ROCKVILLE, Md., Nov. 17 /PRNewswire-FirstCall/ -- Human Genome Sciences, Inc. announced today that the results of two Phase 1 clinical trials demonstrate that HGS-ETR2 is well tolerated and can be administered safely and repetitively in patients with advanced solid tumors, and support further evaluation in Phase 2 trials.(1-2) Stable disease was observed in a number of patients in each of the studies. The results were presented in Philadelphia at the AACR-NCI-EORTC International Conference on Molecular Therapeutics.(3)
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A poster entitled “Phase 1 and Pharmacokinetic Study of HGS-ETR2, a Human Monoclonal Antibody to TRAIL-R2, in Patients with Advanced Solid Malignancies” presented data on 37 patients in an open-label, dose-escalation two-center Phase 1 study.(1) Patients participating in the study previously received multiple cancer treatment regimens, including chemotherapy, immunotherapy, radiotherapy, hormone therapy and/or surgery. The patients were enrolled into 6 cohorts (0.1, 0.3, 1.0, 3.0, 10.0 or 20.0 mg/kg) and received HGS-ETR2 administered intravenously on a 21-day schedule, with dosing to disease progression in the absence of dose-limiting toxicities. The primary purpose of the study, which was conducted in the United Kingdom, was to evaluate the safety and tolerability of escalating doses of HGS-ETR2 in patients with relapsed or refractory solid tumors. Pharmacokinetics (PK) and tumor response also were evaluated.
Results of the Phase 1 study demonstrate that HGS-ETR2 was well tolerated, with minimal toxicity at doses up to 10 mg/kg, and could safely be administered intravenously every 21 days. Dose-limiting toxicity (DLT) was defined at a dose of 20 mg/kg. No DLT’s occurred at the 10-mg/kg dose level. The pharmacokinetics of HGS-ETR2 were found to be linear across a 200-fold dose range (0.1-20.0 mg/kg). Stable disease was observed in 11 of these heavily pre-treated patients, including patients with refractory sarcoma.
A poster entitled “A Phase 1 Clinical Trial of HGS-ETR2, a Fully Human Activating Monoclonal Antibody to TRAIL-R2, in Patients with Advanced Solid Tumors” presented data on 31 patients in an open-label, dose-escalation two- center Phase 1 study.(2) Study participants previously received multiple cancer treatment regimens, including chemotherapy, surgery and/or radiotherapy. The patients were enrolled into 5 cohorts (0.1, 0.3, 1.0, 3.0, and 10.0 mg/kg) and received HGS-ETR2 administered intravenously on a 14-day schedule, with dosing to disease progression in the absence of dose-limiting toxicities. The primary objective of the study, which was conducted in the United States, was to evaluate the safety and tolerability of escalating doses of HGS-ETR2 in patients with advanced solid malignancies. Secondary objectives were to evaluate the PK of HGS-ETR2 and to evaluate tumor response.
Results of the Phase 1 trial show that HGS-ETR2 was well tolerated, with minimal toxicity at doses up to 10 mg/kg, and could safely be administered intravenously every 14 days. One patient experienced a dose-limiting toxicity (DLT) at the 10-mg/kg dose that was determined to be possibly related to HGS- ETR2 and also possibly related to a nutritional supplement the patient was taking. The pharmacokinetics of HGS-ETR2 were found to be linear up to 10 mg/kg. Stable disease was observed in 10 of these heavily pre-treated and refractory patients.
Anthony W. Tolcher, M.D., Director of Clinical Research at the Institute for Drug Development of the Cancer Therapy and Research Center, and Clinical Professor, Department of Medicine/Oncology, University of Texas Health Sciences Center, San Antonio. Texas, said, “The clinical results presented at AACR-NCI-EORTC demonstrate that HGS-ETR2 is well tolerated at doses as high as 10-mg/kg in patients with advanced solid tumors. The DLT dose has been identified as 20 mg/kg. In both studies for which data were presented, stable disease was observed in a number of these heavily pretreated and refractory patients. Phase 2 trials of HGS-ETR2 are warranted to evaluate its potential for use in the treatment of specific cancers.”
David C. Stump, M.D., Executive Vice President, Drug Development, said, “The results of the Phase 1 studies of HGS-ETR2 show that it is well tolerated and can be safely and repetitively administered in patients with advanced malignancies. I am encouraged by the observation of stable disease in a number of the patients in each of the studies, all of whom had been treated previously with multiple courses of anti-cancer therapy. The clinical data presented here today, combined with the results of preclinical studies of HGS- ETR2, provide strong support for our plan to advance it to Phase 2 trials.”
An additional poster entitled “HGS-ETR2, a Fully Human Agonist Monoclonal Antibody That Targets TRAIL-R2, Synergizes with Chemotherapeutic Agents to Increase in Vitro Cytotoxicity and Induce Tumor Regression in NSCLC Xenografts"(4) described the results of preclinical studies to assess the in vitro and in vivo efficacy of HGS-ETR2 alone and in combination with chemotherapeutic agents in a non-small cell lung cancer (NSCLC) tumor cell line, H460, in cytotoxicity assays and xenograft tumor models. The study results demonstrated that the in vitro cytotoxicity of HGS-ETR2 was amplified through the addition of chemotherapeutic agents including paclitaxel and docetaxel. Increased cytotoxicity was observed when both agents were combined and was correlated with activation of the cell death cascade as exemplified by increased caspase activity. In the NSCLC H460 xenograft model, the results demonstrated a synergistic interaction between HGS-ETR2 and docetaxel or docetaxel and carboplatin in vivo. In vivo, HGS-ETR2 alone was ineffective in inhibiting tumor growth of H460 xenografts. When combined with docetaxel, or docetaxel and carboplatin, there was a significant (p less than 0.0001) and rapid (~50% decrease in tumor volume in 6 days) tumor regression after a single 10mg/kg IV dose. These preclinical data support the evaluation of chemotherapeutic agents in combination with HGS-ETR2 in future clinical studies.
Human Genome Sciences, using genomic techniques, originally identified the TRAIL receptor-2 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 2 plays a key role in triggering apoptosis, or programmed cell death, in human tumors. Human Genome Sciences took the approach of developing human monoclonal antibodies that would bind to the receptor and stimulate the TRAIL receptor-2 protein to trigger apoptosis in cancer cells, in much the same way that the native TRAIL ligand (tumor necrosis factor-related apoptosis-inducing ligand) does, but with the advantage of a longer serum half-life and an exclusive specificity for TRAIL receptor 2. Human Genome Sciences’ own clinical and preclinical studies, along with published results in the scientific literature, demonstrate that agonistic antibodies to the death domain-containing TRAIL receptors have significant potential to provide novel therapeutic options to patients with a variety of cancer types.(1-2, 4-43)
HGS-ETR2 is a Human Genome Sciences drug that was generated through a collaboration between Human Genome Sciences and Cambridge Antibody Technology.(44) Under a June 1996 agreement, GlaxoSmithKline (GSK) has an option to co-develop and co-commercialize HGS-ETR2 when it completes a Phase 2a clinical trial.(45) Under the agreement, GSK and Human Genome Sciences would share equally in Phase 3/4 development costs, and would share equally in sales and marketing expenses and profits of any product that is commercialized.
Human Genome Sciences is a company with the mission to discover, develop, manufacture and market innovative drugs that serve patients with unmet medical needs, with a primary focus on protein and antibody drugs.
For more information about HGS-ETR2, see http://www.hgsi.com/products/ETR2.html. Health professionals interested in more information about trials involving Human Genome Sciences products are encouraged to inquire via the Contact Us section of the company’s web site, http://www.hgsi.com/products/request.html, or by calling (301) 610-5790, extension 3550.
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. Attard G, Plummer R, de Bono JS, Calvert H, et al. Phase 1 and pharmacokinetic study of HGS-ETR2, a human monoclonal antibody to TRAIL-R2, in patients with advanced solid malignancies. 2005 AACR- NCI-EORTC International Conference on Molecular Therapeutics. Abstract #B114. 2. Sarantopoulos J, Wakelee H, Mita M, Tolcher A, Sikic B, et al. A Phase 1 clinical trial of HGS-ETR2, a fully human activating monoclonal antibody to TRAIL-R2, in patients with advanced solid tumors. 2005 AACR-NCI-EORTC International Conference on Molecular Therapeutics. 3. The conference is jointly organized by the American Association for Cancer Research (AACR), National Cancer Institute (NCI) and European Organisation for Research and Treatment of Cancer (EORTC). 4. Humphreys R, et al. HGS-ETR2, a fully human agonist monoclonal antibody that targets TRAIL-R2, synergizes with chemotherapeutic agents to increase in vitro cytotoxicity and induce tumor regression in NSCLC xenografts. 2005 AACR-NCI-EORTC International Conference on Molecular Therapeutics. 5. Hariharan S, Gore L, Eckhardt SG, Cohen RB, et al. A Phase 1 and pharmacological study of HGS-ETR1, an antibody targeting TRAIL-R1, in combination with paclitaxel and carboplatin in patients with advanced solid malignancies. 2005 AACR-NCI-EORTC International Conference on Molecular Therapeutics. 6. Mom CH, Sleijfer S, Gietema JA, et al. A Phase 1 study of HGS-ETR1, a fully human monoclonal antibody to TRAIL-R1, in combination with gemcitabine and cisplatin in subjects with advanced solid malignancies. 2005 AACR-NCI-EORTC International Conference on Molecular Therapeutics. 7. (HGSI Press Release) Human Genome Sciences Reports Interim Results of Phase 1 Clinical Trials of HGS-ETR1 in Combination with Chemotherapy in Patients with Advanced Solid Tumors. November 17, 2005. 8. Kanzler S, Trarbach T, Heinemann V, Köhne CH, Seeber S, et al. Results of a Phase 2 trial of HGS-ETR1 (agonistic human monoclonal antibody to TRAIL receptor 1) in subjects with relapsed or refractory colorectal cancer (CRC). ECCO 13 - the European Cancer Conference, 2005: Abstract #630. 9. (HGSI Press Release) Human Genome Sciences Completes Patient Enrollment in a Phase 2 Clinical Trial of HGS-ETR1 for the Treatment of Colorectal Cancer. February 23, 2005. 10. Bonomi P, Greco FA, et al. Results of a Phase 2 trial of HGS-ETR1 (agonistic human monoclonal antibody to TRAIL receptor 1) in subjects with relapsed/recurrent non-small cell lung cancer. 11th World Conference on Lung Cancer. July 4, 2005. Abstract #1851. 11. (HGSI Press Release) Human Genome Sciences Reports Results of Phase 2 Clinical Trial of HGS-ETR1 in Patients with Non-Small Cell Lung Cancer. July 5, 2005. 12. Younes A, et al. Activity of selective agonistic monoclonal antibodies to TRAIL death receptors R1 and R2 in primary and cultured tumor cells of lymphoid origin. 9th International Conference on Malignant Lymphoma, 2005. Oral presentation. 13. (HGSI Press Release) Human Genome Sciences Reports Interim Results of Phase 2 Clinical Trial of HGS-ETR1 in Patients with Advanced Non- Hodgkin’s Lymphoma. June 13, 2005. 14. Hirte HW, Hotte SJ, Chen EX, Oza AM, et al. HGS-ETR1, a fully human monoclonal antibody to the tumor necrosis factor-related apoptosis- inducing ligand receptor 1 (TRAIL-R1) in patients with advanced solid cancer: results of a Phase 1 trial. 2005 AACR-NCI-EORTC International Conference on Molecular Therapeutics. 15. Pacey S, et al. Phase 1 and pharmacokinetic study of HGS-ETR2, a human monoclonal antibody to TRAIL-R2, in patients with advanced solid malignancies. 2005 Annual Meeting of the American Society of Clinical Oncology (ASCO), Orlando, Florida. Abstract #3055. 16. (HGSI Press Release) Human Genome Sciences Reports Results of Phase 1 Clinical Trials of HGS-ETR2 and HGS-ETR1 in Patients with Advanced Solid Tumors. May 17, 2005. 17. Mita M, et al. A Phase 1, pharmacokinetic (PK) study of HGS-ETR1, an agonistic monoclonal antibody to TRAIL-R1, in patients with advanced solid tumors. 96th Annual Meeting of the American Association for Cancer Research, Anaheim, California, 2005. Abstract #544. 18. Tolcher, et al. A Phase 1 clinical trial HGS-ETR2, a fully human monoclonal antibody to TRAIL-R2 in patients with advanced solid tumors. 96th Annual Meeting of the American Association for Cancer Research, Anaheim, California, 2005. Abstract #543. 19. (HGSI Press Release) Human Genome Sciences Reports Results of Phase 1 Clinical Trial of HGS-ETR1 in Patients with Advanced Solid Tumors. April 18, 2005. 20. Pukac L, Kanakaraj P, Humphreys R, et al. HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo. British Journal of Cancer (April 2005): 92; 1430-1441. 21. Hotte SJ, et al. HGS-ETR1, a Fully Human Monoclonal Antibody to the Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Receptor 1 (TRAIL-R1) in Patients with Advanced Solid Cancer: Results of a Phase 1 Trial. 2005 Annual Meeting of the American Society of Clinical Oncology (ASCO), Orlando, Florida. Abstract #3052. 22. Tolcher, et al. A Phase 1 clinical trial HGS-ETR2, a fully human monoclonal antibody to TRAIL-R2 in patients with advanced solid tumors. 96th Annual Meeting of the American Association for Cancer Research, Anaheim, California, 2005. Abstract #543. 23. Cohen RB, 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. 24. Hotte SJ, 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. 25. (HGSI Press Release) Human Genome Sciences Reports Results of Ongoing Phase 1 Clinical Trials of HGS-ETR1 in Patients with Advanced Cancers. September 29, 2004. 26. Tolcher AW, 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. 27. Le LH, 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. 28. (HGSI Press Release) Human Genome Sciences Reports Results of Phase 1 Clinical Trials of HGS-ETR1 (TRAIL-R1 mAb) in Patients with Advanced Cancers. June 7, 2004. 29. Halpern W, 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. 30. Georgakis GV, 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. 31. Gillotte D, Zhang Y, Poortman C, et al. Human agonistic anti-TRAIL receptor antibodies, HGS-ETR1 and HGS-ETR2, induce apoptosis in ovarian tumor lines and their activity is enhanced by taxol and carboplatin. Proceedings from the AACR 2004; 73:3579. 32. Younes A, Kadin ME. Emerging applications for the tumor necrosis factor family of ligands and receptors in cancer therapy. J Clin Oncol 2003;21:3526-3534. 33. Humphreys RC, et al. 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. 94th AACR Annual Meeting. Abstract 642. 34. Alderson RF, et al. TRAIL-R2 mAb, a human agonistic monoclonal antibody to tumor necrosis factor-related apoptosis inducing ligand receptor 2, induces apoptosis in human tumor cells. 94th AACR Annual Meeting. Abstract 963. 35. Buchsbaum DJ, Zhou T, Grizzle WE, et al. Antitumor efficacy of TRA-8 anti-DR5 monoclonal antibody alone or in combination with chemotherapy and/or radiation therapy in a human breast cancer model. Clin Cancer Research 2003; 9:3731-3741. 36. Pukac, Kanakaraj, Alderson, et al. TRAIL-R1 mAb, a human agonistic monoclonal antibody to tumor necrosis factor-related apoptosis- inducing ligand receptor 1, induces apoptosis in human tumor cells in vitro and in vivo. American Association for Cancer Research 94th Annual Meeting. July 2003, Abstract 6429. 37. Ashkenazi A. Targeting death and decoy receptors of the tumor necrosis factor superfamily. Nat Revs Cancer 2002; 2:420-430. 38. Salcedo, Alderson, Basu, et al. TRM-1, a fully human TRAIL-R1 agonistic monoclonal antibody, displays in vitro and in vivo anti- tumor activity. American Association for Cancer Research 93rd Annual Meeting. April 2002, Abstract 4240. 39. Humphreys R, et al. TRAIL-R1 and TRAIL-R2 human agonistic monoclonal antibodies display in vitro and in vivo activity on human cancer cells. Society for Biological Therapy 2002; oral presentation. 40. Chuntharapai A, Dodge K, Grimmer K, et al. Isotype-dependent inhibition of tumor growth in vivo by monoclonal antibodies to death receptor 4. J Immunol 2001; 166:4891-4898. 41. Ichikawa K, Liu W, Zhao L, et al. Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity. Nat Med 2001; 7:954-960. 42. Ashkenazi A. Apo-2L/TRAIL in Cytokine Reference. Academic Press 2000. 43. Ashkenazi A. et al. Safety and anti-tumor activity of recombinant soluble APO2 ligand. J Clin Inv July 1999; 104(2): 155-162. 44. (HGSI Press Release) Cambridge Antibody Technology and Human Genome Sciences Announce Second Drug Partnership. January 8, 2002. 45. (HGSI Press Release) Human Genome Sciences and SmithKlineBeecham Sign Revised Genomics Collaboration Agreement. July 2, 1996.
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