From Stem Cell Therapy to Cancer Treatment Elisha Edwards MHC

From Stem Cell Therapy to Cancer Treatment

Elisha Edwards MHC 360: The Purpose, Practice, and Politics of Science Dr. Harold Varmus May 15th, 2017

Geron Corporation was founded by Michael D. West on November 28th, 1990. It is currently a clinical stage biopharmaceutical company that innovates and examines a telomerase inhibitor called Imetelstat for hematologic myeloid malignancies. However, Geron

Corporation initially geared their resources toward gerontology and human embryonic stem cell technology (2,3).

Stem cells are undifferentiated cells that have the potential to transform into other types of cells, such as muscle, bone, skin, etc. Stem cells are extracted from either adult tissue or embryos formed during the blastocyst phase. Embryonic stem cells are classified as pluripotent because they are capable of being the precursor to a variety of human cells.

Furthermore, they are easily self-sustainable within a culture and can reproduce themselves indefinitely (5,6).

All clinical trials that introduce the testing of a new pharmaceutical drug must be reviewed and approved by the U.S. Food and Drug Administration. First, the scientific researchers of a company will have to complete the Investigational New Drug application, which will then be reviewed by an institutional review board comprised of doctors, researchers, and community members. Application details include safety concerns, manufacturing procedures, protocol and criteria of the study, etc. The testing of the drug will, then, have to pass through several trial stages. In Phase I clinical trials, the safety of the drug is examined on a small group of participants. Phase II clinical trials include a larger group of participants and test the new drug’s potency and performance. Phase III clinical trials consist of anywhere from

1,000 to 3,000 participants. This phase examines the efficacy of the drug, establishes side effects, and compares the study’s results of the drug to that of similar drugs currently on the

1 market. New drugs must successfully pass through the three aforementioned phases in order to be marketed to the public. Lastly, a phase IV is utilized to gain additional information once the drug is released for sale (2).

The U.S. Food and Drug Administration provided Geron Corporation with approval for the first human clinical trials of embryonic stem cells in January 2009. Geron Corporation aimed to conduct its study on ten patients who have suffered complete thoracic-level spinal cord injuries, but it only ended up observing four patients. Complete spinal cord injuries are defined as the removal of the brain’s ability to send impulses down the spinal cord below the site of the injury (2). The therapeutic product they were testing was named GRNOPC1, consisting of embryonic stem cell-derived oligodendrocyte progenitor cells that have demonstrated remyelination and nerve growth-inducing properties. Oligodendrocytes provide support and insulation to axons in the central nervous system by creating the myelin sheath. The trial was originally expected to start in the summer of 2009. However, it was delayed by the U.S. Food and Drug Administration after cysts were discovered on mice that were tested with these stem cells. Phase I of the clinical trials were approved to start in 2010 (1).

In 2005, the study of human embryonic stem cell-derived oligodendrocyte progenitor cell transplants on laboratory rats was completed at the University of California at Irvine (4).

Following anesthetization, a contusion injury was induced to the spinal area on female adult rats using an Infinite Horizon Impactor, which can deliver a sudden impact of a desired force to a specific area. One group of rats were injected with the stem cells 7 days after injury and the other group of rats were injected 10 months after injury (4).

2 In both groups, the transplant cells survived, reproduced over short distances, and differentiated into oligodendrocytes. Although the rats that received the stem cells 7 days after injury showed improvements in remyelination and locomotor ability, the rats that received it 10 months after injury showed no neurological or muscular improvements. Keirstead et al. concluded that embryonic stem cells were capable of differentiating into functional oligodendrocytes. Their study also supported that therapeutic potential after spinal injury at earlier points in time leads to improvements. All rats were euthanized 8 weeks after stem cell transplantation (4).

In 2010, Geron Corporation began to execute their trials on patients. In order to be eligible to participate, patients were required have a complete spinal cord injury within seven to fourteen days before enrollment and had to be between the ages of 18 and 65. Patients also could not have a history of cancer or significant organ damage, could not be pregnant or nursing, and could not participate in any other interventional studies. Participants received one dose of GRNOPC1, which consists of over two million stem cells. The first patient, Timothy

Atchison, was enrolled into the study two weeks after he was involved in a car accident. After being injected with GRNOPC1, he began to experience a few slight sensations and could indicate discomfort when his leg hairs were pulled (2,7).

Preliminary results of this study demonstrated that no changes to the spinal cord were present. Also, no adverse side effects were reported. In November 2011, Geron Corporation made a public announcement that it was closing the study in order to turn its main focus toward cancer research (7). This resulted in the company’s stock price quickly dropping from

$2.28 to $1.50 per share. The scientific community was highly disappointed as many were

3 looking forward to advancing their knowledge on stem cells based on the official results of the study (3). Another biotechnology company, BioTime, Inc., acquired several patents on the stem cell products from Geron Corporation. Despite the discontinuation of the stem cell research,

Geron Corporation agreed to continue monitoring the patients’ progress for the upcoming years (2).

Presently, Geron Corporation has fully invested its time and money into Imetelstat.

Imetelstat is revolutionary in a way because it can bind to telomerase with high affinity, which results in direct inhibition of telomerase enzymatic activity whereas its drug counterparts produce an indirect effect via inhibition of protein translation (2). The only drug that is approved for the treatment plans of myelofibrosis is Jakafi, developed and marketed by Incyte

Corporation. Jakafi resolves some of the symptoms associated with myelofibrosis while

Imetelstat is the first drug to ever induce partial and complete responses in myelofibrosis patients during early-stage clinical trials. If Geron Corporation’s revolutionary drug manages to pass through all phase trials, Imetelstat could entirely replace Jakafi and earn Geron

Corporation a substantial increase in revenue. Johnson & Johnson's biotechnological subsidiary, Janssen, is handling the drug's clinical program through a collaborative license with

Geron Corporation (3).

Preclinical studies have supported that Imetelstat inhibits telomerase activity and decreases the length of telomeres. It also inhibits the rapid reproduction of a various types of tumor cells, reducing the growth of primary tumors and thus reducing metastases. When coupled with approved anti-cancer therapy methods, such as chemotherapy, Imetelstat produces a synergistic anti-cancer effect (9).

4 Tefferi et al. (9) conducted a study with 33 patients that had high-risk or intermediate-II- risk myelofibrosis. Imetelstat was administered as a 2-hour intravenous infusion and patients received 9.4 mg per kg of their body weight every one to three weeks. A complete or partial remission of myelofibrosis was observed in 7 patients with a median response range of 18 months for complete remissions and 10 months for partial remissions. Imetelstat was found to be active in patients with myelofibrosis, but it also had the potential to cause myelosuppression, a condition in which bone marrow activity is lessened and results in less blood cells. Other adverse effects included grade 4 thrombocytopenia in 18% of patients, grade

4 neutropenia in 12% of patients, grade 3 anemia in 30% of patients, grade 1 or 2 elevation in levels of total bilirubin in 12% of patients, alkaline phosphatase in 21% of patients, and aspartate aminotransferase in 27% of patients (9).

In another study by Tefferi et al. (8), nine patients took Imetelstat for refractory anemia with or without thrombocytosis. Based on their previous study’s concern for the development of myelosuppression, the 2-hour intravenous infusion of Imetelstat was reduced to 7.5 mg per kg of body weight for every four weeks. Four patients remained on treatment throughout the study, while the other five patients’ treatment plans were discontinued due to death unrelated to Imetelstat, discovery of second malignancy, etc. Three patients become transfusion- independent in a median time of 11 weeks and one patient had their leukocytosis and thrombocytosis resolved (8).

Imetelstat is presently being studied in two separate clinical trials: one evaluating the activity of two different dosages of Imetelstat on myelofibrosis and the other evaluating how

Imetelstat impacts myelodysplastic syndrome. Both of these trials are within phase II. On April

5 10th, 2017, Geron Corporation’s stock price went up an outstanding 19.53% per share, raising their market price to $2.59 by closing (3). This surge followed a report that their current studies have affirmed that 9.4 mg per kg of body weight is supported to be the appropriate dosage for patients with relapsed or refractory myelofibrosis (2). As of market closing on May 12th, 2017,

Geron Corporation’s stock price was at $2.85 per share (3).

6 References

1. Alper J. Geron gets green light for human trial of ES cell-derived product. Nature Biotechnology. 2009; 27:213-214.

2. Geron Corporation. “For Patients: Clinical Trials.” Accessed on April 21, 2017.

3. Geron Corporation. “Investors: Press Releases.” Accessed on May 12, 2017.

4. Keirstead HS, Nistor G, Bernal G, Totoiu M, Cloutier F, Sharp K, and Steward O. Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. The Journal of Neuroscience. 2005; 25:4694-4705.

5. Lebacqz K, Mendiola M, Peters T, Young EWD, and Zoloth-Dorfman L. Research with human embryonic stem cell: ethical considerations. Hastings Center Report. 1999; 29:31-36.

6. Schwartz SD, Hubschman JP, Heilwell G, Franco-Cardenas V, Pan CK, Ostrick RM, Mickunas E, Gay R, Klimanskaya I, and Lanza R. Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet. 2012; 379:713-720.

7. Stein, Rob. “First test of human embryonic stem cell therapy in people discontinued.” The Washington Post. Nov. 2011. Web. Accessed on April 21, 2017.

8. Tefferi A, Al-Kali A, Begna KH, Patnaik MM, Lasho TL, Rizo A, Wan Y, and Hanson CA. Imetelstat therapy in refractory anemia with ring sideroblasts with or without thrombocytosis. Blood Cancer Journal. 2016; 6:405.

9. Tefferi A, Lasho TL, Begna KH, Patnaik MM, Zblewski DL, Finke CM, Laborde RR, Wassie E, Schimek L, Hanson CA, Gangat N, Wang X, and Pardanani A. A pilot study of the telomerase inhibitor imetelstat for myelofibrosis. The New England Journal of Medicine. 2015; 373:908-919.