Efficacy observed in breast cancer patients refractory to trastuzumab and trastuzumab-emtansine treatments.

Synthon Biopharmaceuticals (‘Synthon’) reports positive  initial results from the dose-escalation part of its ongoing first-in-human trial with SYD985, an investigational HER2-targeting antibody-drug conjugate (ADC). Partial responses were observed in breast cancer patients who are refractory to previous HER2-targeted treatments. The data were presented on 27 September 2015 during the European Cancer Congress in Vienna, Austria.

In the ongoing dose-escalation part of the trial, safety and efficacy of SYD985 have been evaluated in patients with locally advanced or metastatic solid tumors of any origin. The patients were enrolled in leading European oncology centers Radboud University Medical Center (Nijmegen, the Netherlands), the Jules Bordet Institute (Brussels, Belgium) and the Institute of Cancer Research at The Royal Marsden Hospital (London, United Kingdom). Partial responses are observed in breast cancer patients who are refractory to previous HER2-targeted treatments, including trastuzumab emtansine (T-DM1). In addition, efficacy was reported in a HER2 2+ / FISH-negative breast cancer patient. 
Although the maximum tolerated dose has not yet been reached and the dose escalation part is ongoing, initial results, including safety, tolerability and pharmacokinetics, were reported on investigated dose cohorts up to 2.4 mg/kg.

Continuation of the dose-escalation part of the trial will further define the safety and efficacy profile of SYD985 before selection of the recommended Phase II dose and initiation of the expanded patient cohort part. These expanded cohorts will include breast cancer and gastric cancer patients with at least HER2 1+ expression. Apart from that, patients will be recruited in indications where presently no effective anti-HER2 therapy is available, including lung cancer, endometrial cancer and bladder cancer. 

SYD985 is a HER2-targeting ADC based on trastuzumab and Synthon’s proprietary cleavable linker-duocarmycin (vc-seco-DUBA) payload.

Dr. Marco Timmers, chief scientific officer of Synthon, said: “These exciting initial results suggest that SYD985 may provide an additional treatment option for patients refractory to the established HER2-targeting drugs and may broaden the patient population eligible for HER2-targeted treatment.” 

-ENDS-

Notes to Editors

The results were presented as abstract 333 during the poster Session: "Early Drug Development" on Sunday 27 September 2015 from 16:45 to 18:45 (board P144):
Phase I dose-escalation trial with the DNA-alkylating anti-HER2 antibody-drug conjugate SYD985
C.M.L. van Herpen1, U. Banerji2, E.C.M. Mommers3, N.P. Koper3, P. Goedings3, J. Lopez2, A. Awada4, H.B. Fiebrich1, P.G. Aftimos4
1 Department of Medical Oncology, Radboud University Medical Center, Nijmegen, NETHERLANDS
2 Drug Development Unit, The Institute of Cancer Research and The Royal Marsden, London, UK
3 Clinical Development, Synthon Biopharmaceuticals, Nijmegen, NETHERLANDS
4 Medical Oncology Clinic, Institut Jules Bordet - Université Libre de Bruxelles, Brussels, BELGIUM

About trial SYD985.001

Trial SYD985.001 is a two part first-in-human Phase I study with the anti-HER2 ADC SYD985 to evaluate the safety, pharmacokinetics and efficacy in patients with histologically-confirmed, locally advanced or metastatic tumors. These are patients who have progressed on standard therapy or for whom no standard therapy exists. 
During part I (dose escalation) patients with solid tumors of any origin are enrolled. For part II (expanded cohorts) enrollment is focused at patients with breast or selected non-breast tumors with demonstrated HER2 expression and measurable disease lesions as per protocol defined criteria. 

This trial is registered in ClinicalTrials.gov with identifier NCT02277717.

Preclinical in vitro and in vivo findings in a head-to-head comparison of SYD985 and T-DM1 

In vitro, SYD985 and T-DM1 (trastuzumab-emtansine, Kadcyla®) 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+) SYD985 and T-DM1 showed similar potencies. However, in cell lines with low or moderate HER2 expression (characterized as HER2 1+ and HER2 2+), SYD985 was substantially more potent than T-DM1. 
In vivo anti-tumor activity was assessed in a series of xenograft models using tumor cell lines and patient-derived breast-cancer tissues with varying HER2 expression levels (HER2 3+, HER2 2+ and HER2 1+). 
Both SYD985 and T-DM1 showed anti-tumor activity in the HER2 3+ models. 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 moderate- or low-expressing HER2 tumor models, SYD985 was even able to induce complete tumor remission after a single dose of 3 mg/kg. 
For more information refer to Miranda M.C. van der Lee, Patrick G. Groothuis, Ruud Ubink, et al. The Preclinical Profile of the Duocarmycin-Based HER2-Targeting ADC SYD985 Predicts for Clinical Benefit in Low HER2-Expressing Breast Cancers. Mol Cancer Ther 2015; 14(3): 692–703. 
* Kadcyla® is a registered trademark of Genentech, Inc. (U.S.) / F. Hoffmann-La Roche AG (EU)

Unique technology based on duocarmycin analogs

Antibody-drug conjugates are designed to combine the specificity of antibodies directed against tumor-associated targets with potent cytotoxicity. Upon internalization of the ADC, the antibody-bound cytotoxins are released intracellularly, leading to programmed tumor cell death. 

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 − applying valine-citrulline-seco-DUocarmycin-hydroxyBenzamide-Azaindole (vc-seco-DUBA) − is based on synthetic duocarmycin analogs, which have a unique mechanism of action. Duocarmycins, first isolated from Streptomyces bacteria in the 1970s, bind to the minor groove of DNA and subsequently cause irreversible alkylation of DNA. This disrupts the nucleic acid architecture, which eventually 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 phase. Growing evidence suggests that DNA damaging agents, such as duocarmycins, are more efficacious in tumor cell killing than tubulin binders, particularly in 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, and induces efficient release of the cytotoxin in the tumor. 

About Synthon

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 oncology and autoimmune diseases. Synthon products are currently approved by regulatory agencies in over 90 countries worldwide and marketed through strategic partnerships and – in dedicated areas – through direct sales. Synthon employs about 1,500 staff worldwide, and in 2014 it recorded a turnover of EUR 218 million. For more information, go to www.synthon.com.  

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