Byondis Initiates Phase II Study of Antibody-Drug Conjugate [Vic-]Trastuzumab Duocarmazine in Advanced Endometrial Cancer

July 28,2020

Byondis B.V. (formerly Synthon Biopharmaceuticals B.V.) today announced that the first patients have started treatment in its Phase II study evaluating the safety and efficacy of its investigational antibody-drug conjugate (ADC) [vic-]trastuzumab duocarmazine (SYD985) in patients with HER2-expressing recurrent, advanced or metastatic endometrial (uterine) cancer.

A Single-arm Phase II Trial to Evaluate the Safety and Efficacy of the Antibody-Drug Conjugate (ADC) [vic-]trastuzumab duocarmazine (SYD985) in Patients With HER2-Expressing Endometrial Carcinoma Who Previously Progressed on or After First-Line Platinum-based Chemotherapy (SYD985.003) will enroll approximately 60 patients in up to 40 clinical sites in the United States, Europe and Asia-Pacific. The first patients started treatment at Severance Hospital, Yonsei University Health System, South Korea, where Associate Professor Jung-Yun Lee, M.D., Ph.D., is the principal investigator.

In the U.S., renowned endometrial cancer expert Alessandro Santin, M.D., Yale Cancer Center professor of obstetrics, gynecology, and reproductive sciences, will serve as principal investigator for the Yale study site. About 20 years ago, Professor Santin’s lab discovered the connection between some types of an aggressive form of endometrial cancer, known as Uterine Serous Carcinoma (USC), and HER2 expression. In 2018, preliminary data from Professor Santin’s Phase II study (1) led to the inclusion of the chemotherapy-trastuzumab combination for new treatment of women with HER2-positive USC in the National Comprehensive Cancer Network (NCCN) guidelines. Recently, Clinical Cancer Research published the final results of this same study (2), which confirmed trastuzumab with chemotherapy improves survival rates for women with USC whose tumors expressed high levels of the HER2 protein.

“My team and I are excited to participate in the Phase II study of the investigational antibody-drug conjugate [vic-]trastuzumab duocarmazine in HER2-expressing advanced endometrial cancer,” said Professor Santin. “We had the opportunity to study the potential of SYD985 in our preclinical models for endometrial cancer and were impressed by its potential. This ADC combines the ‘double punch’ of anti-HER2 monoclonal antibody trastuzumab with a powerful duocarmycin-based cytotoxin – a combination that could prove beneficial for patients whose disease has progressed.”

[Vic-]trastuzumab duocarmazine (SYD985) is Byondis’ most advanced ADC, targeting a range of HER2-positive cancers including breast and endometrial cancer. Previously, the U.S. Food & Drug Administration granted SYD985 fast track designation based on promising data from heavily pre-treated last-line HER2-positive metastatic breast cancer patients participating in a two-part Phase I clinical trial (SYD985.001).

“As we near the completion of enrollment in our Phase III study of SYD985 in metastatic HER2- positive breast cancer, we are pleased to examine its possible contribution to improving patient outcome in advanced endometrial cancer, another difficult disease with unmet need,” said Byondis CEO Marco Timmers, Ph.D.

About SYD985.003
SYD985.003 is an open-label, single-arm study in patients with HER2-expressing recurrent, advanced or metastatic endometrial carcinoma. Eligible patients for this study should have progressed on or after first-line platinum-based chemotherapy. They will receive SYD985 once every three weeks until disease progression or unacceptable toxicity. Patients who have had two or more lines of chemotherapy for advanced/metastatic disease are not eligible.
The study’s primary endpoint is objective response rate (ORR), which is the proportion of patients with an assessed best overall response of complete response or partial response. Secondary endpoints are: progression-free survival (PFS); overall survival (OS); and treatment-emergent adverse events (AEs).

[Vic-]Trastuzumab Duocarmazine (SYD985), a Next Generation Antibody-Drug Conjugate
SYD985 uses Byondis’ unique, proprietary linker-drug (LD) technology. Although marketed ADCs have improved therapeutic indices compared to classical non-targeted chemotherapeutic agents, there is still room for improvement.
The ADC [vic-]trastuzumab duocarmazine is comprised of the monoclonal antibody trastuzumab and a cleavable linker-drug called valine-citrulline-seco-DUocarmycin-hydroxyBenzamide-Azaindole (vc-seco-DUBA). The antibody part of SYD985 binds to HER2 on the surface of the cancer cell and the ADC is internalized by the cell. After proteolytic cleavage of the linker, the inactive cytotoxin is activated and DNA damage is induced, resulting in tumor cell death. SYD985 can be considered a form of targeted chemotherapy.

Byondis’ Unique, Proprietary Linker-Drug Technology
In traditional chemotherapy, a cytotoxin enters the bloodstream and moves through the body to kill rapidly dividing cells that are common in tumors. The problem is that it also attacks rapidly dividing cells in normal tissue, potentially resulting in severe side effects. 
Monoclonal antibodies are created to allow improved specificity by targeting receptors expressed on tumor cell membranes. To improve the cell-killing capability of antibodies, cytotoxic drugs can be attached to the antibodies using a linker molecule, forming antibody-drug conjugates or ADCs.
While earlier generation ADCs improved targeting and cell killing, they can be unstable in the bloodstream, and that can lead to an early release of the cytotoxic payload, impacting healthy tissue and narrowing the therapeutic window. Byondis’ next generation ADCs carry an intricate, inactivated cytotoxic drug that rapidly self-destructs in case it is prematurely released, limiting damage to healthy tissue and improving the therapeutic window.
Byondis’ differentiated linker-drug, vc-seco-DUBA, owes its potent antitumor activity to a synthetic duocarmycin-based cytotoxin. Duocarmycins, first isolated from Streptomyces bacteria in the 1970s, bind to the minor groove of DNA and disrupt the nucleic acid architecture, which eventually leads to tumor cell death.
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. Uptake of the activated payload by neighboring tumor cells with lower HER2 expression may improve the efficacy potential, the so-called bystander effect.

About Endometrial Cancer
According to GLOBOCAN cancer statistics, an estimated 382,069 new cases and 89,929 deaths were attributed worldwide to endometrial cancer in 2018. Moreover, in the same year, endometrial cancer was the second most common and fourth leading cause of global deaths due to gynecological cancer (3). Metastatic endometrial cancer remains incurable (4,5). For advanced/metastatic disease, platinum-based chemotherapy is the preferred first-line treatment. Only a few agents have been shown to produce meaningful response rates in the second-line setting, highlighting a need for new therapies in advanced, recurrent, metastatic endometrial cancer (6).

About Byondis (formerly Synthon Biopharmaceuticals)
Driven to improve patients’ lives, Byondis is an independent biopharmaceutical research and development company creating innovative precision medicines targeting intractable cancers and auto-immune diseases. The company is developing new biological entities (NBEs) and new chemical entities (NCEs) and differentiates itself from other biopharmaceutical companies by its proprietary molecular concepts, such as its linker-drug (LD) and site-specific conjugation technologies to generate antibody-drug conjugates (ADCs).
Byondis’ broad development portfolio comprises preclinical and early- and late-stage clinical programs, including the anti-HER2 ADC [vic-]trastuzumab duocarmazine (SYD985, Phase III). The company has a dedicated team of more than 350 staff including highly educated scientists and skilled technicians working in its state-of-the-art R&D and GMP manufacturing facilities in Nijmegen, the Netherlands. Byondis collaborates with global biotechnology and pharmaceutical companies and national and international academic research institutions.