The biopharmaceutical company Antisense Pharma announced today that its international, randomized and active-controlled Phase IIb study G004-AP 12009 is published in the official journal of the American Society for Neuro-Oncology (SNO).
The article is already available online on the homepage of the journal. The investigated drug trabedersen (AP 12009) is a gene silencing antisense compound – a phosphorothioate oligodeoxynucleotide – designed to selectively downregulate the production of transforming growth factor-beta 2 (TGF-β2) at the translational level.
The trial revealed encouraging efficacy results. Based on these data, a pivotal Phase III study in recurrent or refractory AA patients (SAPPHIRE) has already started.
"We are very pleased that our Phase IIb results have been published in such an important journal as Neuro-Oncology" said Dr Hubert Heinrichs, Chief Medical Officer at Antisense Pharma. “This scientific publication substantiates the remarkable clinical benefit of trabedersen to fight high-grade glioma."
The completed randomized, active controlled Phase IIb clinical study evaluated efficacy and safety of two doses of trabedersen (10 µM; 80 µM) in comparison to currently approved standard chemotherapy (TMZ or PCV) in high-grade glioma patients.
Very good safety and tolerability of trabedersen had been demonstrated in three prior clinical Phase I/II studies with 24 patients with recurrent high-grade glioma. 1 In the subsequent Phase IIb study 134 out of 145 randomized patients with either recurrent or refractory anaplastic astrocytoma (AA, N=39) or glioblastoma multiforme (GBM, N=95) received treatment.
Trabedersen was locally administered using an intratumoural catheter and a portable pump allowing outpatient treatment. GBM patients had a comparable overall survival rate among the three treatment groups (10 µM trabedersen, 80 µM trabedersen, standard chemotherapy).
In the pre-specified GBM subgroup with the two prognostic factors age = 55 years and Karnofsky Performance Status > 80% (about 40% of the GBM patients in this study), treatment with 10 µM trabedersen resulted in long-term survival rates at two and three years that were three times higher than those of patients who had received standard chemotherapy. In AA patients, the efficacy of 10 µM trabedersen was even more pronounced.
A significantly higher tumor control rate of trabedersen treated patients was observed at 14 months when compared to patients who had received standard chemotherapy (58% vs. 0%; p=0.0032). Similarly the overall response rate at 14 months was significantly higher (p=0.0337). The duration of this response exceeded the 6-month treatment period impressively with 29.1 vs. 8.0 months (p=0.10) and the two-year survival rate were clearly improved under trabedersen (83.3% vs. 41.7%). Importantly, these trabedersen effects were associated with a median overall survival benefit of 17.4 months vs. standard chemotherapy (39.1 months vs. 21.7 months, non-significant).
The current situation for the treatment of malignant brain tumours is still insufficient: Despite surgical tumor resection, radio- and chemotherapy, the tumour recurs in almost all cases and the patients die within a few months.
"Trabedersen fulfills a great demand for medical innovation and could contribute a considerable advance in the treatment of malignant brain tumors“ said Ulrich Bogdahn, MD, Director of the Department of Neurology, University of Regensburg and international head of the Phase IIb study.
Particularly the reversal of TGF-β2-mediated immunosuppression plays an important role to achieve long-term response effects: "Overexpression of TGF-β2 sustainably inhibits the activity of practically all types of immune cells, thereby forming an immunosuppressive environment around the tumor." explained Dr Karl-Hermann Schlingensiepen, Chief Executive Officer at Antisense Pharma. "Furthermore, invasion and metastasis, proliferation and angiogenesis are simultaneously promoted by TGF-β2 in a variety of malignant tumors, especially brain tumours. Therefore, trabedersen is a targeted multimodal therapy."
Ongoing pivotal Phase III study with trabedersen in AA patients
The recently published data demonstrate that TGF-β2 suppression by trabedersen is a promising treatment against high-grade gliomas. Based on these results, a pivotal international Phase III study in recurrent or refractory AA patients has started ( SAPPHIRE). The SAPPHIRE study is currently conducted in about 50 study centers worldwide, 132 patients with recurrent or refractory anaplastic astrocytoma will be included. In July 2010 the FDA has issued an IND-authorisation for clinical studies with trabedersen for patients with highgrade-glioma. Therefore the SAPPHIRE study will also be conducted in US-American clinics soon.
Original Publication: Bogdahn U. et al, Targeted Therapy for High-Grade Glioma with the TGF-β2 Inhibitor Trabedersen: Results of a Randomized and Controlled Phase IIb Study. 2010, Neuro-Oncology - in press
Neuro-Oncology is the official journal of the American Society for Neuro-Oncology (SNO).
Antisense Pharma GmbH
1 Hau P et al, Inhibition of TGF-beta2 with AP 12009 in recurrent malignant gliomas: from preclinical to phase I/II studies, Oligonucleotides 17(2): pp 201-212, 2007
