Human Genome Sciences Reports Results of Ongoing Phase 1 Clinical Trials of HGS-ETR1 in Patients With Advanced Cancers
Wednesday September 29, 9:40 am ET
Results of Phase 1 Clinical Studies Support Further Evaluation of HGS-ETR1 in Phase 2 Clinical Trials Both as a Single Agent and in Combination With Chemotherapy
Data Presented at 16th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics
ROCKVILLE, Md., Sept. 29 /PRNewswire-FirstCall/ -- Human Genome Sciences, Inc. (Nasdaq: HGSI - News) announced today that the results of ongoing Phase 1 clinical trials demonstrate the safety and tolerability of HGS-ETR1 (agonistic human monoclonal antibody to TRAIL Receptor 1) in patients with advanced solid tumors or non-Hodgkin's lymphoma, and support further evaluation of HGS-ETR1 in Phase 2 clinical trials, both as a single agent and in combination with chemotherapy.
Safety, pharmacokinetic and biological activity data from two Phase 1 studies of HGS-ETR1 were presented today at the 16th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Geneva, Switzerland. The conference is jointly organized by the European Organisation for Research and Treatment of Cancer (EORTC), National Cancer Institute (NCI) and American Association for Cancer Research (AACR).
In an oral presentation at the EORTC-NCI-AACR Symposium's plenary session, entitled "A Phase 1 Clinical Trial of HGS-ETR1, an Agonistic Monoclonal Antibody to TRAIL-R1, in Patients with Advanced Solid Tumors," data were presented on thirty-nine patients treated to date in an ongoing open-label, dose-escalation clinical trial.(1) The median number of chemotherapeutic treatment regimens previously received was two, and ranged as high as nine. The patients were enrolled into seven cohorts (0.01, 0.03, 0.1, 0.3, 1.0, 3.0, or 10.0 mg/kg) and received HGS-ETR1 administered intravenously on a 28-day or14-day schedule. The primary purpose of the study is to determine the safety, maximum tolerated dose (MTD), dose-limiting toxicities, and pharmacokinetics of HGS-ETR1 in patients with relapsed or refractory advanced tumors. Disease response also is being evaluated. Available tumor tissue samples from patients participating in the trial will be evaluated for expression of the TRAIL Receptor-1 protein using immunohistochemical (IHC) techniques.
Results to date of the ongoing Phase 1 clinical trial demonstrate that HGS-ETR1 can be administered safely and repetitively to patients with advanced solid malignancies at doses up to and including 10 mg/kg intravenously every 28 days. No evidence of drug-related hematologic or hepatic toxicity has been observed at doses up to and including 10 mg/kg. The MTD has not been reached, and accrual in the trial continues at a dose of 10 mg/kg every 14 days. Dose- proportional pharmacokinetics were observed up to a dose of 1.0 mg/kg, with a terminal elimination half-life of 15 days. In seven patients treated at the 10 mg/kg dose level, the terminal elimination half-life of HGS-ETR1 was longer, averaging about 18 days. Some preliminary evidence of biological activity has been observed. Durable stable disease for greater than eight months was observed in one patient with metastatic sarcoma. Durable stable disease was observed for four months in one patient with head-and-neck cancer and in one patient with Ewing's sarcoma; both patients continue on treatment.
A poster entitled "Phase 1 Study of a Fully Human Monoclonal Antibody to the Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Receptor 1 (TRAIL- R1) in Subjects with Advanced Solid Malignancies or Non-Hodgkin's Lymphoma" (Abstract #208) presented data on twenty-four patients treated to date in an open-label, dose-escalation clinical trial currently ongoing at two centers in Canada.(2) All patients admitted to the trial have relapsed or refractory disease and had received prior anti-cancer treatments (chemotherapy, radiotherapy, or hormone therapy). To date, twenty-four patients have been enrolled into five cohorts (0.01, 0.03, 0.3, 3.0, or 10.0 mg/kg) and received HGS-ETR1 administered intravenously every 28 days. Patients continue to be enrolled into the 10 mg/kg dose cohort. The study design calls for enrollment of an additional cohort at a dose of 20 mg/kg. Patients are treated every 28 days in the absence of disease progression or dose-limiting toxicities. The primary objective of the trial is to evaluate the safety and tolerability of repeated doses of HGS-ETR1 administered intravenously in patients with advanced solid tumors or non-Hodgkin's lymphoma. The secondary objectives are to evaluate the pharmacokinetics of repeated doses of HGS-ETR1 and to assess tumor response.
Results to date of the ongoing clinical trial demonstrate that HGS-ETR1 is well tolerated with no clearly attributable toxicities to date and that the MTD has not been reached. The median number of treatment cycles delivered is two (1-12). Stable disease has been observed in eight patients for greater than two cycles. Preliminary data indicate that the pharmacokinetics of HGS- ETR1 are dose-proportional up to 0.3 mg/kg. The trial continues to enroll patients.
An additional poster presented at the EORTC-NCI-AACR Symposium, "Variable Distribution of TRAIL Receptor 1 in Primary Human Tumor and Normal Tissues" (Abstract #225), described the results of a preclinical study designed to identify specific malignancies that are most likely to express TRAIL Receptor 1.(3) Such malignancies could be strong candidate indications for HGS-ETR1. The study, conducted by scientists at Human Genome Sciences in collaboration with scientists from DakoCytomation(4) and Fox Chase Cancer Center, used a highly specific immunohistochemical assay to evaluate TRAIL-R1 in human tumor and normal tissue. Of the first 134 malignancies evaluated, a total of 87 tumors (65 percent) showed some degree of TRAIL-R1 specific staining. TRAIL- R1 specific staining was consistently weak or absent in all 17 normal tissues assayed. Tumors of the pancreas, colon and lung were the most likely to have substantial staining for TRAIL-R1. Prostatic carcinomas were least likely to demonstrate TRAIL-R1 staining. The level of TRAIL-R1 protein in the colon was explored further in 26 additional samples representative of typical neoplastic progression. TRAIL-R1 staining distribution and intensity were increased in malignancies of the colon as compared to benign lesions or focal carcinomas in situ.
Roger B. Cohen, M.D., Director, Phase 1 Clinical Trials Program, Fox Chase Cancer Center, Philadelphia, said, "The Phase 1 clinical results we presented today demonstrate that HGS-ETR1 is well tolerated and can be safely and repetitively administered to patients with advanced malignancies. We have seen no evidence of drug-related hematological or hepatic toxicity at the dose levels administered to date. We have not reached a maximum tolerated dose, and we have seen preliminary evidence of biological activity. Patient accrual continues in the ongoing Phase 1 trials. Further evaluation of HGS-ETR1 is appropriate in Phase 2 clinical trials, both as a single agent and in combination with chemotherapy."
David C. Stump, M.D., Executive Vice President, Drug Development, said, "We continue to be encouraged by the results emerging from our ongoing Phase 1 clinical trials of HGS-ETR1. The data show that HGS-ETR1 is well tolerated in patients with advanced solid tumors or non-Hodgkin's lymphoma. Stable disease has been observed in a number of patients in these studies as well. Based on the encouraging interim clinical results from our Phase 1 studies, along with the strongly supportive preclinical evidence(1-3, 6-11), we announced at the beginning of September that we have advanced HGS-ETR1 to a Phase 2 clinical trial in patients with relapsed or refractory non-small cell lung cancer.(5) We plan to initiate additional Phase 2 clinical trials of HGS-ETR1 in the weeks and months to come."
Human Genome Sciences, using genomic techniques, originally identified the TRAIL Receptor-1 protein as a member of the tumor necrosis factor receptor super-family. The company's own studies, as well as those conducted by others, show that TRAIL Receptor 1 plays a key role in triggering apoptosis, or programmed cell death, in tumors. Human Genome Sciences took the approach of developing human monoclonal antibodies that would bind the receptor and stimulate the TRAIL Receptor-1 protein to trigger apoptosis in cancer cells, in much the same way that the native TRAIL ligand (tumor necrosis factor- related apoptosis-inducing ligand) triggers it, but with the advantage of a longer half-life and an exclusive specificity for TRAIL Receptor 1. The TRAIL Receptor-1 agonistic human monoclonal antibody, HGS-ETR1, was made in a collaboration between Human Genome Sciences and Cambridge Antibody Technology.(12) The drug will be produced in the Human Genome Sciences clinical manufacturing facilities located in Rockville, Maryland. Human Genome Sciences holds the commercial rights to the drug.
For more information about HGS-ETR1, see hgsi.com. Health professionals interested in more information about trials involving HGSI products are encouraged to inquire via the Contact Us section of the Human Genome Sciences web site, hgsi.com, or by calling (240) 314-4400, extension 3550.
Human Genome Sciences is a company with the mission to treat and cure disease by bringing new gene-based protein and antibody drugs to patients.
HGS and Human Genome Sciences are trademarks of Human Genome Sciences, Inc.
This announcement contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. The forward-looking statements are based on Human Genome Sciences' current intent, belief and expectations. These statements are not guarantees of future performance and are subject to certain risks and uncertainties that are difficult to predict. Actual results may differ materially from these forward-looking statements because of the Company's unproven business model, its dependence on new technologies, the uncertainty and timing of clinical trials, the Company's ability to develop and commercialize products, its dependence on collaborators for services and revenue, its substantial indebtedness and lease obligations, its changing requirements and costs associated with planned facilities, intense competition, the uncertainty of patent and intellectual property protection, the Company's dependence on key management and key suppliers, the uncertainty of regulation of products, the impact of future alliances or transactions and other risks described in the Company's filings with the Securities and Exchange Commission. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of today's date. Human Genome Sciences undertakes no obligation to update or revise the information contained in this announcement whether as a result of new information, future events or circumstances or otherwise.
Footnotes:
1. R.B. Cohen, et al. "A Phase 1 Clinical Trial of HGS-ETR1, an
Agonistic Monoclonal Antibody to TRAIL-R1, in Patients with Advanced
Solid Tumors." 16th EORTC-NCI-AACR Symposium on Molecular Targets
and Cancer Therapeutics, 2004: Oral Presentation.
2. S.J. Hotte, et al. Phase 1 Study of a Fully Human Monoclonal Antibody
to the Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand
Receptor 1 (TRAIL-R1) in Subjects with Advanced Solid Malignancies or
Non-Hodgkin's Lymphoma (NHL). 16th EORTC-NCI-AACR Symposium on
Molecular Targets and Cancer Therapeutics, 2004: Abstract #208.
3. W. Halpern, et al. Variable Distribution of TRAIL Receptor 1 in
Primary Human Tumor and Normal Tissues. 16th EORTC-NCI-AACR Symposium
on Molecular Targets and Cancer Therapeutics, 2004: Abstract #225.
4. (HGSI Press Release) Human Genome Sciences Announces License Agreement
with DakoCytomation for Development of Pharmacogenomic Diagnostic
Assays. March 31, 2004.
5. (HGSI Press Release) Human Genome Sciences Advances Anti-Cancer Drug
to Phase 2 Clinical Development. September 8, 2004.
6. A.W. Tolcher, et al. A Phase 1 and Pharmacokinetic Study of HGS-ETR1,
A Fully Human Monoclonal Antibody to TRAIL-R1 (TRM-1), in Patients
with Advanced Solid Tumors. American Society of Clinical Oncology
Annual Meeting, 2004: Abstract #3060.
7. L.H. Le, et al. Phase 1 Study of a Fully Human Monoclonal Antibody to
the Tumor Necrosis Factor-Related Apoptosis-Inducting Ligand Death
Receptor 4 (TRAIL-R1) in Subjects with Advanced Solid Malignancies or
Non-Hodgkin's Lymphoma. American Society of Clinical Oncology Annual
Meeting, 2004: Abstract #2533.
8. G.V. Georgakis, et al. Selective Agonistic Monoclonal Antibodies to
the TRAIL Receptors R1 and R2 Induce Cell Death and Potentiate the
Effect of Chemotherapy and Bortezomib in Primary and Cultured Lymphoma
Cells. American Society of Clinical Oncology Annual Meeting, 2004:
Abstract #6595.
9. TRAIL R2-mAb, a human agonistic monoclonal antibody to tumor necrosis
factor-related apoptosis inducing ligand receptor 2, affects tumor
growth and induces apoptosis in human tumor xenograft models in vivo.
Robin C. Humphreys, Ralph F. Alderson, Eliel Bayever, Kevin Connolly,
Gil H. Choi, Norma Lynn Fox, Gilles Gallant, Krzystof J.
Grzegorzewski, Viktor Roschke, Theodora W. Salcedo, Jing Zhang, Junli
Zhang, Vivian R. Albert. 94th AACR Annual Meeting. Abstract 642.
10. TRAIL-R2 mAb, a human agonistic monoclonal antibody to tumor necrosis
factor-related apoptosis inducing ligand receptor 2, induces apoptosis
in human tumor cells. Ralph F. Alderson, Charles E. Birse, Kevin
Connolly, Gil H. Choi, Norma Lynn Fox, Gilles Gallant, Ina Han, Robin
C. Humphreys, Ron Johnson, Palanisamy Kanakaraj, Vikram Patel, Oxana
Pickeral, Laurie Pukac, Viktor Roschke, Theodora Salcedo, Tara Shah,
Junli Zhang, Vivian R. Albert. 94th AACR Annual Meeting. Abstract
963.
11. Ashkenazi A. et al. Safety and anti-tumor activity of recombinant
soluble APO2 ligand. J Clin Inv July 1999; 104(2): 155-162.
12. (HGSI Press Release) Cambridge Antibody Technology and Human Genome
Sciences Announce Second Drug Partnership. January 8, 2002. |
