Human embryonic stem cells clinical trials

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The Food and Drug Administration (FDA) approved the first clinical trial in the United States involving human embryonic stem cells on January 23, 2009. Geron Corporation, a biotechnology firm located in Menlo Park, California, originally planned to enroll ten patients with spinal cord injuries to participate in the trial. The company hoped that GRNOPC1, a product derived from human embryonic stem cells, would stimulate nerve growth in patients with debilitating damage to the spinal cord. [1] The trial began in 2010 after being delayed by the FDA because cysts were found on mice injected with these cells, and safety concerns were raised. [2]

Contents

FDA approval process

In the United States, the FDA must approve all clinical trials involving newly developed pharmaceuticals. Researchers must complete an Investigational New Drug (IND) application in order to earn the FDA's approval. IND applications typically include data from animal and toxicology studies in which the drug's safety is tested, drug manufacturing information explaining how and where the drug will be produced, and a detailed research protocol stating who will be included in the study, how the drug will be administered and how participants will be consented. [3] Testing for new drugs must successfully go through three phases of research before a drug can be marketed to the public. In Phase I trials, the drug's safety is tested on a small group of participants. The drug's effectiveness is tested during Phase II trials with a larger number of participants. Phase III trials, involving 1,000- 3,000 participants, analyze effectiveness, determine side effects and compare the outcomes of the new drug to similar drugs on the market. [4] An additional phase, Phase IV, is included to continually gain information after a drug is on the market. Geron's IND application for the GRNOPC1 clinical trial, nearly 28,000 pages in length, was one of the most extensive applications ever to be submitted to the FDA. [2]

Pre-clinical data

Before Geron could test GRNOPC1 in humans, tests in animals had to occur. At the University of California at Irvine, Dr. Hans Keirstead and Dr. Gabriel Nistor, credited with the technique used to develop oligodendrocytes from human embryonic stem cells, injected the cells into rats with spinal cord injuries. The condition of the rats improved after treatment. [5]

Geron Spinal Cord Injury Trial

The first patient, identified in an article by the Washington Post as Timothy J. Atchison of Alabama, enrolled in the trial in October 2010. The patient was treated at the Shepherd Center in Atlanta, GA just two weeks after he sustained a spinal cord injury in a car accident. The Shepherd Center and six other spinal centers were recruited by Geron to participate in the clinical trial. The Washington Post reported that Atchison "has begun to get some very slight sensation: He can feel relief when he lifts a bowling ball off his lap and discern discomfort when he pulls on hairs on some parts of his legs. He has also strengthened his abdomen." Atchison underwent therapy at the Shepherd Center for three months before returning home to Alabama. [6]

Although Geron initially aimed to enroll ten patients in the trial, only three additional patients were added after Atchison. As specified by Geron, eligible patients had to experience a neurologically complete spinal cord injury within seven to fourteen days prior to enrollment. In addition, patients had to be between the ages of 18 and 65 and could not have a history of malignancy, significant organ damage, be pregnant or nursing, unable to communicate or participate in any other experimental procedures. Participants received one injection of GRNOPC1 containing approximately 2 million cells. Even though the trial has officially ended, Geron will continue to monitor participants for fifteen years. [7]

Although no official results from the trial have been published, preliminary results from the clinical trial were presented at the American Congress of Rehabilitation Medicine (ACRM) conference in October 2011. None of the participants experienced serious adverse events, although nausea and low magnesium were reported. In addition, no changes to the spinal cord or neurological condition were found. [8]

After investing millions of dollars in the research leading up to this trial, Geron Corporation discontinued the study in November 2011 to focus on cancer research. John Scarlett, Geron's chief executive officer, said "In the current environment of capital scarcity and uncertain economic conditions, we intend to focus our resources on advancing our two novel and promising oncology drug candidates." [9] The company's stocks fell dramatically to $1.50 per share from $2.28 per share when news of the trial's discontinuation became public. A spokesperson for the company said that Geron would save money by ending the trial despite the loss in investors. Because many believed Geron's trial offered hope for advancing knowledge related to stem cells and their potential uses, there was disappointment in the scientific community when the trial was cut short. An article on Bioethics Forum, a publication produced by The Hastings Center, stated, "It is one thing to close a trial to further enrollment for scientific reasons, such as a problem with trial design, or for ethical reasons, such as an unanticipated serious risk of harm to participants. It is quite another matter to close a trial for business reasons, such as to improve profit margins." [10]

In 2013 Geron's stem cell assets were acquired by biotechnology firm BioTime, led by CEO Michael D. West, the founder of Geron and former Chief Scientific Officer of Advanced Cell Technology. BioTime indicated that it plans to restart the embryonic stem cell-based clinical trial for spinal cord injury. [11]

Two clinical trials involving derivatives of human embryonic stem cells were approved in 2010. Advanced Cell Technology (ACT) located in Marlborough, Massachusetts, leads the trials aimed at improving the vision of patients with Stargardt's Macular Dystrophy and Dry Age-Related Macular Degeneration. Originally, twelve patients were estimated to enroll at three hospitals in the U.S.; participating institutions included the Casey Eye Institute in Portland, Oregon, University of Massachusetts Memorial Medical Center in Worcester, Massachusetts, and the New Jersey Medical School in Newark, New Jersey. [12] Patients' eyes were injected with retinal pigmented epithelial cells derived from human embryonic stem cells. While no definitive findings from this study have been produced, an article published in Lancet in January 2012 stated that preliminary findings appear to be promising. In this article, outcomes from two patients treated as part of the trial were discussed. During the trial, neither patients' vision worsened, and no negative side effects were reported. [13]

Phase I/II clinical trials involving retinal pigment epithelial (RPE) cells, derived from human embryonic stem cells, for the treatment of severe myopia were approved in February 2013. [14]

ViaCyte Human stem cell-derived beta cells for the treatment of Diabetes Clinical Trial

The FDA approved a phase I clinical trial with ViaCyte beta cells derived from human embryonic stem cell for the treatment of diabetes in August 2014. [15] The cells will be delivered in immunoprotective capsules and pre-clinical results in animal models showed remission of symptoms within a few months. [16] The company reported the successful transplantation of the cells in the first of the 40 patients that will be treated under the trial in late October 2014. [17]

Future funding

As state funding for human embryonic stem cell research grows, there seems to be more support for state sponsored clinical trials. In 2010, California committed fifty million dollars to early-stage clinical trials. Although approved trials must take place in California, scientists are hopeful that this funding will bolster future research in the field. [18]

See also

Related Research Articles

Stem cell Undifferentiated biological cells that can differentiate into specialized cells

In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of cell in a cell lineage. They are found in both embryonic and adult organisms, but they have slightly different properties in each. They are usually distinguished from progenitor cells, which cannot divide indefinitely, and precursor or blast cells, which are usually committed to differentiating into one cell type.

Embryonic stem cell Pluripotent stem cell of the inner cell mass of the blastocyst

Embryonic stem cells are pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage pre-implantation embryo. Human embryos reach the blastocyst stage 4–5 days post fertilization, at which time they consist of 50–150 cells. Isolating the embryoblast, or inner cell mass (ICM) results in destruction of the blastocyst, a process which raises ethical issues, including whether or not embryos at the pre-implantation stage have the same moral considerations as embryos in the post-implantation stage of development.

Geron Corporation Biotechnology company

Geron Corporation is a biotechnology company located in Foster City, California, which specializes in developing and commercializing therapeutic products for cancer that inhibit telomerase.

The stem cell controversy is the consideration of the ethics of research involving the development and use of human embryos. Most commonly, this controversy focuses on embryonic stem cells. Not all stem cell research involves human embryos. For example, adult stem cells, amniotic stem cells, and induced pluripotent stem cells do not involve creating, using, or destroying human embryos, and thus are minimally, if at all, controversial. Many less controversial sources of acquiring stem cells include using cells from the umbilical cord, breast milk, and bone marrow, which are not pluripotent.

Stem-cell therapy is the use of stem cells to treat or prevent a disease or condition. As of 2016, the only established therapy using stem cells is hematopoietic stem cell transplantation. This usually takes the form of a bone-marrow transplantation, but the cells can also be derived from umbilical cord blood. Research is underway to develop various sources for stem cells as well as to apply stem-cell treatments for neurodegenerative diseases and conditions such as diabetes and heart disease.

Clinical research is a branch of healthcare science that determines the safety and effectiveness (efficacy) of medications, devices, diagnostic products and treatment regimens intended for human use. These may be used for prevention, treatment, diagnosis or for relieving symptoms of a disease. Clinical research is different from clinical practice. In clinical practice established treatments are used, while in clinical research evidence is collected to establish a treatment.

Automated insulin delivery systems are automated systems designed to assist people with diabetes, primarily type 1, by automatically adjusting insulin delivery to help them control their blood glucose levels. Currently available systems can only deliver a single hormone—insulin. Other systems currently in development aim to improve on current systems by adding one or more additional hormones that can be delivered as needed, providing something closer to the endocrine functionality of a healthy pancreas.

Mecasermin rinfabate, also known as rhIGF-1/rhIGFBP-3, is a drug consisting of recombinant human insulin-like growth factor 1 (IGF-1) and recombinant human insulin-like growth factor binding protein-3 (IGFBP-3) which is used for the treatment of amyotrophic lateral sclerosis.

Astellas Institute for Regenerative Medicine is a subsidiary of Astellas Pharma located in Marlborough, Massachusetts, US, developing stem cell therapies with a focus on diseases that cause blindness. It was formed in 1994 as a company named Advanced Cell Technology, Incorporated (ACT), which was renamed to Ocata Therapeutics in November 2014. In February 2016 Ocata was acquired by Astellas for $379 million USD.

Foundation Fighting Blindness

The mission of the Foundation Fighting Blindness is to fund research that will lead to the prevention, treatment and cures for the entire spectrum of retinal degenerative diseases, including retinitis pigmentosa, macular degeneration, Usher syndrome, Stargardt disease and related conditions. These diseases, which affect more than 10 million Americans and millions more throughout the world, often lead to severe vision loss or complete blindness.

A glossary of terms used in clinical research.

Phases of clinical research Clinical trial stages using human subjects

The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases start with testing for safety in a few human subjects, then expand to many study participants to determine if the treatment is effective. Clinical research is conducted on drug candidates, vaccine candidates, new medical devices, and new diagnostic assays.

Nivolumab

Nivolumab, sold under the brand name Opdivo, is a medication used to treat a number of types of cancer. This includes melanoma, lung cancer, malignant pleural mesothelioma, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, urothelial carcinoma, colon cancer, esophageal squamous cell carcinoma, liver cancer, gastric cancer, and esophageal or gastroesophageal junction (GEJ) cancer. It is used by slow injection into a vein.

Lineage Cell Therapeutics Clinical-stage biotechnology company developing novel cell therapies

Lineage Cell Therapeutics, Inc. is a clinical-stage biotechnology company developing novel cell therapies for unmet medical needs. Lineage’s programs are based on its robust proprietary cell-based therapy platform and associated in-house development and manufacturing capabilities. With this platform Lineage develops and manufactures specialized, terminally differentiated human cells from its pluripotent and progenitor cell starting materials. These differentiated cells are developed to either replace or support cells that are dysfunctional or absent due to degenerative disease or traumatic injury or administered as a means of helping the body mount an effective immune response to cancer.

Spinal cord injury research seeks new ways to cure or treat spinal cord injury in order to lessen the debilitating effects of the injury in the short or long term. There is no cure for SCI, and current treatments are mostly focused on spinal cord injury rehabilitation and management of the secondary effects of the condition. Two major areas of research include neuroprotection, ways to prevent damage to cells caused by biological processes that take place in the body after the insult, and neuroregeneration, regrowing or replacing damaged neural circuits.

Faricimab Medication for macular degeneration

Faricimab, sold under the brand name Vabysmo, is a monoclonal antibody used for the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). Faricimab is the first bispecific monoclonal antibody, to target both vascular endothelial growth factor (VEGF), and angiopoietin 2 (Ang-2) inhibitor. By targeting these pathways, faricimab stabilizes blood vessels in the retina. It is given by intravitreal injection by an ophthalmologist.

Sotorasib Chemical compound

Sotorasib, sold under the brand names Lumakras and Lumykras, is an anti-cancer medication used to treat non-small-cell lung cancer (NSCLC). It targets a specific mutation, G12C, in the protein KRAS which is responsible for various forms of cancer.

Stem cell tourism, a form of medical tourism, is the internet based-industry in which stem cell procedures are advertised to the public as a proven cure. In the majority of cases, it leads to patients and families traveling abroad to obtain procedures that are not proven, nor part of a clinical trial approved by an authority like the Food and Drug Administration in the United States. These procedures have not gone through the vetting process of clinical research and they lack rigorous scientific support. Although for the general public, this advertising in glossy websites, may sound authoritative, for translational doctors and scientists this leads to the exploitation of vulnerable patients. These procedures lack the reproducibility, the rigor that is required for successful development of new effective medications. Although the term may imply traveling overseas, in recent years, there has been an explosion of "stem cell clinics' in the US which has been well documented. These activities are highly profitable for the clinic but no benefit for the patients, sometimes experiencing complications like spinal tumors, death, or financial ruin, all of which are documented in the scientific literature. There is a great deal of interest in educating the public and patients, families and doctors who deal with patients requesting stem cells clinics. In recent years, the FDA has become more active in overseeing stem cell clinics, taking a number of concrete steps including sending warning letters, putting out advisories, and in two cases filing suit in federal court to impose permanent injunctions on specific clinic firms.

Atoltivimab/maftivimab/odesivimab, developed as REGN-EB3 and sold under the brand name Inmazeb, is a fixed-dose combination of three monoclonal antibodies for the treatment of Zaire ebolavirus. It contains atoltivimab, maftivimab, and odesivimab-ebgn and was developed by Regeneron Pharmaceuticals.

Stem cell therapy for macular degeneration

Stem cell therapy for macular degeneration is the use of stem cells to heal, replace dead or damaged cells of the macula in the retina. Stem cell based therapies using bone marrow stem cells as well as retinal pigment epithelial transplantation are being studied. A number of trials have occurred in humans with encouraging results.

References

  1. ↑ Alper, J. (2009). "Geron gets Green Light for Human Trial of ES Cell-Derived Product." Nature Biotechnology 27: 213-214.
  2. 1 2 Pollack, A. (July 30, 2010). "Stem Cell Trial Wins Approval of FDA". New York Times .
  3. ↑ U.S. Food and Drug Administration. (2011). "Investigational New Drug (IND) Application." Retrieved April 12, 2012, from https://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/investigationalnewdrugindapplication/default.htm.
  4. ↑ ClinicalTrials.gov. (2007). "Understanding Clinical Trials." Retrieved April 12, 2012, from http://clinicaltrials.gov/ct2/info/understand Archived 2017-12-22 at the Wayback Machine
  5. ↑ Keirstead, H., Nistor, G., Bernal, G., Totoiu, M., Cloutier, F., Sharp, K., Steward, O. (2005). "Human Embryonic Stem Cell Derived Oligodendrocyte Progenitor Cell Transplants Remyelinate and Restore Locomotion after Spinal Cord Injury." The Journal of Neuroscience, 25(19).
  6. ↑ Stein, R. (2011). "Stem Cells were God's Will, says First Recipient of Treatment." Washington Post, April 15.
  7. ↑ ClinicalTrials.gov. (2012). "Safety Study of GRNOPC1 in Spinal Cord Injury." Retrieved April 12, 2012, from http://clinicaltrials.gov/ct2/show/NCT01217008
  8. ↑ Geron. (2011). "GRNOPC1." Retrieved April 12, 2012, from "Archived copy". Archived from the original on 2013-05-10. Retrieved 2017-02-25.{{cite web}}: CS1 maint: archived copy as title (link)
  9. ↑ Stein, R. (2011). "First Human Embryonic Stem Cell Therapy in People Discontinued." Washington Post, November 14.
  10. ↑ Baylis, F. (2011). "Geron's Discontinued Stem Cell Trial: What About the Research Participants?" Bioethics Forum, December 2.
  11. ↑ "BioTime acquires stem cell assets from Geron, raises $10 million". San Francisco Business Times. January 7, 2013.
  12. ↑ Vergano, D. (2010). "Second Human Embryonic Stem Cell Clinical Trial to Start." USA Today, November 22.
  13. ↑ Schwartz, S et al. (2012). "Embryonic Stem Cell Trials for Macular Degeneration: Preliminary Report." Lancet. January 23.
  14. ↑ ACT announces clinical trials for myopia February 11, 2013
  15. ↑ http://viacyte.com/press-releases/viacyte-inc-announces-fda-acceptance-of-ind-to-commence-clinical-trial-of-vc-01-candidate-cell-replacement-therapy-for-type-1-diabetes/ ViaCyte, Inc. Announces FDA Acceptance of IND to Commence Clinical Trial of VC-01™ Candidate Cell Replacement Therapy for Type 1 Diabetes
  16. ↑ "Archived copy". Archived from the original on 2016-04-03. Retrieved 2014-11-24.{{cite web}}: CS1 maint: archived copy as title (link)
  17. ↑ "ViaCyte's VC-01™ Investigational Stem Cell-Derived Islet Replacement Therapy Successfully Implanted into First Patient".
  18. ↑ Torres, C. (2010). "State Stem Cell Agency to Fund Clinical Trials." Nature Medicine 16; 352.
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