[January 25, 2018]

Synthon's [vic-]trastuzumab duocarmazine (SYD985) granted FDA Fast Track designation for pre-treated HER2-positive metastatic breast cancer

Synthon Biopharmaceuticals ('Synthon') today announced that the U.S. Food & Drug Administration (FDA) has granted Fast Track designation for its investigational anti-HER2 antibody-drug conjugate (ADC (News - Alert)) [vic-]trastuzumab duocarmazine (SYD985). This designation is for treating patients diagnosed with HER2-positive metastatic breast cancer (MBC) that has progressed during or after at least two HER2-targeting treatment regimens for locally advanced or metastatic disease, or progressed during or after [ado-]trastuzumab emtansine treatment.

The U.S. FDA Fast Track designation is one of four programs that are intended to facilitate and expedite development and review of new drugs to address unmet medical need in the treatment of a serious or life threatening condition.

Fast Track designation for [vic-]trastuzumab duocarmazine was granted based on promising data from heavily pre-treated last-line HER2-positive MBC patients participating in a two-part Phase I clinical trial (SYD985.001). The positive clinical results indicate that this HER2-targeting ADC is efficacious and safe and could therefore provide substantial benefit to patients with no other treatment options.

In November 2017, Synthon initiated the pivotal Phase III TULIP^® trial, a multi-center, open-label, randomized clinical trial comparing the efficacy and safety of the ADC [vic-]trastuzumab duocarmazine to physician's choice treatment in patients with HER2-positive unresectable locally advanced or metastatic breast cancer. Patients are currently being enrolled in this trial, which will be conducted in up to 100 sites in the United States, Canada, Europe and Singapore.

Dr. Jacques Lemmens, chief executive officer of Synthon, commented: "We are very pleased with this Fast Track designation for [vic-]trastuzumab duocarmazine based on the promising Phase I data. There is a high unmet medical need in patients that have HER2-positive MBC and have progressed on trastuzumab and [ado-]trastuzumab emtansine. I believe that the benefit/risk balance of [vic-]trastuzumab duocarmazine is favorable and that it can provide extended benefit to these patients. Fast Track designation will support efficient development and review of [vic-]trastuzumab duocarmazine and enable early access of this promising new single-agent therapy option."

-Ends-

About trial SYD985.002 (Phase III)

Trial SYD985.002 (or TULIP^®) is a multi-center, open-label, randomized clinical Trial comparing the efficacy and safety of the antibody-drUg conjugate [vic-]trastuzumab duocarmazine (SYD985) to physician's choice in HER2-positive unresectable Locally advanced or metastatIc breast cancer Patients.

Primary objective is to demonstrate that [vic-]trastuzumab duocarmazine is superior to physician's choice in prolonging progression-free survival (PFS) on the basis of the blinded independent central reviw of tumor assessment. Secondary objectives are to compare the two treatment groups with respect to overall survival (OS); objective response rate (ORR) on the basis of the blinded independent central review; Investigator assessed PFS; patient-reported outcomes (PRO) for health related quality of life (EORTC QOL C30 & BR23); safety and tolerability.

This trial is registered in ClinicalTrials.gov with identifier NCT03262935.

About trial SYD985.001 (Phase I)

Trial SYD985.001 is a two part first-in-human 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 were enrolled. For part II (expanded cohorts) enrollment was focused at patients with breast or selected non-breast tumors with demonstrated HER2 expression including HER2-low expressing (IHC 1+/2+, ISH-) tumors and measurable disease as per RECIST 1.1.

Preliminary results of the trial were presented at the San Antonio Breast Cancer Symposium in December 2016 (Abstract P6-12-02; SYD985, a novel anti-HER2 ADC, shows promising activity in patients with HER2-positive and HER2-negative metastatic breast cancer. Aftimos PG, van Herpen CM, Mommers EC, Koper NP, Goedings P, Oesterholt M, Awada A, Desar IM, Lim J, Dean E, Rolfo C, Macpherson I and Banerji U.)

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

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 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.

For more information regarding Synthon's ADC platform technology, please refer to:

Design, Synthesis, and Evaluation of Linker-Duocarmycin Payloads: Toward Selection of HER2-Targeting Antibody-Drug Conjugate SYD985. Ronald C. Elgersma, Ruud G.E. Coumans, Tijl Huijbregts, et al. Mol Pharm 2015; 12(6): 1813-35.

For more information on the preclinical in vitro and in vivo findings in a head-to-head comparison of SYD985 and T-DM1 please refer to:

The Preclinical Profile of the Duocarmycin-Based HER2-Targeting ADC SYD985 Predicts for Clinical Benefit in Low HER2-Expressing Breast Cancers. Miranda M.C. van der Lee, Patrick G. Groothuis, Ruud Ubink, et al. Mol Cancer Ther 2015; 14(3): 692-703.

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 auto-immune 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 1,900 staff worldwide, and in 2016 it recorded a turnover of EUR 258 million. For more information, go to www.synthon.com.

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