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Cell Stem Forum

Pharma’s Developing Interest in Stem Cells

Ruth McKernan,1,* John McNeish,2 and Devyn Smith3 1Pfizer , Cambridge CB21 6GP, UK 2Pfizer Regenerative Medicine, Cambridge, MA 02139, USA 3Pfizer Strategic Management Group, New London, CT 06340, USA *Correspondence: ruth.mckernan@pfizer.com DOI 10.1016/j.stem.2010.05.012

Human is driving the promise of novel regenerative into clinical trials. Although the has embraced stem cells as tools in drug discovery, few companies have taken the risk to deliver stem cell-based medicines. Here, we evaluate the various cell-based opportunities and corpo- rate strategies.

Recently, pharmaceutical and biotech- ultimate promise of stem cell biology is tion. As this research paradigm is the nology companies have taken an cell/tissue replacement . Cell strength of compa- increased interest in stem cell biology. replacement therapies are anticipated nies, a commitment to regenerative medi- The use of stem cells as research tools because of the fact that stem cell deriva- cine based on combining drug discovery has expanded with most of the major tives may accurately recapitulate the and stem cell platforms is taking hold pharmaceutical companies using embry- normal biology of cells or tissues and across the industry, through internal onic stem cells (ESCs) or adult stem cells restore function in degenerative diseases. growth or external partnerships (Trounson for internal drug discovery programs. Therefore, we expect that stem cell- et al., 2010, this issue). These new drug These internal efforts are often enhanced based therapeutic approaches will discovery opportunities could be applied through the expertise of external partner- become of particular relevance as phar- as stand-alone treatments that induce ships with academics or biotech compa- maceutical companies seek opportunities cell fate (e.g., ) or combined nies. The specific use of stem cell-based in disease modification and away from with existing or emerging stem cell-based tools in conventional drug discovery a focus on purely palliative treatment. As therapies. Furthermore, the advent of programs are varied but based on the pharmaceutical companies have been induced pluripotent stem cells (iPSCs) reproducibility of deriving clinically rele- working for years with global regulatory has created an important new opportunity vant cell types as diverse as sensory agencies and clinical centers to create for human pluripotent stem cells carrying , cardiac myocytes, and pancre- strong partnerships, this experience is specific genetic variants, mutations, and atic progenitors. Here, rather than focus a key strength that the pharmaceutical patient specific cell lines to be used in on the extensive application of the tech- industry will bring to the Regenerative drug discovery and personalized regener- nology as tools for drug discovery, we Medicine space. In this discussion, we ative medicine. (reviewed in Rowntree will discuss the emerging opportunities have focused on large pharmaceutical and McNeish, 2010). for biopharmaceutical companies to companies, (Table 1, note that this anal- In terms of using stem cells as thera- engage in stem cell-based regenerative ysis is limited to publicly disclosed infor- peutics, 68 cell-based approaches are medicine. In some instances, the ap- mation), although opportunities for listed under clinical development in proach will apply the pharmaceutical biotech companies could be stronger in a commercial pipeline database. Of these strength in the research and development autologous cell-based therapies. listings, over 90% are company spon- of small or large molecules projects to find Since the earliest protocols using sored, with the only large biopharmaceut- novel therapeutics that modify endoge- murine ESCs for differentiation ical companies listed being Teva, Baxter, nous stem/ fate. For experiments, it was established that small and Genzyme (Table 2). However, when example, discovery programs that stimu- molecules, such as retinoic acid and 5- current/completed clinical studies in four late the endogenous activation of cardiac azacytidine, could be used to direct and therapeutic areas are evaluated, less progenitors for congestive heart failure modify stem cell fate. The interest in than 20% are company sponsored (and (CHF) or (MI) (Wu developing drug screens for human ESC only three are large company sponsored), et al., 2004), expansion of pancreatic differentiation has heightened with better whereas a large number are investigator islet precursor cells for (Chen understanding of developmental path- initiated studies (Table 2). Pharma’s et al., 2009), or activation or release of ways and the identification of specific involvement may be obscured when there adult progenitors in immune disorders molecules to improve cell differentiation is an equity stake in the small company or (Flomenberg et al., 2010). In other cases, (reviewed in Ding and Schultz, 2004). if a company sponsors an academic to run autologous or allogeneic adult stem cells This finding raises the distinct possibility the study. Nonetheless, this trend begs are used to induce the body’s endoge- that small and large molecule (e.g., anti- the question: why is the pharmaceutical nous processes in diseased bodies, nucleotides, ) modifiers industry hesitant to explore cell-based tissue (e.g., ischemia), typically via the will also be identified that can enhance therapy? Significant factors may include action of paracrine factors. Finally, the endogenous cell and tissue regenera- the following: insufficient demonstration

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Table 1. Timeline of Large Pharma Activity in Regenerative Medicine Drug Modifiers of Stem Cells Autologous Adult Stem Cells Allogenic Adult Stem Cells ESCs/iPSCs Company LC EI LC EI LC EI LC Pfizer 01/09: ViaCyte 06/08: 12/09: 04/09: UCL (Diabetes) Eyecyte (eye) Athersys (eye) (IBD) Novartis 03/09: Epistem 11/09: 08/09: Opexa 11/06: ESCs 11/09: HSCI Cellerix (GI) (MS) (CNS) (CNS) Roche 06/09: I-STEM 11/09: Cellerix (CNS) (GI) Sanofi Aventis 04/10: CureDM (Diabetes) Johnson & 08/05: Tengion 07/02: 04/07: ViaCyte Johnson (Bladders) Neuronyx 06/06: (Diabetes) Viacell (CV) Amgen 08/03: Viacell ( bank) Novo Nordisk 07/08: Allocure 10/08: Cellartis (AKI) (Diabetes) Teva (Generics 12/09: MGVS 07/05: 02/05: 09/07: CellCure 06/07: Company) (PVD) Proneuron Gamidacell (eye) Technion (ESC) (SCI) (Transplant) Medtronic 04/08: Scil 11/07: (Device (Dental) Arteriocyte Company) (Ischemia) Smith & Nephew 10/07: (Device REMEDI Company) (Orthopedic) Abbreviations are as follows: EI, date of equity investment made in company; LC, date of collaboration or licensing deal made with company; AKI, acute kidney injury; CNS, central ; CV, cardiovascular; GI, gastrointestinal; HSCI, Harvard Stem Cell Institute; IBD, inflammatory bowel disease; MGVA, multigene vascular systems; MS, multiple sclerosis; PVD, peripheral vascular disease; SCI, ; UCL, University College London. Note that Merck, GSK, Abbott, AstraZeneca, Lilly, , BMS, Takeda show no public activity pursuing cell-based therapeutics, but most are pursuing stem cells as tools for enabling R&D. Source: EvaluatePharma (5/09 and generics excluded from Rx) for 2014 revenue projections and data on Regenerative Medicine activity from public data searches primarily from company websites.

of efficacy, regulatory, and safety con- continue to rely on autologous cells, for markers, such as left ventricular ejection cerns; a belief that cell therapies will not example, the patients’ own fraction (LVEF), with reduction in left offer substantial benefit over existing marrow-derived mesenchymal stromal ventricular end-systolic volume and lesion therapies or demonstrate uptake by cells (MSCs). This therapeutic approach area (reviewed in Abdel-Latif et al., 2007, patients; and lack of familiarity with both typically focuses on cellular induction of Martin-Rendon et al., 2008). Therefore, the business model for commercializing immune modulation or tissue regenera- the data suggest that autologous stem cell-based products and the complexity tion rather than cell replacement and is, cell therapy in cardiac disease results in of developing a product. Therefore, to therefore, amenable to investigator-spon- improved cardiac functioning outcomes. date, few large pharmaceutical compa- sored studies given the low cost and However, the field will need more nies are actively conducting clinical trials minimal technical capabilities required adequately powered, randomized trials given the challenges outlined above. For for the trials. One area of active research to demonstrate clinical outcomes (e.g., pharmaceutical companies to move into has been the application of autologous mortality benefit) and extended clinical the commercialization of cellular regener- human MSCs for acute myocardial infarc- assessments of patient outcomes in order ative medicine products, a ‘‘tipping point’’ tion, where cells are delivered directly to to become a standard of care. As autolo- needs to be reached, and the barriers the ischemic cardiac tissue. Numerous gous stem cell therapy becomes a reliable facing this industry will be dependent on trial designs have resulted in hundreds treatment in ischemic, inflammatory, or the type of cell-based approach under of patients being treated to date. The autoimmune diseases, biopharmaceuti- development. meta-analysis from collective clinical cal companies will evaluate business Of the existing clinical trials using stem data suggest MSCs show a modest, yet models to determine the commercial cells (Table 2), the majority have relied and significant, improvement in functional opportunity associated with investment.

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Table 2. Current Pipeline of Cell-Based Therapies in Development Cell-Based Company-Sponsored Proportion of Company- Large Company-Sponsored Clinical Phasea Therapies Therapies Sponsored Therapies (%) Therapies Phase I 38 35 92 0 Phase II 24 22 92 3 (Teva, Baxter, Genzyme) Phase III 6 5 83 0 Total 68 62 91 3 (5%) Disease-Specific Viewb Disease Trials Company Sponsored Proportion of Company Large Companies Trials Sponsored trials (%) Cardiac Disease 117 24 20 1 (Baxter) Autoimmune Disorders 60 6 10 1 (Genzyme) Endocrine/Metabolic 43 11 26 1 (Genzyme) CNS 43 7 16 0 Total 263 48 18% 1% a ADIS Insight database search using cell replacement therapy as the search parameter with Phase I/II trials put in Phase I bucket and Phase II/III trials placed in Phase II bucket. b From clinicaltrials.gov. Search parameters used were ‘‘Cardiac Stem Cell,’’ ’’Autoimmune Stem Cell,’’ ‘‘Endocrine Stem Cell,’’ and ‘‘Nervous System Stem Cell’’ with additional parameters of ‘‘NOT tumor,’’ ‘‘NOT ,’’ and ‘‘NOT proliferative disorder’’ used to winnow out oncology-related trials.

In health economic terms, autologous reconstructive surgery in Europe and engraft and rely on a variety of mecha- cell-based therapies can be cost effec- Asia. Cytori’s autologous MSCs are also nisms to deliver efficacy, including secre- tive. For example, a recent analysis of in clinical trials for autologous treatment tion of paracrine factors prior to immune stem cell-derived bladder replacement in of acute and chronic heart disease. This destruction. Therefore, the mechanism the UK demonstrated a cost benefit of organization recently partnered with GE of action is not dissimilar to autologous £36,000 over existing therapies. Creating Healthcare for the distribution of the Celu- approaches. There are, however, data therapies for each individual is a very tion devices and commercialization of that suggest that human MSCs may not different business from pharma’s normal stem cell banking and research markets. illicit an allogeneic immune response operating model, in that each patient Even if a significant proportion of the when delivered therapeutically (Klyush- becomes a lot of 1 and entails significant registered autologous stem cell clinical nenkova et al., 2005). Therefore, the logistical challenges (Smith, 2009). trials underway/completed show efficacy, potential exists to treat thousands of Companies considering this opportunity several hurdles must be overcome to patients with expanded adult stem cells will need to evaluate if there are sufficient bring this approach into pharma’s from a single donor. True replacement patients requiring one cell replacement to commercial sphere. Closed-loop devices and integration using allogeneic cells will develop a scaleable process. Two (sterile, transportable, single-use produc- require re-education of the host’s immune feasible commercial approaches to autol- tion units) that simplify cell isolation and system, some type of immune suppres- ogous cell therapy have been taken: expansion and preclude using costly sion treatment, or HLA matching prior to a centralized and distributed model. Tige- GMP facilities may be necessary. treatment. Treatment with immunosup- nix have developed a centralized cell Evidence that efficacy and/or safety pressive therapy can be done today but production approach for ChondroCelect, profiles are superior to existing traditional is not a preferred option, while the other an approved therapy for repair or biologic therapies will options do not seem likely in the short in Europe. A centralized model requires be required to justify the likely high cost term. A robust understanding of the ther- patients to travel to a specialized center of goods and the subsequent selling apeutic areas where adult progenitor cells for treatment. An alternative is the distrib- price. Regulatory oversight will depend have clinical efficacy is likely to emerge uted model, in which cells are removed on the level of manipulation (e.g., drug over the next few years. The majority of from patients and isolated locally by treatment, expansion, etc.) of the autolo- studies being pursued in the clinical trials means of a device before being reintro- gous cells. Nevertheless, recognition database use mesenchymal stem cells or duced to the patient. In this model, that future opportunities exist in this area multipotent adult progenitors for treat- patients are treated on site and are not is evidenced by licensing and invest- ment of immune disorders, given their required to travel to a specific dedicated ment by biopharmaceutical companies anti-inflammatory and immune-modifying center for treatment. The Cytori Celution (Table 1). properties (reviewed in Uccelli et al., device allows bedside isolation of mesen- Human adult and umbilical/placental- 2008). Although ap- chymal stem/stromal cells derived from derived stem cell sources are being proaches have been documented as following liposuction. developed as allogeneic cell-based thera- safe thus far, further studies using hu- These cells are then available for readmi- pies. Current allogeneic stem cell-based man adult stem cells will be required nistration to patients for cosmetic and approaches are not typically designed to to demonstrate efficacy in immune or

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inflammatory conditions. While promising the myriad of ways of generating iPSCs benefit or will revolutionise healthcare. If data has been reported (albeit only in do everything that the gold standard of the latter, pharma needs to be prepared press releases) by Osiris/Genzyme for hESCs do—and no more—but the data for investment and change. Should signif- multiple indications, including GvHD, this have thus far been mixed (Rowntree and icant benefit be demonstrated by stem and other partnerships (e.g., Pfizer/ McNeish, 2010). cell-based medicine, one must anticipate Athersys in inflammatory bowel disease) a flurry of acquisitions and partnering will help define the opportunity for adult Conclusion deals to make way for the future. allogeneic cell therapy. In terms of stimu- Commercially, any approach can be lating wound repair and treating critical viable if two major hurdles are overcome: WEB RESOURCES limb ischemia and myocardial infarction, overall cost of the product and significant as with autologous cell trials, modest patient-benefits. As payers implement AdisInsight (2010). AdisInsight. (http://www. benefits have already been observed, more rigorous health economic analysis adisinsight.com). and many others studies have yet to in decision-making, truly restorative or ClinicalTrials.gov (2010). Clinical Trials Database. conclude. As a business model, alloge- disease-modifying therapies will offer (http://www.clinicaltrials.gov). neic cell sources are more aligned with greater value and subsequent reimburse- EvaluatePharma (2009). Pharma and Biotech Fore- the pharmaceutical business practice of ment value over palliative ones. Cell- casting. (http://www.evaluatepharma.com). centralized product production and distri- based therapies move us toward this Daily. (2010) Surgeons Transplant New Into Child Using His Own Stem Cells bution to health care providers. However, goal, although currently launched prod- to Rebuild Airway. (http://www.sciencedaily. for pharma to aggressively adopt alloge- ucts (e.g., Dermatology and Orthopaedic com/releases/2010/03/100325114400.htm). neic adult cell therapy, multiple issues focused) have been limited commercially will need to be addressed, including cell due to their inability to show significant expansion and manufacturing, product efficacy benefits over standard of care, ACKNOWLEDGMENTS consistency, product delivery to the particularly as related to the costs of patient, and successful well-designed, cell-based therapies relative to the cost The authors wish to thank Maura Charlton for crit- well-controlled clinical trials showing of standard of care. pharma is moving ical review of the manuscript. significant benefits over standard of gradually into stem cells, first using tools care. Given that cell-based therapies are for traditional drug discovery, enhanced REFERENCES already available (e.g., Apligraf from by the greater availability of cell types ), this set of challenges is through iPSC technology. The opportu- Abdel-Latif, A., Bolli, R., Tleyjeh, I.M., Montori, not insurmountable but will require addi- nity to generate novel molecules that V.M., Perin, E.C., Hornung, C.A., Zuba-Surma, E.K., Al-Mallah, M., and Dawn, M. (2007). Arch. tional investment to minimize the cost of modify endogenous stem cells is very Intern. Med. 167, 989–997. making the cell therapy and providing it much in scope and will likely lead to new routinely at the point of care. therapeutic approaches using small Chen, S., Borowiak, M., Fox, J.L., Maehr, R., Osa- fune, K., Davidow, L., Lam, K., Peng, L.F., Direct involvement from pharma in molecules and biologics to enhance the Schreiber, S.L., Rubin, L.L., and Melton, D. human ESC therapy has been modest. body’s natural repair mechanisms. These (2009). Nat. Chem. Biol. 5, 258–265. Concerns regarding the use of a human are near-term options and need little Ding, S., and Schultz, P.G. (2004). Nat. Biotechnol. ESCs notwithstanding, there are advan- change in the way that pharmaceutical 22, 833–840. tages of using pluripotent stem cells as industry works today. The move to true source material for therapy because all cell-based therapeutics by pharma is still Flomenberg, N., Comenzo, R.L., Badel, K., and Calandra, G. (2010). Biol. Blood Marrow Trans- cell types are theoretically possible for modest. Some companies have preferred plant. 10.1016/j.bbmt.2009.12.538, in press. expansion and use in cell replacement to take equity stake in active biotech Klyushnenkova, E., Mosca, J.D., Zernetkina, V., therapies. Examples include the encap- companies while others are adopting Majumdar, M.K., Beggs, K.J., Simonetti, D.W., sulated beta-cells for treatment of type 1 a ‘‘watchful waiting’’ approach until the Deans, R.J., and Mcintosh, K.R. (2005). J. Biomed. diabetes as proposed by ViaCyte myriad of clinical trials currently underway Sci. 12, 47–57. (formerly Novocell) and supported by read out definitively one way or another Martin-Rendon, E., Brunskill, S.J., Hyde, C.J., J&J’s equity stake, Geron’s oligodendro- before actively investing in the space. Stanworth, S.J., Mathur, A., and Watt, S.M. cyte therapy for spinal cord injury, and As there are hundreds of regenerative (2008). Eur. Heart J. 29, 1807–1818. Pfizer’s collaboration with University medicine-focused compa- Rowntree, R., and McNeish, J. (2010). Regen. College London to produce retinal nies globally, it is expected that partner- Med., in press. pigment for the treatment of ships with biopharmaceutical companies Smith, D.M. (2009). The World Stem Cell Report age-related macular degeneration. will develop following the demonstra- 2009, B. Siegal, ed. (Genetics Policy Institute), Concerns around safety, anticipated tion of clinically safe and efficacious pp. 131–137. regulatory complexity, and lack of experi- approaches. Pfizer and Teva have taken Trounson, A., Baum, E., Gibbons, D., and Tekamp- ence in this new area of research may be a much more proactive ‘‘partner and Olson, P. (2010). Cell Stem Cell 6, this issue, 513– significant barriers to entry. While iPSCs learn’’ approach, and it is highly likely 516. may remove ethical concerns, the safety that some companies may have stealth Uccelli, A., Moretta, L., and Pistoia, V. (2008). Nat. and regulatory hurdles remain undimin- efforts that are not yet visible in the public Rev. Immunol. 8, 726–737. ished and may even be greater. Much domain. We still do not know whether Wu, X., Ding, S., Ding, Q., Gray, N.S., and Schultz, research needs to be done to show that regenerative medicine will provide niche P.G. (2004). J. Am. Chem. Soc. 126, 1590–1591.

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