L avenir industriel de l ingénierie tissulaire et cellulaire

Transcription

1 L avenir industriel de l ingénierie tissulaire et cellulaire Vincent Ronfard, UNTHSC, Fort Worth, Texas 6/7/2015 Lyon VO in English with subtitles Skin and Wound healing business as model

2 LE FUTUR

3 2020 Organ Replacements By 2020, a landmark is reached, with scientists having fully characterized how every part of the heart works enabling complete replacements for use in transplants. The need for external donors is eliminated, and since the organ is genetically matched to the patient, there is no chance of rejection. This new treatment offers hope to millions affected by cardiovascular disease. Until now, 15 million people had died each year from such conditions. As well as the heart, other organs are gradually being developed: lungs, livers, kidneys, spleens, stomachs, pancreas. Internal organ failure will eventually become a thing of the past; for those who can afford the treatments, at least. Furthermore, new vitrification techniques. allow organ banking without damage from ice crystal formation.

4 2020 Stem Cell Therapy Worldwide stem cell therapy market is poised to grow at a CAGR (Compound Annual Growth Rate) of 39.5% from 2015 to 2020, to reach $330million by The global stem cell therapy market is estimated to grow at a lower CAGR in developed countries as compared to emerging countries such as China, India, and Korea in the forecast period ( ). SOURCE RnR Market Research

5 2020 consumers Informed and demanding patients are now partners in their own healthcare Individuals are better informed about their genetic profile, the diseases they have and might have, and the availability of healthcare Expectations of healthcare and better outcome for themselves and loved one are at their highest. Patients are educated, embraced prevention and ask for specific treatment and are willing to pay Patients are now true consumers Deloitte 2015

6 2020 R&D The networked laboratory-partnership and big data amidst new scrutiny R&D has few boundaries R&D model is networked built around academic and other partnerships The share of in-house only discovery is at an all time low. R&D activities are widely distributed with Pharma companies coordinating and integrating at the center Focus is on: understanding disease biology and genetics, current SOC and treatments pathways Patient are more involved in prevention and treatments Market divided in 2: high value low volume Western market and Low value high volume emerging market Deloitte 2015

7 LE PRESENT

8 NEED FOR TISSUE/ORGANS HUGE 8

9 Wound Market Sizes and Unmet Medical Need Cost of treating chronic wounds is rising sharply, representing >$25B in healthcare expenses in the US annually Total Wounds 5,324, ,186 Hard-to-Heal Wounds 1,913,499 45,119 2,823, , , , , , , ,360 DFU VU AU PU Burn Source: BioMedGPS SmartTRAK Wound Biologics database,

10 Timelines very long and costly Probability of success Probability: 66% Probability: 70% Probability: 40% Steps Outcome Basic & Discovery Research Proof of Concept. Preclinical Research Preclinical Development Therapeutic Candidate Clinical Phase I Clinical Phase II 1-3 years year years IND Safety Efficacy Clinical Phase III Product Release Market Investment Amount $5-10MM PI $10-15MM PII $20-25MM PIII $50-75MM $75=100MM Actors Universities, Research Institutes, Hospitals Venture Investments Big Pharma / Bio Average Time to Market: Years Key Metrics: Costs: $100M-$1B Failure Less than 30% of all approved drugs recoup development costs Centre for Biological Engineering Greg Bonfiglio: Proteus venture partners

11 Clinical Trials Design not Optimal 167 Randomized Controlled Trials: - Short duration of Follow-up (median 12 weeks) - Small sample size (Median 63) - Fail to define primary outcome (41%) - 40 % of the trials use appropriate method of randomization

12 Need for Evidence-Based Products Clinical Trials in VLUs in the US 66 trials reported Only 17 had N>100 6,335 patients total 20 trials were randomized controlled trial with valid outcomes Only 6 were multicenter 5 reported significant improvement in %closed

13 Financial Challenges

14 Regulatory Challenges There are approximately 500 cell therapy companies spread across Asia, Europe and North America with combined annual revenues in excess of 1 billion in 2012 and predicted to double by A million patients have received cell-based therapies and well over a 1,000 clinical trials are underway, and yet the total number of regulatory agency approved products is still only 20. Chris Mason, July 2013 Cells and cell-based therapies are being managed by the FDA under the same logics as DRUGS are managed. Cells are not single molecular agents but are,rather, site-regulated, adaptive agents capable of very complex functions involving a multitude of bioactive factors and reactivity. interview with Arnold Caplan, Part 4: the FDA and the Future Posted on April 7, 2013

15 ENVIRONMENT IS MOVING Medicare/Medicaid reduce reimbursement for Regenerative Medicine wound care treatments Apligraf and Dermagraft Shire who had bought Dermagraft for $750M sold it for $300M milestone payments to Organogenesis Organogenesis close Dermagraft manufacturing facility and lay off many of their own staff including all of R+D Sanofi sold RM business purchased through Genzyme acquisition to Aastrom for 10% of 2013 sales May , L'Oreal USA Announces Research Partnership with Organovo to Develop 3-D Bioprinted Skin Tissue

16 Historique

17 Chronology 17

18 Skin is the body s largest organ Accounts for 12 16% of the total body weight. The average adult skin extends to about 20 square feet The skin is constantly renewing from the bottom up every 27 or 28 days totaling 1,000 new skins in a lifetime

19 Connections to multiple market opportunities Burns Scars Chronic Wounds Acute Wounds Cell- and Cell- Matrix Technolog ies Aesthetics Reconstruc tion Cosmetics 19

20 30 years ago. 3 main discoveries: In the late 1970s early 80s, All From MIT (Boston) 1- Rheinwald and Green were able to grow serial passage keratinocytes from a single cell suspension of dissociated skin tissue, enabling human epidermal cells to be cultured into multiple epithelia suitable for grafting 2- Eugene Bell and collaborators produced a tissue-like structure in vitro by contraction of collagen lattices using human fibroblasts 3- Yannas and collaborators designed the first bilayer artificial skin composed of a temporary silastic epidermis and a porous collagen-chondroitn 6-sulfate fibrillar dermis. Followed by publication of Naughton et al (1987) Hematopoiesis on nylon mesh which will lead to the development of Dermagraf

21 It all started with the 3T3 The Story of 3T3 Cells: A Voyage of Discovery Without an Itinerary (Howard Green) 21

22 The Story of 3T3 Cells: Clinical Applications The Cultivation Of Keratinocytes In 1974, Jim Rheinwald, at that time a graduate student, was working on a mouse teratoma, a germ line tumor able, while growing as a transplanted tumor, to differentiate into a number of somatic tissues. Without these fibroblasts, the epithelial cell type could grow only slowly, but when lethally irradiated 3T3 cells were added, the epithelial cells grew beautifully, while growth of the teratomal fibroblasts was suppressed. We then asked whether normal human diploid keratinocytes of the skin could grow under these conditions. They could (Rheinwald and Green, 1975), and diploid keratinocytes became a cultivable cell type Detachment of a coherent epithelial sheet with Dispase (Green, Kehinde, and Thomas, 1979). Graft to the surface of athymic mice (Banks-Schlegel and Green, 1980) Graft on humans (O'Connor and J. B. Mulliken, 1981), (Gallico et al., 1984; Green, 1991). Similar procedure has been used to restore corneal epithelium (Pellegrini et al., 1999; Pellegrini, 1997). Improvements and simplification of the method of preparing the cultures for grafting are likely to expand the use of cultured autologous keratinocytes in the treatment of disease (Pellegrini, 1999; Ronfard et al., 2000). 22

23 THE FIRST EPITHELIUM RECONSTRUCTED IN VITRO Cultured Epithelial Autograft (Epicel) Cultured epidermal autografts (CEA) In 1975, James Reinwald, Ph.D. and Howard Green, M.D. (Rheinwald and Green) first demonstrated that human epidermal keratinocytes could be isolated and serially culture in vitro with mouse fibroblasts that had been lethally irradiated to halt their proliferation. A few years later, this process was used to produce large sheets of cultured epithelium suitable for grafting. Such cultured epidermal autografts (CEAs) were first used in the treatment of major burns in

24 Development of a Fibrin substrate to grow keratinocytes No enzyme treatment No graft retraction Coherent and Solid Sheet Ready to graft

25 Clonal Analysis of Keratinocytes Barrandon et al

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27 LSE, Graftskin, Apligraf The living skin equivalent is a tissue formed when selfassembled collagen fibrils are contracted by fibroblasts. The rate and extent of volume contraction is proportional to the number of cells incorporated into the lattice. The fibroblasts are biochemically active in the lattice, synthesizing collagen and adding it to the matrix. This compacted lattice provides a substrate allowing attachment of keratinocytes and the formation of a multilayered keratinized epidermis with a basement lamella. When a skin equivalent grafted to a recipient animal is wounded, it is capable of wound contraction and repair. Scan Electron Microsc. 1984;(Pt 4): The living skin-equivalent as a structural and immunological model in skin grafting. Bell E, Sher S, Hull B.

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29 Evolution of definition Graftskin, a Human Skin Equivalent, Is Effective in the Management of Noninfected Neuropathic Diabetic Foot Ulcers (Veves A. et al. Diabetes Care February 2001 vol. 24 no ) Biological Skin Equivalents (BSE) These wound-healing therapies are laboratory-derived tissue constructs, designed to resemble various layers of real human skin. They consist of cultured, metabolically active skin cells grown over a scaffold or mesh framework Apligraf is a unique, advanced treatment for healing. It is created from cells found in healthy human skin. Which explains why it looks like a thin, piece of real skin.

30 Evolution of usage We report on three basic scenarios of healing: (i) promotion of healing by secondary intention, (ii) persistent biological wound closure with stimulation of underlying healing, and (iii) healing by frank graft take of the cultured material with remodelling of the tissue over time. Sabolinski et al. Cultured skin as a 'smart material' for healing wounds: experience in venous ulcers. Biomaterials 1996 Feb;17(3): An average of 3.9 Graftskin applications was performed during the study. As complete wound healing was achieved in a considerable number of patients after one or two applications, it may be proved that weekly application is not necessary in all patients. As an alternative, we believe that a single application can be contemplated and the clinician may defer a second application if a successful wound closure rate is achieved to indicate complete wound healing needing no further intervention. (Veves A. et al. Diabetes Care February 2001 vol. 24 no ) National Government Services, one of the country's largest federal health care contractors, is changing its coverage policy for Apligraf to five applications with weekly assessments for reapplications for both DFU and VLU patients ( Canton, Mass. Tuesday, April 17, 2012 )

31 Organogenesis 1979: Bell et al.: Production of a tissue-like structure by contraction of collagen lattices by human fibroblasts of different proliferative potential in vitro Proc Natl Acad Sci 1985: Organogenesis Inc. 1990: Testskin ( skin equivalent in vitro use) 1996: Agreement Novartis worldwide marketing of Apligraf 1998: FDA approval for the treatment of healing resistant venous leg ulcers 2000: FDA approval for the treatment of healing resistant diabetic foot ulcers 2012: Shipped 500,000 th unit of Apligraf for patient care

32 Dermagraf

33 Dermagraft 1986: Marrow-Tech incorporates; tissue-engineering platform technology 1990: Markets skin 2 for cytotoxicity testing (pre-cursor to Dermagraft) 1991: Marrow-Tech renamed Advanced Tissue Sciences; began development of Dermagraft (burns) 1993: Began development of TransCyte (burns) 1996: ATS / Smith & Nephew form joint venture 1996: Dermagraft clinical trials for ulcers initiated 1997: TransCyte approved for partial and full-thickness burns 1998: ATS / S&N joint venture expanded to include TransCyte 2001:Dermagraft approved for diabetic foot ulcers 2002: ATS files Chapter 11; S&N acquires the JV Dec 2005: S&N decided to exit the business, put assets related to Dermagraft and TransCyte up for sale May 2006: ABH purchased assets Feb 2007: ABH revalidated Manufacturing facility and shipped first Dermagraft to customers June 2011: Shire acquired ABH, VLU pivotal trial not successful January 2014: Organogenesis acquired Dermagraft

34 ACELLULAR SYNTHETIC ACELLULAR BIOSYNTHETIC ACELLULAR BIOMATERIAL / TISSUE DERIVED CELLULAR BIOLOGICAL List of products available or in development (US/EU) Autologous, not cultured FULL THICKNESS GRAFT SPLIT THICKNESS GRAFT RECELL FB KC FB KC KC Autologous cultured LYOFOAM EXTRA SUPRATHEL BIOBRANE (B) EZ-DERM (P) INTEGRA (B) JALOSKIN LASERSKIN YALOMATRIX TRANSCYTE (H) XELMA ALLODERM ALLOPATCH ALLOSKIN ARTHROFLEX DERMACELL ENDOFORM (O) FLEX HD (H) GAMMAGRAFT GRAFTJACKET INTEXEN (P) MATRIDERM (B) MATRISTEM (P) MATRIX HD MEMODERM OASIS (P) PERMACOL (P) PRIMATRIX (B) PUROS DERMIS REPLIFORM STRATTICE (P) TISSUEMEND (B) UNITE BIOMATRIX (E) BIOSEED-S KC CELLSPRAY KC EPIBASE KC EPISKIN KC HYALOGRAFT FB KC KERAGRAF (EPIDEX) KC LASERSKIN (VIVODERM) FB KC MYSKIN KC MYDERM FB KC PERMADERM FB KC Autologous cultured & Xenogeneic EPICEL KC Allogeneic minimally manipulated EPI-FIX GRAFFIX THERASKIN Allogeneic cultured CELADERM DERMAGEN ICX-SKN Allogeneic + synthetic DERMAGRAFT KC FB FB FB Allogeneic + xenogeneic APLIGRAF (B) ORCEL (B) FB KC FB KC Allogeneic immortal STRATAGRAFT KC

35 Standard Guide for Classification of Therapeutic Skin Substitutes ASTM (American Society for Testing and Materials) F2311http:// Skin substitutes Skin equivalents Bioengineered alternative tissues Bioprocessed alternative tissues Bioengineered alternative cells and tissues Bioprocessed alternative cells and tissues Bioengineered cells and tissue alternatives Bioprocessed Cells and Tissue Alternatives for Wounds Biologic Products for Wound Treatment and Surgical Interventions (BPWTSI) Cellular and Engineered Tissue Alternatives (CETA) Cellular and Bioprocessed Tissue Alternatives Bioengineered Tissue- Promoter for Wounds Biodynamic Tissue-Promoter for Wounds Bioprocessed Cells and Tissue-Derived Products for Skin Wounds Cells and tissue for wounds Terms Alliance Discussed ASTM International F04.41 Meeting November 15, 2012 Atlanta, Georgia

36 Les Echecs

37 EPIDEX Epidex, is a differentiated, cultured epithelial autograft made of outer root sheath (ORS) keratinocytes

38 VCT01 next generation of bio-engineered cell based technology

39 HP : Spray Keratinocytes, Fibroblasts and Fibrin The improvement in complete healing in the cell treatment group over vehicle observed at the end of the double-blind study was maintained at the end of the open-label follow-up Lancet 2012

40 HP Failure in Phase III(1) Mon Oct 13, :41am LONDON Smith & Nephew 'spray-on-skin' for leg ulcers flops in trial A novel spray-on skin treatment consisting of living cells made by Smith & Nephew, which is designed to work with the body s own cells to help heal leg ulcers, has failed in a late-stage clinical trial. The product, known as HP , was viewed by some analysts as a key pipeline asset in the company's advanced wound management division and the Phase III failure is a setback for the healthcare group, which is a regular subject of takeover talk. The unsuccessful North American trial, announced on Monday, is also something of a surprise, given the promise of earlier studies.

41 Autologous ADSCs Failure in Phase III (2)

42 CYZACT Failure in Phase III (3) Phase III results of Cyzact fail to meet primary endpoint Friday, March Intercytex Group plc (LSE: ICX) ( Intercytex or the Company ) announces that the Phase III study of Cyzact for the treatment of venous leg ulcers has failed to meet its primary endpoint. The primary endpoint was demonstration of a statistically significant (p<0.05) increase in complete wound closure at up to 12 weeks compared to four layer compression bandaging alone. The 396-patient Phase III trial was conducted in the US, the UK and Canada. The three arm study involved all patients receiving four layer compression bandaging (the current standard of care for venous leg ulcers) with either Cyzact (n=196), vehicle (a fibrin disc with no cells, n=100) or standard of care alone (n=100). The primary endpoint of the study was the incidence of complete wound closure at up to 12 weeks for the Cyzact arm of the study versus the standard of care arm

43 CYZACT Failure in Phase III (3) Paul Kemp 2013

44 LES RAISONS D ESPERER Science - Basic Science - Thinking Out of the Box - Understanding diseases - Characterization, MOA, Potency - Manufacturing CMO - Data collection and processing Funding, Organization, Government, Regulatory Quality (QbD), Project management, Design Control, Critical mass: learning curve, TPP, Patient involvement, Market

45 AMELIORATIONS A APPORTER Health System and Reimbursement Regulatory Path Logistics upstream/downstream Storage Reduction COGS Target Patient Population (personalized medicine, Home diagnostics)

46 CHALLENGES

47 Industry Challenges To develop a scalable process that guarantees product viability at an affordable price. The product must satisfy the medical community, the regulators, the payers and the customers.

48 Process Challenges Sourcing of raw material (cells and Scaffolds) Quality control Sterility GMP compliance Process Validation: equivalence between laboratory and industrial processes Risk Analysis Scalable (evaluation of product volume needed to payback the investment). Automation means sometimes to redesign the product or materials and methods Stemming from a laboratory environment, many tissue engineering processes use manual procedures and hence may not be easily scaled to meet commercial requirements Process development must be considered early in the research cycle. This means that investor must give enough resources and time to perform the research Comparability

49 Some clues about Mechanism of Action? It has become clear that keratinocyte allografts (and, probably autografts) have beneficial effects on wound healing apart from providing cover: these include production of growth factors and extracellular matrix proteins. (Hancock K, Leigh IM. BMJ 1989) In contrast to autografts, allografts do not survive permanently. The postulated mechanism of action is the release of various growth factors, which stimulate the reepithelialization from the wound edge as well as from epidermal appendages. (Siedler S, Schuller-Petrovic S. Arch Dermatol 2000) The mechanism of action of bilayered substitutes is unclear. It is thought that they supply necessary growth factors in the appropriate concentration and sequence that are otherwise lacking in chronic wounds. Also, the metabolic activity of young cells may supply larger numbers of growth factors. (Morton LM, Phillips TJ. Semin Cutan Med Surg 2012)

50 Scientific challenges in defining potency Challenges: Cells depend on their (micro) environment and react to it Cells may dedifferentiate and become heterogeneous during culturing processes Preclinical toxicity (animal) studies often are not applicable Current approaches for dose dependency / efficacy studies don t work for cell-based therapies Solution: Cell viability (active therapy), Surrogate assays to measure Cell Fitness* (ability to react to the environment) * Paul Kemp

51 Quality attributes Standardization Ensuring quality manufacturing: QbD Procurement isolation Manufacturingg Release criteriag Biopsy harvest Expansion process Quality control Cell yield Viability Safety Cell growth Viability IPCs Identity Purity Potency Sterility

52 REGULATORY There is no sense in regulating MSCs as a drug. MSC = Medicinal Signaling Cell. (the injury-specific DRUG STORE) BIOFORMULATION These facts require new management logics and regulatory values. interview with Arnold Caplan, Part 4: the FDA and the Future Posted on April 7,

53 SOLUTIONS

54 NEW MODELS: Progressive translation Paul Kemp 2015

55 Define a New Path for Commercialization A million patients have received cell-based therapies and well over a 1,000 clinical trials are underway, and yet the total number of regulatory agency approved products is still only 20. Solution are investigated in Japan, UK, US Chris Mason, July 2013

56 Partnering Academia Industry Translation Centers Alliance, Organization

57 Health Economic : Benefit Analysis for Wound Therapy Chronic Venous leg ulcers: the future of cell-based therapies. Published online August 3,

58 There will come a time when you believe everything is finished; that will be the beginning. Louis Lamour

59 MERCI ET A BIENTOT

60 Symposium Industry: September 10, 10:30 am to 12 noon and 1 pm to 2:30 pm How Regenerative Medicine Stakeholders adapt to the ever changing technology and regulatory challenges? Symposium part 1: Evaluating the Past, Present of Regenerative Medicine (10:30 am to noon) 4 Lectures Symposium part 2: How to overcome obstacles encountered when bringing products to the commercial phase (1 pm to 2:30 pm) Panel discussion