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Antisense Pharma Presents Trabedersen Phase I/II Complete Data at ASCO

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Antisense Pharma presents trabedersen complete data from its clinical Phase I/II study in patients with advanced pancreatic cancer, malignant melanoma or colorectal cancer at the international cancer congress ASCO 2012 in Chicago, USA (Abstract #4034).

Trabedersen, is an antisense compound that specifically inhibits expression of transforming growth factor beta 2 (TGF-β2) - a protein which is over expressed in advanced tumors and which triggers key cancer pathomechanisms, i.e. suppression of antitumor immune response and metastasis.

“Trabedersen shows excellent safety and encouraging survival results in patients with advanced solid tumors”, concludes Dr. Hubert Heinrichs, Chief Medical Officer at Antisense Pharma.

Dr. Heinrichs continued, “In comparison to current treatments for late stage pancreatic carcinoma or malignant melanoma, our compound may prove to be a very novel and attractive therapeutic alternative.”

Study design P001
Antisense Pharma’s open-label, multi-center, dose-escalation P001 Phase I/II study’s primary objectives were to evaluate trabedersen’s maximum tolerated dose (MTD) and dose limiting toxicities (DLTs).

Safety, tolerability, pharmacokinetics and efficacy were evaluated as secondary study objectives. A total of 61 patients with advanced pancreatic adenocarcinoma (PanCa, n=37), malignant melanoma (MM, n=19), or colorectal cancer (CRC, n=5), KPS ≥ 80%, were treated with continuous i.v. trabedersen as 2nd to 4th-line therapy with escalating doses in two treatment schedules (1st schedule: 7 d on/ 7 d off; 2nd schedule: 4 d on/10 d off; for up to 10 cycles).

MTD and Phase II part of the study
Within the 7 d on/ 7 d off schedule, the MTD was established at 160 mg/m2 /d. In the 4 d on/10 day off schedule, dose-escalation was stopped before reaching MTD.

The study demonstrated trabedersen’s optimal treatment schedule as being 4 d on/10 d off for a well-tolerated dose of trabedersen of 140 mg/m2/d.

Therefore, in the Phase II part of the study additional 14 PanCa and MM patients respectively were enrolled and treated with 140 mg/m2/d (4 d on/ 10 d off).

Safety and tolerability of trabedersen
Trabedersen was safe and very well tolerated. Dose-limiting toxicities (DLTs) were maculopapular rash (one event, non-serious), moderate, reversible thrombocytopenia (two events, non-serious), and gastrointestinal hemorrhage (one event, serious).

Only 2 SAEs (gastrointestinal hemorrhage and pyrexia) were considered as possibly related to the study medication. These two SAEs were both reversible.

Antitumor activity of trabedersen
Survival analysis of all patients with advanced PanCa (any number of pretreatments; any schedule or dose) revealed a mOS of 4.9 months (n= 37; 95% CI: 3.2, 7.1) and a mOS of 13.4 months (n=9; 95% Cl: 4.9, 18.2) for PanCa patients who had received trabedersen 2 nd-line with a dose of 140 mg/m2/d (4 d on/ 10 d off).

Case Report PanCa: One PanCa patient with liver metastasis had a complete response and is still alive after 76.2 months (as of Jan 2012).

Very promising efficacy data were also seen in the extensively pretreated 19 Stage IV MM patients treated with trabedersen as they reached a mOS of 11.4 months (95% Cl: 7.5, 13.9).

Case Report MM: A 75-year old female (stage IV DTIC resistant MM, disseminated lymph node metastases) treated with 10 cycles of trabedersen (330 mg/m2 /d), showed stable disease during the entire six-month treatment period.

No NCI-CTC grade 3 or 4 AEs associated with the administration of trabedersen were reported. The patient survived for 25.7 months after trabedersen treatment was initiated without any further salvage therapy.

CRC-patients (n=5) showed a mOS of 3.0 months.

Antisense Pharma’s clinical program:
Antisense Pharma’s strategy is aimed at deepening the knowledge of trabedersen’s mode of action in order to optimize the compound’s clinical development in selected indications characterized by high unmet medical need in life-threatening forms of cancer disease.

Targeting transforming growth factor beta 2 - a promising immunotherapeutic approach
Trabedersen is the only antisense molecule targeting mRNA encoding the tumor protein transforming growth factor beta 2 (TGF-β2) - a cytokine with an important role in the progression of several advanced and aggressive cancers.

Proteins of the TGF-β family are known to be growth inhibitors of most normal cells. Those proteins play a crucial role in cellular differentiation during embryogenesis as well as in cellular homeostasis.

In contrast to its suppressive role in normal tissue, in patients with advanced tumors, TGF-β2 is over expressed and has been shown to stimulate malignant conversion, invasion, metastasis and, most importantly, it inhibits immune function.

The multiple key roles of TGF-β2 in tumor progression make it an attractive drug target for a multimodal anti-tumor approach in the treatment of advanced tumors. Trabedersen is one of the most advanced anti-TGF-β2 drug candidates currently undergoing extensive clinical development.