New Drug: GRN163L Geron Initiates Clinical Trial of Telomerase Inhibitor Drug in Multiple Myeloma

Geron Corporation (Nasdaq: GERN) today announced that it enrolled its first patient in a clinical trial of GRN163L in multiple myeloma. The trial is the fourth underway involving Geron’s novel inhibitor of telomerase, an enzyme that is expressed in all major types of cancer cells.

The primary objective of the Phase I/II study is to determine the safety and maximum tolerated dose (MTD) of GRN163L when administered intravenously in patients with multiple myeloma who have failed at least two courses of standard chemotherapy. In addition, researchers will perform correlative laboratory studies on primary patient samples to characterize the effects of GRN163L on myeloma cancer cells.

“We’re pleased to have participated in the design of this study,” said Asher Chanan-Kahn, M.D., an attending physician with Roswell Park Cancer Institute’s Department of Medicine and the lead investigator of the trial. “Despite recent advances in the treatment of patients with multiple myeloma, the need for curative therapy still exists. GRN163L is intriguing because of its novel mechanism of action and demonstrated preclinical activity as a single agent in animal models. This trial should help us to understand the role that telomerase inhibition could play in multiple myeloma treatment regimens.”

GRN163L has been investigated broadly in preclinical models of multiple myeloma. It has been shown in animal models to have single-agent activity as well as additive activity to bortezomib, a widely used drug for patients with multiple myeloma. Preclinical studies utilizing both myeloma cell lines and samples from myeloma patients have demonstrated activity of GRN163L against subpopulations of myeloma cells enriched for stem cell markers. It is believed that cancer stem cells may be responsible for relapses that are observed after patients have an initial response to cancer therapy, and that cancer stem cells are particularly resistant to standard therapies.

About Telomerase and GRN163L

Telomerase is a broadly applicable and critical tumor target. The enzyme is expressed in a broad array of malignant tumors, is essential for malignant cell growth and is absent or expressed transiently at low levels in most normal adult tissues.

GRN163L is a short chain oligonucleotide that is unique in its resistance to nuclease digestion in blood and tissues and in its very high affinity and specificity for telomerase. The molecule has superior cellular and tissue penetration properties due to its proprietary manufacturing chemistry and its 5’ lipid chain.

GRN163L has been demonstrated to have anti-tumor effects in a wide range of hematological and solid tumor models and appears to be unique in its observed effects on cancer stem cells: the rare, chemotherapy-resistant cancer cells that cause cancer recurrence.

Geron is developing first-in-class biopharmaceuticals for the treatment of cancer and chronic degenerative diseases, including spinal cord injury, heart failure and diabetes. The company is advancing an anti-cancer drug and a cancer vaccine that target the enzyme telomerase through multiple clinical trials. Geron is also the world leader in the development of human embryonic stem cell-based therapeutics, with its spinal cord injury treatment anticipated to be the first product to enter clinical development. For more information, visit www.geron.com.

This news release may contain forward-looking statements made pursuant to the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995. Investors are cautioned that statements in this news release regarding potential applications of GRN163L and Geron’s telomerase technology constitute forward-looking statements that involve risks and uncertainties, including, without limitation, risks inherent in the development and commercialization of potential products, uncertainty of clinical trial results or regulatory approvals or clearances, need for future capital, dependence upon collaborators, and maintenance of our intellectual property rights. Actual results may differ materially from the results anticipated in these forward-looking statements. Additional information on potential factors that could affect our results and other risks and uncertainties are detailed from time to time in Geron’s periodic reports, including the quarterly report on Form 10-Q for the quarter ended September 30, 2007.

Stress Hormone May Hasten The Progression Of Certain Blood Cancers

Researchers here have shown that in cell cultures, the stress hormone norepinephrine appears to promote the biochemical signals that stimulate certain tumor cells to grow and spread.

The finding, if verified, may suggest a way of slowing the progression and spread of some cancers enough so that conventional chemotherapeutic treatments would have a better chance to work.

The study also showed that stress hormones may play a completely different role in cancer development than researchers had once thought.

“We would not be surprised if we see similar effects of norepinephrine on tumor progression in several different forms of cancer,” explained Eric Yang, a research scientist with the Institute for Behavioral Medicine Research at Ohio State University.

Yang and colleague Ron Glaser, a professor of molecular virology, immunology and medical genetics, last year showed that the stress hormone norepinephrine was able to increase the production of proteins in cultures of tumor cells that can foster the aggressive spread of the disease.

Yang and Glaser focused on three multiple myeloma tumor cell lines, each representing a different stage in the life of the disease, for their experiments. While all three tumor cell lines reacted to the presence of norepinephrine, only one, a cell line known as FLAM-76, responded strongly to the hormone.

The norepinephrine binds to receptors on the surface of the cells, sending a signal to the nucleus to produce a compound known as VEGF -- vascular endothelial growth factor – that is key to the formation of new blood vessels, which the tumor must have to grow.

The FLAM-76 cell line was prepared from multiple myeloma tumor cells taken from a patient whose disease had not yet progressed too far from its original site in the bone marrow where blood cells are formed.

“It turns out that FLAM-76 tumor cells more closely represent the earlier stages of the disease when blood vessel formation, a process called angiogenesis, is needed for disease progression,” Yang said.

“The fact that this one cell line, of the three multiple myeloma cell lines studied, closely represents the early stages of the tumor, and that this is where we see the biggest effect, is what makes this work more clinically relevant,” Glaser said.

The researchers believe that blocking these receptors would slow the process of the growth of more blood vessel to the tumor, delaying disease progression and perhaps allowing treatments to be more effective. Widely used “beta-blocker” drugs now prescribed for high blood pressure work by blocking these same particular cell surface receptors, Yang said.

“This approach wouldn't kill the tumor cells but it would diminish the blood supply to the tumor cells and slow them down, and that could translate into a longer and better quality of life for the patient,” Glaser said.

The researchers and their colleagues are now working with other forms of cancer to test the effects of stress hormones like norepinephrine on their growth.

Glaser added that these kinds of results may change the way scientists are looking at a link between stress and the development and spread of cancer. In the past, he said, the focus was on how stress hormones weakened the immune system, allowing certain tumors to evade the body's defenses.

“Now we have these stress hormones, not only affecting the immune response, but also acting directly on the tumor cells and inducing changes in the molecules made by those same tumor cells,” Glaser said.

“This has important implications for the spread of the tumor and metastasis.”

The results appear in the current issue of the journal Brain, Behavior and Immunity.

Recent Increase in Multiple Myeloma Survival attributed o Novel Therapies

Multiple myeloma is one of the most common and devastating bone marrow cancers in the U.S., but survival rates have risen dramatically over the past decade. Recent analyses suggest that this trend may be attributed to new types of drugs and aggressive therapeutic interventions such as stem cell transplantation, according to the results of two studies prepublished online in Blood, the official journal of the American Society of Hematology.

Multiple myeloma (MM) is a neoplasm of plasma cells, a type of cell that resides in the bone marrow and produces antibody proteins. Survival rates for MM have traditionally been grim, with most patients dying within two to three years after diagnosis. However, within the last decade, a group of new therapies has been developed and approved for use in MM patients, including thalidomide (Thalidomid®), lenalidomide (Revlimid®), and bortezomib (Velcade®). Used alone or paired with traditional chemotherapy, these drugs have been shown to be highly effective in recently diagnosed and relapsed MM patients. Also, over the past decade high-dose chemotherapy and peripheral blood stem cell transplantation has been increasingly used for treatment of MM, especially in younger patients. Two recent studies analyzed outcomes in large populations of MM patients, comparing results with regard to diagnosis date, age, and gender.

Recent Major Improvement in Long-Term Survival of Younger Patients with Multiple Myeloma
In one study, a research team from the German Cancer Research Center and Weill Cornell Medical Center in New York analyzed trends in five- and 10-year survival of MM patients in the U.S. to understand how new therapies and innovative approaches have translated into better survival for patients. In this large epidemiologic study, 26,523 patients diagnosed with MM in the U.S. were studied from the 1990-1992 to 2002-2004 SEER (Surveillance, Epidemiology, and End Results) database.

The analyses found a definitive overall increase in the survival of MM patients over the past decade. In particular, five-year survival increased from 28.8 to 34.7 percent, and 10-year survival increased from 11.1 to 17.4 percent. Importantly, survival increased most dramatically in the youngest age group – more than half (56.7 percent) of patients younger than 50 survived at least five years, and more than 40 percent (41.3 percent) survived at least 10 years. In real years, the average relative survival increased from four years after diagnosis in 1990-1992 to almost seven years after diagnosis in 2002-2004.

Patients age 50-59 also fared well, with approximately half (48.2 percent) surviving at least five years, and nearly a third (28.6 percent) surviving at least 10 years. However, only modest increases were seen in the age group 60-69, and virtually no improvement was seen in patients older than 70. Since about half of MM patients are diagnosed when they are 60 or older, the lack of improvement in the eldest groups is a critical finding of the research.

“The rise in survival among MM patients in this study may be attributed to improvements in stem cell protocols, supportive care, and therapies with better efficacy and lower toxicity,” said Hermann Brenner, MD, of the Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, and lead author of the study. “However, the improvements among older patients in our analysis remained much more modest, suggesting a need to better understand the natural history and treatment options for multiple myeloma in this population.”

Improved Survival in Multiple Myeloma and the Impact of Novel Therapies
A second study conducted by researchers at the Mayo Clinic evaluated outcomes for a large group of MM patients by comparing survival among two date-specific analyses – one from time of diagnosis and one from time of relapse – to better understand trends in survival over time. “We wanted to understand if the new therapies available to these patients would translate directly into improved survival,” said lead author Shaji Kumar, MD, of the Mayo Clinic.

The first analysis studied 387 patient records to compare disease relapses before and after December 31, 2000, based on the availability of thalidomide and subsequent clinical trials of bortezomib and lenalidomide. The second analysis was conducted over a 36-year period (1971-2006) with a larger group of 2,981 patients with newly diagnosed MM. These patients were divided by date of diagnosis (before or after January 1, 1997) to understand the significance of the novel advances in MM therapies.

Study results illustrated a dramatic improvement in survival among patients diagnosed in recent years, both from the time of diagnosis and from relapse after stem cell transplantation. Among the patients in the relapse group, the researchers noted a significant improvement in overall survival for patients relapsing after 2000, compared with those relapsing before 2000 (24 vs. 12 months). Patients relapsing before 2000 were less likely to receive a prompt transplant and more likely to have relapsed disease at the time of transplant and to have had more treatment regimens prior to transplant, compared with the group who relapsed after 2000, but the improvement seen in the recent times was independent of these differences.

In the larger group of newly diagnosed MM patients, diagnosis within the last decade translated into a 50 percent improvement in overall survival (45 vs. 30 months). Though the team divided the groups into six-year intervals to understand trends throughout the 36 years, they found no significant changes in survival until the most recent six-year period. When the team examined the relative impact of age and gender, they found that patients younger than 65 benefited the most from the recent improvements and that female patients fared slightly better.

“These results demonstrate a clear improvement in survival among myeloma patients in the last decade, and while supportive care may have contributed to this trend, we believe that the introduction of novel drugs played a major role,” said Dr. Kumar. “This study also highlights the need to target the older patient population for innovative approaches to improve outcomes, considering these patients are more frail and more likely to have co-morbidities that may limit their treatment options. This progress reflects the effort of myeloma researchers worldwide, making myeloma a model for other cancers to follow.”

Source: American Society of Hematology