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
* Kadcyla® is a registered trademark of
Genentech, Inc. (U.S.) / F. Hoffmann-La Roche AG (EU)
Notes to Editors
In vivo and in vitro findings in more detail
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
Unique technology based on duocarmycin analogs
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
- 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.
Synthon, with headquarters in Nijmegen, The Netherlands, is an
international pharmaceutical company and a leader in the field of
generic medicines. The company started its biopharmaceutical franchise
in 2007 and is building a promising portfolio of next generation
medicines. Synthon is developing rapidly into a specialty pharmaceutical
company, focusing on the therapeutic areas of auto-immune diseases and
oncology. Synthon products are currently approved by regulatory agencies
in over 80 countries worldwide and marketed through strategic
partnerships and - in dedicated areas - through direct sales. Synthon
employs about 1,400 staff worldwide, and in 2013 it recorded a turnover
of EUR 215 million. For more information, go to www.synthon.com.
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