3.2 M patients could benefit from cartilage repair Surgeons believe cell based technology will provide superior outcomes to alternatives Headwinds:High expectations Ease of use is often a deciding factor for target surgeons Handling during surgery is a concern and off-the-shelf options are used with increasing frequencySurgeons express concern with a 2 step procedure Recovery protocols may be an issue for patients, especially non-weight bearing time. Surgeons want evidence long term durability, maybe over 10 years (patients will likely want this too)Manual manufacturing processes will not meet commercial capacity/cost demandThe cost of procedures and insurance obstacles Many physicians won’t offer options that cause office reimbursement hassles.Most patients won’t agree to procedures that require high out of pocket expenses.Specific Pros/Cons for US Aesculap Biologics:Fully automated manufacturing process to address commercial demand/costInjectable (arthroscopic) version in late-stage development (EU clinical evaluation)Second/third to market No presence or relationships in sports medicine *OrthoSpine News, June 2018Cartilage Regeneration: NOVOCART 3D

5. 1997-2007 2018 2019 2020 2025U.S.Carticel (Vericel)DeNovo NT (Zimmer)MACI ® (Vericel)NeoCart ® (Histogenics)NOVOCART® 3D(Aesculap)Failed Phase 3 trialTwo-step (two surgical procedures), cultured autologous cell-based productsOne-step (single surgical procedure) device products in development (clinical trial)?Hyalofast C® (Anika Therapeutics)Agili C® (CartiHeal)Gelrin C® (Regentis)US NOVOCART® 3D Competitive LandscapeNOVOCART® 3D PositioningMACI® rapidly expanding market adoption/acceptanceCommercial demand will outstrip manual manufacturing capacityN3D fully automated manufacturing process can meet demandCapacity, quality and cost advantagePoint-of care potentialNext generation injectable version in late stage development (EU)

6. Next generation autologous chondrocyte cell-scaffold combination productTreatment of focal articular cartilage defects (condyles, trochlear groove) Composed of ex vivo-expanded autologous chondrocytes (biologic component) seeded on a bioresorbable biphasic scaffold (device component)CSuperficial zoneMineralized zone BoneCartilage for chondrocyte isolationExpanded Autologous ChondrocytesBiphasic Collagen Scaffold+BiopsyCartilage-Bone plugCartilage Regeneration: NOVOCART 3D

7. NOVOCART 3D: The Procedure A small piece of cartilage is extracted from a non-weight bearing section of the knee jointProduction of the NOVOCART 3D transplant: culture expanded chondrocytes are seeded on to the 3D porous component of the biphasic scaffold.The defect area of damaged cartilage is measured, cleaned out and prepared for implantation of NOVOCART 3DThe transplant is cut to fitThe transplant containing cartilage cells is placed into the defectThe transplant is fixed in place with resorbing suture materialNOVOCART 3D contains 8.25 x 106 to 40 x 106 viable chondrocytes per 9 cm2 scaffoldNOVOCART 3D will be implanted approximately 21 - 25 days after biopsy harvest

8. NOVOCART 3D: Clinical Experience Extensive human clinical experience data available for NOVOCART 3DCommercial and clinical research: over 20,000 patients treated to dateSummary of Clinical Experience:On market in Germany and 4-5 other EU countries since 2003Ongoing pivotal Phase III clinical trial in EU for full EU market authorization (EMA approval)Ongoing pivotal Phase III clinical trial in US under approved IND for FDA approvalApproval through Health Canada to open investigational sites in CanadaApproved Rescue Study in US with goal of treating patients who fail the Microfracture treatment arm on the core trial with NOVOCART 3DPlanned Submission:Preparing to submit Rescue Study through Health Canada for approval

9. NOVOCART 3D: Clinical Experience Time PointMean Change in IKDCMean Lysholm GillquistMean Cincinnati scoreBaseline42.261.553.46 months9.2--1 year14.222.119.82 year20.618.926.33 year19.8--4 year24.2--5 year27.6--6 year34.8--Sponsored StudiesTwo EU studies followed 422 (retrospective) and 149 (prospective) N3D treated subjects, respectively. The clinical data from both studies demonstrated significant improvements in pain and function, and high levels of patient safety with a low risk of complications.

10. NOVOCART 3D Clinical ExperiencePublished Zellner et al, 2014 Clin Orthop Relat Res (2013) 471:2852–2861. Zellner et al, 2014. Image F is 1 year post implant

11. NOVOCART 3D: Clinical Experience Arthroscopic biopsy and histologic evaluation at 30 months demonstrates complete defect fill and integration with surrounding native cartilage tissue.MRI results: T2 Relaxation times of 13 patients treated with NOVOCART 3D were similar to surrounding native cartilage at 24 and 36 months. **5 months post- implantationNative cartilageN3D cartilage

12. Considering Microfracture? Consider the NOVOCART 3D TrialNOVOCART 3D Clinical Trial

13. Phase III Clinical Trial under an Investigational New Drug (IND) ApplicationMeasure Safety & Efficacy of NOVOCART 3D compared to Microfracture2:1 Randomization (NOVOCART 3D vs MICROFRACTURE)Long Term Safety & EfficacyPrimary EndpointAnalysisNOVOCART 3D: Clinical Trial Design & Schedule

14. 233 Total EnrollmentGoalUnited States &Canada32 SitesParticipating102 ParticipantsTreated to DateN3D Trial OverviewRescue Study

15. Primary and Secondary ObjectivesPrimary ObjectivesCo-primary pain AND function endpoint (superiority over microfracture)Changes from baseline:KOOS Activities of Daily Living subdomain score at 24 monthsKOOS Pain subdomain score at 24 monthsSecondary ObjectivesSafety: To evaluate the safety profile of NOVOCART 3DEfficacy: To assess post-surgical symptoms and function including pain, overall efficacy, knee-related quality of life, and activity levels How does a patient qualify?

16. * Contact Aesculap Biologics, LLC Medical Scientific Affairs for a full list of Inclusion criteriaCommon Inclusion CriteriaThe following criteria must be fulfilled to participate in this clinical trial:Able and willing to give Informed ConsentBetween the ages of 18 and 65 yearsBMI below 40Stable, properly aligned knee joint or sufficiently reconstructed ligamentsInadequate response to conservative treatmentPain in only one kneeCartilage defect between 2.0 and 6.0 cm2 and Grade III/IV ICRS ClassificationIntact meniscus (in case of meniscal resection, rim must be intact with normal configuration and meniscus must be functional

17. Common Exclusion Criteria* Contact Aesculap Biologics, LLC Medical Scientific Affairs for a full list of Inclusion criteriaExclusion Criteria:Defect size less than 2 cm2 or greater than 6cm2Cartilage lesions requiring more than one prepared defectBone loss or deep defects which require bone graftingClinically significant arthritis/arthrosisPresence of autoimmune diseaseHistory of cancerOsteoporosisPrior surgical treatment for cartilage repair (debridement/lavage is acceptable)Chrondroplasty by laser or other thermal or plasma ablation (closure of veins are acceptable)

18. Other Key ConsiderationsThe following concomitant procedures are permitted:Meniscal repair (no meniscus transplants)Ligament repair/reconstructionRealignments (these procedures would be done at the time of the Microfracture or at the time of the NOVOCART 3D implant. They cannot be done at the time of biopsy.)A few things to keep in mind:There is a one month washout period for any patient who has received an intra-articular injection of the affected kneeThere is a three month washout period for any patient on steroid use (anabolic or corticosteroid)Prior meniscal or ligament repair is fine as long as the knee is deemed stable at the time of surgery one

19. Thank You!Thomas M. DeBerardino, MDProfessor of Orthopaedic Surgery, Baylor College of MedicineCo-Director, Baylor-San Antonio, Texas Sports Medicine FellowshipThe San Antonio Orthopaedic Group Medical Director, BRIO