New treatment may broaden target population of cancer patients.
Synthon Biopharmaceuticals today announced the results of a head-to-head comparative program of its antibody-drug conjugate (ADC) SYD985 with Roche’s market leading anti-HER2 ADC, T-DM1 (Kadcyla®*).
SYD985 is a HER2-targeting ADC based on trastuzumab and Synthon’s proprietary cleavable linker-duocarmycin (vc-seco-DUBA) payload. Data support the potential of SYD985 to address the high unmet medical need of patients with HER2 2+ and HER2 1+ breast cancer for whom there is currently no effective therapy available.
Comparisons were drawn in in vitro and in vivo testing. The in vivo study was conducted in patient-derived xenograft models in mice - preclinical models known for their highly predictive value for clinical outcome. In the study, which involved breast cancer models, SYD985 demonstrated unprecedented anti-tumor activity and clearly outperformed T-DM1, particularly where there was a low expression of HER2. See further information in the Notes to Editors.
More in-depth analyses and preclinical data on this benchmark study with SYD985 will be presented at the AACR Annual Meeting 2014.
Based on these findings, the preclinical profile of SYD985 may enable the extension of the target population of cancer patients who may respond to this treatment to include FISH-negative / IHC-HER2 1+ and 2+ patients. Analogous to T-DM1, SYD985 will be tested in refractory breast cancer patients who are FISH-positive and/or IHC-HER2 3+, but these recent data also warrant clinical studies with SYD985 in patients with HER2 1+ and 2+ malignancies.
Jacques Lemmens, chief executive officer of Synthon comments: “We are very pleased with these results. When confirmed in clinical studies, the target population for SYD985 would be significantly broader than that for the current therapy option. This would enable a possible treatment for cancer patients with a high unmet medical need, including triple negative breast cancer patients, where presently there is none.”
Synthon is preparing for the ‘first-in-human study which is planned to start in the second half of 2014. The company believes this Phase I clinical trial will further validate its ADC technology as potentially best-in-class.
* Kadcyla® is a registered trademark of Genentech, Inc. (U.S.) / F. Hoffmann-La Roche AG (EU)
In vivo anti-tumor activity was assessed in a series of tumor cell line and patient-derived breast-cancer xenograft models with varying HER2 expression levels, including HER2 3+, HER2 2+ and HER2 1+ models. Both SYD985 and T-DM1 showed anti-tumor activity in the HER2 3+ models, although SYD985 was slightly more active. SYD985 demonstrated very potent anti-tumor activity in the FISH-negative models that were either HER2 2+ or HER2 1+, contrary to T-DM1 which was completely inactive. In these low expressing HER2 tumor models, SYD985 was even able to induce complete tumor remission after a single dose of 3 mg/kg.
In vitro, SYD985 and T-DM1 were studied in a panel of eight cell lines expressing different levels of HER2. In cell lines with high HER2 expression (characterized as HER2 3+), both SYD985 and T-DM1 showed similar potencies. However, in cell lines with low HER2 expression (characterized as HER2 1+ and 2+), SYD985 was substantially more potent than T-DM1.
Antibody-drug conjugates are designed to combine the specificity of antibodies directed against tumor-associated targets with potent cytotoxity. Upon internalization of the ADC, the antibody-bound cytotoxins are released intracellularly, leading to elimination of the tumor cells. While the cytotoxins used in the majority of advanced programs in the field prevent tubulin polymerization during cell division, Synthon’s differentiating linker-drug technology − vc-seco-DUBA or valine-citrulline-seco-DUocarmycin-hydroxyBenzamide-Azaindole − is based on synthetic duocarmycin analogs, which have a unique mechanism of action. Duocarmycins, first isolated from Streptomyces bacteria in 1988, bind to the minor groove of DNA and subsequently cause irreversible alkylation of DNA. This disrupts the nucleic acid architecture, which leads to tumor cell death. Duocarmycins are able to exert their mode of action at any phase in the cellular cycle, whereas tubulin binders will only attack tumor cells when they are in a mitotic state. Growing evidence suggests that DNA damaging agents, such as duocarmycins, are more efficacious in tumor cell killing than tubulin binders, particularly in case of solid tumors.
Although based on natural products, Synthon’s proprietary ADC linker-drug technology uses fully synthetic duocarmycin analogs. The unique design of the selectively cleavable linker connecting the antibody to the duocarmycin drug, leads to high stability in circulation but also induces efficient release of the cytotoxin in the tumor cell.