Synthon Biopharmaceuticals (‘Synthon’) today announced the initiation of the second part of its ongoing Phase I clinical trial with the investigational anti-HER2 antibody-drug conjugate (ADC) SYD985. The second part will see 48 additional heavily pre-treated patients with HER2-positive breast cancer enrolled into the SYD985.001 trial. This marks an important next step in the development of SYD985, the frontrunner of Synthon’s duocarmycin-based ADC platform.
Promising results were obtained in the dose-finding part of the Phase I trial in 33 cancer patients who were dosed with between 0.3 and 2.4 mg/kg of SYD985 every three weeks. Most noticeably, very high response rates and durable responses were observed in patients whose cancers were refractory to HER2-targeted agents, including trastuzumab (Herceptin®*) and trastuzumab emtansine (Kadcyla®*), following treatment with SYD985 at doses from 1.2 mg/kg onwards.
Although data from the dose-finding part - which includes patients with solid tumors of any origin - will continue to be collected, evaluation of the larger cohort of 48 heavily pre-treated breast cancer patients with HER2-positive tumors (i.e. HER2 3+ or FISH-positive) has been initiated.
Clinical evaluation in this heavily pre-treated patient population, whose cancers are refractory to multiple lines of registered HER2-targeting treatments including Herceptin® and Kadcyla®, will continue to collect data on efficacy, safety and tolerability of SYD985 treatment at a starting dose of 1.2 mg/kg.
Data from this cohort will enable Synthon to design the first pivotal trial with SYD985 as suggested by several national regulatory authorities and subject to an ongoing EMA scientific advice request regarding the most optimal development pathway.
Synthon will shortly submit a pre-IND (Investigational New Drug Application) meeting request to the U.S. FDA addressing the same topic, with the aim of extending this clinical development program to include U.S. clinical sites under an IND.
“The auspicious data we have already obtained with SYD985 confirms our belief in this potential new HER2-targeting treatment for patients whose cancers have become refractory to currently available anti-HER2-treatments,” said Jacques Lemmens, founder and CEO of Synthon.
He continued: “Encouraged by the enthusiasm of our principal investigators and the regulatory bodies that have been consulted, we are further expediting our efforts to drive this compound forward towards a market authorization. The expanded cohort will provide us with information about the minimum effective dose; a very important parameter in this vulnerable group of patients.”
Meanwhile, the evaluation in the dose-finding part of the trial continues to further investigate efficacy and safety of repeated treatment cycles. After determination of the recommended dose later this year, more patients will be enrolled in this trial, including those with breast cancer with lower HER2 expression (HER2 1+/2+ or FISH-negative) as well as those with gastric, endometrial or bladder cancer.* Herceptin® and Kadcyla® are registered trademarks of Genentech, Inc. (U.S.) / F. Hoffmann-La Roche AG (EU)
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. Initial results of this part of the trial were presented at the European Cancer Congress in Vienna, Austria, in September 2015 (Abstract 333: C.M.L. van Herpen, U. Banerji, E.C.M. Mommers, et al. Phase I dose-escalation trial with the DNA-alkylating anti-HER2 antibody-drug conjugate SYD985).
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.
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 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. Elgersma RC, Coumans RG, Huijbregts T, 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:
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.
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 1,600 staff worldwide, and in 2015 it recorded a turnover of EUR 267 million. For more information, go to www.synthon.com.