Date: 2013-02-26
Type of information:
phase: 1-2
Announcement: update
Company: Antisense Pharma, now Isarna Therapeutics (Germany)
Product: trabedersen
Action
mechanism: This gene-silencing substance inhibits the tumor factor Transforming Growth Factor beta 2 (TGF-Beta 2) at its translational level.
Disease: advanced pancreatic cancer
malignant melanoma
colorectal cancer
Therapeutic area: Cancer - Oncology
Country:
Trial
details: 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).
Latest
news: * On February 26, 2013, Antisense Pharma GmbH, has announced its revised corporate and development strategy. The updated corporate strategy focuses on streamlining the organization to meet its current business objectives and strengthen key senior management positions in light of the new direction for trabedersen’s clinical development program and the advancement of Antisense Pharma’s ‘Next Generation’ TGF-Beta inhibitor oligonucleotide program. The data analysis of “SAPPHIRE” (G005), trabedersen’s early terminated phase III study in glioma, is in progress. However, preliminary safety data analyses revealed that the benefit/risk ratio might not be in favor of the trabedersen treatment arm due to serious adverse events (SAE) associated with the local mode of administration of the drug in this trial. The company will no longer pursue further development of the local administration of trabedersen in glioma. From now onwards, trabedersen’s development path will only focus on the systemic intravenous (IV) mode of administration.
This decision is further supported by the findings from the Phase I/II clinical study (P001) presented at ASCO in June 2012. The data demonstrated that the systemic IV administration of trabedersen treatment is safe and well tolerated by patients. First clinical signs of efficacy were observed in this study with encouraging survival outcomes for patients suffering from pancreatic cancer or malignant melanoma when compared to historical controls (See below).
With this intent, Antisense Pharma is currently under way to launch a clinical Phase II study to evaluate systemic, intravenous trabedersen treatment in patients suffering from malignant melanoma, pancreatic cancer and other tumors by the second half of 2013. This clinical trial will be conducted in two stages. The first stage has a dose-confirmatory component and will further define the pharmacodynamic (PD) activity of trabedersen in terms of TGF-?2 target down-regulation as a primary PD parameter and immunomodulation in the selected patient populations. Upon successful completion of the first stage, the second stage of the study is set to demonstrate a survival benefit over standard chemotherapy for one or two key tumor indications in a larger patient population.
Upon strategic considerations from the company’s senior management team supported by recommendations from the strategic advisory board, Antisense Pharma started a ‘Next Generation’ TGF-Beta inhibitor oligonucleotide program that provides the company with a portfolio of additional assets, comprised of compounds specifically designed to down regulate the TGF-Beta pathway by targeting different TGF-Beta isoforms or combinations thereof, for the treatment of high unmet medical need cancer indications.
This strategic refocusing did impact the organization. Accordingly, Antisense Pharma decided to outsource non-critical expertise and adjusted its headcount, reducing its workforce by half on February 1st, 2013. The company furthermore announced the addition of new talents in several key senior management positions. Added to the team are Eugen Leo, M.D. Ph.D. M.B.A., a board certified hematologist and medical oncologist and Professor of Medicine with a long-standing international targeted therapy clinical development experience in both academia and industry, and Michel Janicot, Ph.D., a biochemist, scientist and drug-developer with extensive global industry expertise in preclinical development of targeted therapies for oncology.
* On June 4, 2012, the biopharmaceutical company Antisense Pharma has presented 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). The Phase I/II study’s primary objectives were to evaluate trabedersen’s maximum tolerated dose (MTD) and dose limiting toxicities (DLTs).
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).
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 2nd-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.
