PIPELINE
ONCOLOGY
CRS-207 is a live attenuated strain of Listeria that Aduro has engineered to express human mesothelin. Mesothelin is a differentiation antigen present on normal mesothelial cells and it is highly overexpressed in several human tumors. The CRS-207 Phase 1 safety trial examined 17 patients with advanced, treatment-refractory, mesothelin-expressing tumors: 7 pancreatic, 5 mesothelioma, 3 non-small-cell lung, and 2 ovarian. Analysis after the completion of the trial revealed that, despite an expected survival of 3-5 months for all subjects, 6 out of 17 subjects lived 15 months or longer. (Please also see Clinical Trials.)
According to the American Cancer Society, approximately 43,000 people were diagnosed in the U.S. with pancreatic in 2010 and approximately 37,000 people died of the disease. The one- and five-year relative survival rates are 24% and 5%, respectively. If the cancer is metastatic, as was the case in the CRS-207 Phase 1 trial, the median survival time for metastatic pancreatic cancer is only 3-6 months.
Seven patients with metastatic pancreatic cancer were treated in the CRS-207 Phase 1 trial. Three of these patients had previously received GVAX Pancreas, another therapeutic cancer vaccine, as part of separate clinical trials, and all three lived 15 months or longer. As a result of these promising, albeit preliminary data, Aduro is planning a multi-site Phase 2 clinical trial of the sequential administration of GVAX Pancreas (along with cyclophosamide) followed by CRS-207.
Approximately 2,000 to 4,500 new cases of mesothelioma are diagnosed in the United States each year. For the majority of patients, the standard of care provides an overall survival of less than 13 months.
Five late-stage mesothelioma patients were treated in the
CRS-207 Phase 1 clinical trial, and one survived more than 15 months.
Based on this preliminary result as well as the observation that
mesothelin is found in ~95-99% of mesothelioma tumors and that other
groups have shown the potential synergy of therapeutic vaccination and
chemotherapy, Aduro is planning a Phase 1 mesothelioma clinical trial of
the sequential administration of chemotherapy and CRS-207.
According
to the American Cancer Society, approximately 200,000 new cases of lung
cancer, of which approximately 80% were non-small-cell lung cancer
(NSCLC), were diagnosed in the U.S. and approximately 150,000 died of
the disease. The majority of patients, including those in the CRS-207
Phase 1 trial, have metastatic disease at the time of diagnosis, with a
5-year survival of approximately 3.5% and a median survival of 6 months.
Three patients with metastatic NSCLC were treated in the
CRS-207 Phase 1 trial. Two of these later had palliative radiation
treatment for distal metastases and both of these patients lived longer
than 23 months. Other studies have shown the potential synergy of
immunotherapy and radiation. Aduro is planning a Phase 1 NSCLC trial of
the sequential administration of CRS-207 and radiation. According
to the American Cancer Society, while mesothelioma is a relatively rare cancer, the average survival time is only 4-18 months, depending on the study, and the 5-year survival is between 5 and 10%.
According to DataMonitor, the incidence of glioblastoma (GBM) is rising and expected to exceed 18,000 by 2015. Despite advances in surgery, radiation and chemotherapy, the prognosis for patients with GBM is poor. Median patient survival times typically range between 3 and 16 months, and the percentage of patients alive at 5 years is barely above 3%. Currently, conventional therapy with surgery, radiation, and chemotherapy is only palliative, and the estimated cost of treatment for each patient with a malignant brain tumor is between thirty thousand and several hundred thousand dollars annually. Aduro has an ongoing collaboration with researchers at the Providence Portland Medical Center to develop a new therapeutic vaccine for GBM.
Prostate
cancer generally is a slow progressing disease. If it is localized, the
5-year relative survival rate is 100%. But if it has metastasized, the
5-year relative survival rate drops to 31% and approximately 30,000 men
die each year in the U.S. Because of this slow progression and the
unpleasant treatment options, therapy generally starts conservatively
and escalates. After initial diagnosis, many patients are monitored
without any therapy at all. When the tumor has progressed far enough, it
is usually removed through invasive surgery (with or without
radiation). The next step is to try to suppress the growth of any
remaining cancer cells with androgen deprivation therapy, which causes
menopause-like symptoms and increases the risk of osteoporosis. When
this fails, the patients are classified as having castration-resistant
prostate cancer (CRPC). The only approved treatment had been
chemotherapy, which is toxic. The recent approval of Provenge®, a
dendritic cell-based vaccine developed by the Dendreon Corporation,
indicates that there is a significant opportunity for therapeutic cancer
vaccines. Aduro has ongoing collaborations with multiple researchers to develop a new therapeutic vaccine for CRPC.
According
to the American Cancer Society, the incidence of melanoma has been
increasing for at least the last 30 years and was projected to reach
68,130 new diagnoses and 8,700 deaths in the United States in 2010.
Melanoma is a promising target for immunotherapies, which have been
shown to induce immune responses not only to the primary tumor, but also
distant metastases.
Aduro
was awarded an SBIR grant in November 2010 to develop a therapeutic
melanoma vaccine in collaboration with Dr. Nina Bhardwaj, Professor of
Medicine, Pathology and Dermatology at the NYU Langone Medical Center.
If this preclinical program is successful, Dr. Bhardwaj is expected to
be the principal investigator for the Phase 1 trial.
INFECTIOUS DISEASE
Malaria is caused by infection with certain protozoan parasites that are spread by mosquitoes. Between 300 and 500 million people worldwide are infected with malaria at any given time and close to 1 million people die from malaria every year. More than half of these deaths are among children in sub-Saharan Africa. While there are current treatments for malaria, they are not widely available, they have undesirable side effects and resistance to some treatments has developed. Current prophylactic treatments must be taken continuously to prevent infection and are only appropriate for short-term use; there are no effective vaccines. Aduro has demonstrated protection against malaria challenge in mice and is working with multiple collaborators to develop a new human prophylactic vaccine.
Tularemia, also known as rabbit fever, is caused by a bacterium called Francisella tularensis. Experts regard Francisella tularensis as a potential bioterrorist weapon due to the possibility of widespread and serious illness if the organism is aerosolized. Aduro has engineered Listeria to express Francisella tularensis antigens, which demonstrated significant protection in tularemia challenge models in rats. For this research, in November 2010, Aduro received the “Outstanding Scientific Achievement” award from the Defense Threat Reduction Agency (DTRA). Aduro received a grant from DTRA (as part of a larger a larger grant led by Dr. Terry Wu at the University of New Mexico) to continue this award-winning development program.
Hepatitis B virus (HBV) is one of the five causative agents for acute viral hepatitis that is characterized by nausea, malaise, abdominal pain and jaundice. Both HBV and hepatitis C virus (HCV) can result in chronic infection that eventually cause liver cirrhosis and hepatocellular carcinoma. Worldwide more than 2 billion people have been infected with HBV and 350 million people are chronically infected. An estimated 600,000 deaths occur each year due to the acute or chronic consequences of hepatitis B. Although there has been a vaccine available for nearly two decades to prevent infection with HBV, an effective immune therapy to treat chronic HBV infection remains a significant unmet medical need in both the US and around the world. While available small molecule-based therapies such as Lamivudine provide benefit, they have complications associated with long-term usage, and are too expensive to support treatment strategies in the developing world. Additionally, the current small molecule-based therapies do not result in complete viral clearance as they only suppress viral gene expression, and therefore do not provide a curative treatment.
Aduro was awarded an SBIR grant in June 2011 for the development of an HBV vaccine engineered to express multiple antigens.
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