Public health and drug development model is broken
Stem cell therapies could arrive just in time to help as new models for health care delivery are sorely needed. Care delivery costs continue to rise, worldwide populations are aging, and physician shortages are expected. The cost to bring a new drug to market has soared to $1.3 billion, [1] and there are fewer drugs seeking approval (in 2011, the U.S. FDA had only 23 new drugs applications as compared with 45 in 1996). [2] Also, new classes of drugs such as cellular and gene therapies will be even more costly and complicated than today’s already expensive small molecule drugs and biologics. Investors have been shrinking from the market, and at the national public health level, there could be a bleak period of care rationing.
Stem cell therapies could find a nice fit within public health landscapes to ease costs and provide effective disease treatment. Even if a few of the 50 therapies currently in development were to be successful, the impact could be substantial in both improving patient outcomes and reducing health care costs. On the other hand, current challenges with stem cell therapies will need to be overcome. The field is nascent with expensive therapies that are challenging to commercialize, for example $93,000 for prostate cancer therapy Provenge. Translation is slow, with few eligible patients actually receiving stem cell therapies, and widespread clinical implementation could be 10-20 years away.
Contemporary stem cell policy issues
There are three main areas of current policy concern in stem cell therapies: the use of embryonic stem cells (ESCs), operational issues in the manufacture of therapies, and medical tourism. Regarding ESCs, while a regulatory ban was lifted in 2009 in the U.S. which previously limited the ESC lines that could be used in federally-funded research, debate about the use of embryos continues. Approximately 48,000 in vitro fertilization babies are born each year in the U.S. [3] In the process, typically 10 blastocysts are created, only one of which is implanted into the prospective mother. The rest are frozen, discarded, or donated to research. Ethical debate about the appropriate use of the unused blastocysts remains unresolved although not limited legally. There are however solutions on the horizon. The regulatory period forced scientists to develop other methods of generating stem cells and much progress has been made in induced pluripotent stem cells (iPSCs), reprograming regular cells such as skin cells back to a pluripotent stage where they can then be differentiated into any cell type.
There continue to be exciting developments in iPSCs and an important current focus is the direct reprogramming of one cell lineage to another without having to induce pluripotency. Two recent efforts in this area were the transformation of adult skin cells directly into functional neurons, [4] and the targeted genetic engineering of human pluripotent cells with nuclease enzymes. [5]
A second set of policy concerns operational issues. Understandably, there is a need for manufacturing standards as the industry scales up in the production of stem cell therapies, particularly with regard to iPSC-derived products. [6] Consistent output, quality control, process reproducibility, and safety testing, within clinical time constraints, are some of the points outlined for regulation. Other cellular therapy-related policy concerns include the issue that therapies may not fit into the current FDA approval phases and may require alternative processes (e.g.; testing Phase I and II safety and efficacy together), and that current loopholes by which physicians administer drugs to patients (e.g.; access to investigational programs and off-label prescribing) may not be appropriate for cellular therapies. [7]
The third contemporary policy issue is medical tourism which has considerable discussion and opinion both in the popular press and from scientists. While scientifically-rigorous stem cell therapies are slowly progressing through regulatory approval, numerous companies in the U.S. and abroad have begun to offer stem cell therapies which many scientists denounce as unproven. Responses range from the outright dismissal of such treatments as quackery and 21st century snake oil to wondering how a better job can be done to deliver effective therapies through the traditional public health system. The issue is compounded by some recent high-profile individuals obtaining overseas stem cell treatments that apparently did not work, for example those received by professional football player Payton Manning [8] and Texas governor Rick Perry. [9] There is a call for the stronger international regulation of stem cell therapies with an emphasis on establishing accountability and efficacy, and the suggestion that other countries adopt regulatory frameworks similar to those used in the U.S. and the U.K. [10] One resource for information about clinics outside of the U.S. is the International Society for Stem Cell Research (www.ISSCR.org). Although at present few Americans are traveling for medical tourism (mainly orthopedic, cardiac, and cosmetic procedures), [11] demand could increase and it may be difficult for laypersons to assess treatment appropriateness and efficacy.
Commercial progress of stem cell therapies and cellular therapies
Dozens of companies are developing a variety of therapeutic solutions using stem cells, assiduously working through clinical trials and regulatory approval processes. The early-stage industry has been advancing quickly since the U.S. ESC ban was lifted, and is starting to attract interest from Big Pharma in both developing therapies in-house and acquiring startups. Some of the most interesting studies with the potential for near-term high-impact results are discussed below.
Neural stem cell lumbar transplantation for neurodegenerative disease - Stem cells may be able to aid in disease conditions which do not have effective current treatments, particularly neurodegenerative disease which has a paucity of clinical therapies for conditions such as Parkinson’s disease, Alzheimer’s disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS). In the case of ALS, the best drug, Riluzole, is only estimated to extend life 3-4 months, and does not change the progression of the disease, generally 3-5 years to death after diagnosis, as motor neuron capability is lost. A potential solution for ALS is underway in clinical trials with Neuralstem (Rockville MD). Positive Phase I safety data for the company’s neural stem cell lumbar transplantation trials was presented on the first 12 patients in September 2011. [12] The trial began in January 2010.
Mesenchymal or bone marrow stromal stem cells (MSCs) for heart, lung, and islet cell repair - Prochymal, an MSC product from Osiris Therapeutics (Columbia MD) is in FDA Phase III clinical trials for the treatment of acute graft versus host disease (GvHD), Crohn’s disease, and in Phase II clinical trials for acute myocardial infarction (repair of heart tissue), diabetes (protection of pancreatic islet cells), and pulmonary disease (repair of lung tissue). Another product, Chondrogen, is being developed for treating osteoarthritis of the knee. These solutions are based on research work finding that pericytes (connective tissue cell occurring around small blood vessels) may behave as stem cells throughout the body [13] and harnessing the capabilities of MSCs in secreting bioactive molecules such as growth factors, cytokines and chemokines. [14]
Cellular immunotherapy treatment for prostate cancer - For the treatment of certain kinds of prostate cancer, Provenge from Dendreon (Seattle WA) was approved in April 2010. It is an autologous (derived from the same individual's body) cellular immunotherapy. [15] Provenge introduces a protein to a patient's own immune cells that acts as an antigen for prostate cancer, which causes the body to activate an immune response against the cancer cells. The company estimated having the capacity to treat 2,000 patients in the first year and opened a third U.S. manufacturing facility in August 2011.
Dermal substitutes - Two of the most-widely used cellular therapies are dermal substitutes: Dermagraft from Advanced BioHealing (Westport CT), and Apligraf from Organogenesis (Canton MA), where an epidermis is formed in a 20-day manufacturing process. Apligraf is the first allogeneic (e.g.; developed with one person’s cells for transfer to another person, using cell types that do not elicit immune response) cell-based product approved by the FDA and has had over 250,000 patient applications.
Cell therapy for wrinkles - LaViv (azficel-T) is a therapy from Fibrocell Science (Exton PA) approved in June 2011. Collagen-producing fibroblasts are biopsied from behind the ear and cultured for 90 days, then injected into smile line wrinkles around the nose and mouth. [16] Apparently, the treatment is longer-lasting than the absorbable fillers used by competitors.
Spinal cord injury - Geron (Menlo Park CA) has the first-ever embryonic stem cell clinical trials underway for spinal cord injury with two enrolled patients as of June 2011 [17] to investigate the use of hESC-derived oligodendrocyte progenitor cells, GRNOPC1, in the treatment of paralysis. [18]
HIV cure - HIV is an example where anti-HIV drugs suppress the virus but do not cure patients. It has been discovered that individuals with a certain genetic mutation, homozygous for the CCR5delta32 allele, are virtually resistant. Sangamo BioSciences (Richmond CA) helped to design zinc finger nucleases that knock out the CCR5-receptor gene and generate CCR5-negative immune cells that would be permanently protected against HIV. The stem cells were then transplanted successfully into the “Berlin patient” who was declared to be cured of HIV after remaining off retroviral therapy for over three years. [19] [20]
Excerpted and summarized from Swan, M. Steady advance of stem cell therapies. Rejuvenation Res. 2011, Dec;14(6):699-704.
NOTES
[1] Gavura S. What does a new drug cost? Science-based Medicine. April 14, 2011. Available at: http://www.sciencebasedmedicine.org/index.php/what-does-a-new-drug-cost. Accessed: March 6, 2012.
[2] Hsu, J. Fear of Risk Threatens Medical Innovation. Innovation News Daily June 29, 2011. Available at: http://www.innovationnewsdaily.com/medical-innovation-pharmaceutical-drugs-2090. Accessed: March 6, 2012.
[3] BabyCenter Medical Advisory Board. Fertility treatment: In vitro fertilization (IVF). Online text from BabyCenter. 2011. Available at: http://www.babycenter.com/0_fertility-treatment-in-vitro-fertilization-ivf_4094.bc. Accessed: March 6, 2012.
[4] Ambasudhan R, Talantova M, Coleman R, Yuan X, Zhu S, Lipton SA, Ding S. Direct reprogramming of adult human fibroblasts to functional neurons under defined conditions. Cell Stem Cell. 2011 Aug 5;9(2):113-8.
[5] Hockemeyer D, Wang H, Kiani S, Lai CS, Gao Q, Cassady JP, Cost GJ, Zhang L, Santiago Y, Miller JC, Zeitler B, Cherone JM, Meng X, Hinkley SJ, Rebar EJ, Gregory PD, Urnov FD, Jaenisch R. Genetic engineering of human pluripotent cells using TALE nucleases. Nat Biotechnol. 2011 Jul 7;29(8):731-4.
[6] Carpenter MK, Couture LA. Regulatory considerations for the development of autologous induced pluripotent stem cell therapies. Regen Med. 2010 Jul;5(4):569-79.
[7] Hyun I. Allowing innovative stem cell-based therapies outside of clinical trials: ethical and policy challenges. J Law Med Ethics. 2010 Summer;38(2):277-85.
[8] Childs, D. Peyton Manning’s Stem Cell Hail Mary. ABC News. September 12, 2011. Available at: http://abcnews.go.com/blogs/health/2011/09/19/peyton-mannings-stem-cell-hail-mary. Accessed: March 6, 2012.
[9] Brown, E. Rick Perry's stem cell surgery worries some doctors. Los Angeles Times. August 19, 2011. Available at: http://articles.latimes.com/2011/aug/19/news/la-heb-rick-perry-stem-cell-back-surgery-20110819. Accessed: March 6, 2012.
[10] Cohen CB, Cohen PJ. International stem cell tourism and the need for effective regulation. Part II: Developing sound oversight measures and effective patient support. Kennedy Inst Ethics J. 2010 Sep;20(3):207-30.
[11] Alleman BW, Luger T, Reisinger HS, Martin R, Horowitz MD, Cram P. Medical tourism services available to residents of the United States. J Gen Intern Med. 2011 May;26(5):492-7.
[12] Neuralstem, Inc. Dr. Eva Feldman, Principal Investigator, Presents Interim Data on Neuralstem ALS Trial. Company press release. September 27, 2011. Available at: http://investor.neuralstem.com/phoenix.zhtml?c=203908&p=irol-newsArticle&ID=1610372&highlight=. Accessed: March 6, 2012.
[13] Meirelles Lda S, Nardi NB. Methodology, biology and clinical applications of mesenchymal stem cells. Front Biosci. 2009 Jan 1;14:4281-98.
[14] Caplan AI, Correa D. The MSC: an injury drugstore. Cell Stem Cell. 2011 Jul 8;9(1):11-5.
[15] Burgess, S. FDA Approves a Cellular Immunotherapy for Men with Advanced Prostate Cancer. U.S. Food and Drug Administration press release. April 29, 2010. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm210174.htm. Accessed: March 6, 2012.
[16] Schmidt C. FDA approves first cell therapy for wrinkle-free visage. Nat Biotechnol. 2011 Aug 5;29(8):674-5.
[17] Geron Corporation. Geron presents data from GRNOPC1 trial at international conferences on spinal cord medicine and rehabilitation. Company press release. June 7, 2011. Available at: http://www.geron.com/media/pressview.aspx?id=1271. Accessed: March 6, 2012.
[18] Keirstead HS, Nistor G, Bernal G, Totoiu M, Cloutier F, Sharp K, Steward O. Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci. 2005 May 11;25(19):4694-705.
[19] Hütter G, Nowak D, Mossner M, Ganepola S, Müssig A, Allers K, Schneider T, Hofmann J, Kücherer C, Blau O, Blau IW, Hofmann WK, Thiel E. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med. 2009 Feb 12;360(7):692-8.
[20] Barre-Sinoussi, F. Toward an H.I.V. Cure. New York Times. June 3, 2011. Available at: http://www.nytimes.com/2011/06/04/opinion/04iht-edsinoussi04.html. Accessed: March 6, 2012.