Alessandro Santin, MD of Byondis answers common questions on the study: Byondis Initiates Phase II Study of Antibody-Drug Conjugate [Vic-]Trastuzumab Duocarmazine in Advanced Endometrial Cancer.


NIJMEGEN, The Netherlands, newswire/-Byondis B.V. July 15, 2020 / B3C (formerly Synthon Biopharmaceuticals B.V.) today reported that in its Phase II research 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, treatment was initiated in the first patients.

A Phase II single-arm trial to evaluate the safety and efficacy of 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 about 60 patients in up to 40 clinical sites in the United States, Europe and Asia-Pacific. At Severance Hospital, Yonsei University Health System, South Korea, where Associate Professor Jung-Yun Lee, M.D., Ph.D., is the principal investigator, the first patients began treating.

In the U.S., renowned endometrial cancer specialist Alessandro Santin, M.D., professor of obstetrics, gynecology, and reproductive sciences at the Yale Cancer Center, will serve as the Yale study site's principal investigator. About 20 years ago, the laboratory of Professor Santin discovered the connection between certain forms of an aggressive form of endometrial cancer, known as Uterine Serous Carcinoma (USC), and the expression HER2. In 2018, preliminary results from Professor Santin's Phase II study (1) resulted in the inclusion of the combination of chemotherapy-trastuzumab in the National Comprehensive Cancer Network (NCCN) recommendations for new treatment of women with HER2-positive USC. The final results of the same study have recently been published by Clinical Cancer Research (2), which indicated that trastuzumab with chemotherapy increases survival rates for women with USC whose tumors have expressed high levels of HER2 protein.

My team and I are excited to participate in a Phase II analysis of HER2-expressing advanced endometrial cancer investigational antibody-drug conjugate [vic-]trastuzumab duocarmazine, said Professor Santin. In our preclinical models for endometrial cancer, we had the opportunity to research the potential of SYD985, and were fascinated by its potential. This ADC combines the 'double punch' of anti-HER2 monoclonal trastuzumab antibody with a potent cytototoxin based on duocarmycin – a combination that may be helpful for patients whose disease has advanced.

[Vic-]trastuzumab duocarmazine (SYD985) is the most advanced ADC in Byondis and targets a number of HER2-positive cancers including breast and endometrial cancer. Earlier, the U.S. Based on promising results from heavily pre-treated last-line HER2-positive metastatic breast cancer patients involved in a two-part Phase I clinical trial (SYD985.001), the Food & Drug Administration approved SYD985 fast track designation.

As we are approaching the completion of enrollment in our Phase III analysis of SYD985 in metastatic HER2- positive breast cancer, we are pleased to explore its potential contribution to improving patient outcomes in advanced endometrial cancer, another difficult condition with unmet need, said Byondis CEO Marco Timmers, Ph.D.



To SYD985.003
SYD985.003 is an open-label, single-arm study of recurrent, advanced or metastatic endometrial carcinoma-expressing HER2-patients. Qualified patients on or after first-line platinum-based chemotherapy should have advanced toward this analysis. They will receive SYD985 once every three weeks before illness develops or toxicity is intolerable. There is no eligibility for patients who have undergone two or more lines of chemotherapy for advanced/metastatic illness.
The primary outcome of the analysis is the objective response rate (ORR), which is the proportion of patients with the best overall complete or partial response response assessed. Secondary endpoints include: progression-free survival (PFS); overall survival ( OS); and emerging adverse reactions (AEs) to care.

A Next Generation Antibody-Drug Conjugate, [Vic-]Trastuzumab Duocarmazine (SYD985),
SYD985 uses patented linker-drug (LD) technology unique to Byondis. Although marketed ADCs have improved therapeutic indices relative to traditional non-target chemotherapeutic agents, there is room for improvement still.
The ADC [vic-]trastuzumab duocarmazine consists of the trastuzumab monoclonal antibody and a cleavable linker drug called valine-citrulline-seco-DUocarmycin-hydroxyBenzamide-Azaindole (vc-seco-DUBA). On the surface of the cancer cell, the antibody component of SYD985 binds to HER2 and the ADC is internalized by the cell. The inactive cytotoxin is triggered after proteolytic cleavage of the linker and DNA damage is caused, leading to tumor cell death. It is possible to consider SYD985 to be a type of targeted chemotherapy.

Byondis' exclusive, patented drug-linker technology
A cytotoxin reaches the bloodstream during standard chemotherapy and travels through the body to destroy rapidly dividing cells that are normal in tumors. The problem is that in normal tissue, it often assaults rapidly dividing cells, possibly resulting in serious side effects.
Monoclonal antibodies are produced by targeting receptors expressed on tumor cell membranes to enable improved specificity. Cytotoxic drugs may be added to the antibodies using a linker molecule, creating antibody-drug conjugates or ADCs to enhance the ability of anticorps to kill cells.
While ADCs of the previous generation enhanced targeting and cell killing, they can be unstable in the bloodstream, leading to an early release of cytotoxic payload, affecting healthy tissue and narrowing the therapeutic window. The next-generation ADCs from Byondis bear an intricate, inactivated cytotoxic drug that rapidly self-destructs if released prematurely, minimizing damage to healthy tissue and enhancing the therapeutic window.
A synthetic duocarmycin-based cytotoxin owes its potent antitumor activity to Byondis' differentiated linker-drug, vc-seco-DUBA. Duocarmycins, first isolated in the 1970s from Streptomyces bacteria, bind to the minor DNA groove and disrupt the architecture of the nucleic acid, which ultimately contributes to the death of tumor cells.
The specific nature of the selectively cleavable linker that binds the antibody to the duocarmycin drug results in high circulatory stability and induces efficient release of the cytotoxin in the tumor. Uptaking the activated payload by neighboring tumor cells with a lower expression of HER2 can boost the potential for efficacy, the so-called bystander effect.

On Endometric Cancer
In 2018, an estimated 382,069 new cases and 89,929 fatalities worldwide were due to endometrial cancer, according to GLOBOCAN cancer statistics. In addition, endometrial cancer was the second most common and fourth leading cause of global deaths from gynecological cancer the same year (3). Remains incurable metastatic endometrial cancer (4,5). The platinum-based chemotherapy is the recommended first-line treatment for advanced/metastatic disease. In the second-line setting only a few agents were shown to generate significant response rates, illustrating the need for new therapies in advanced, recurrent, metastatic endometrial cancer (6).

About Byondis (formerly, Biopharmaceutical Synthon)
Byondis is an international biopharmaceutical research and development organization guided to enhance the lives of patients, developing groundbreaking precision medicines targeting intractable cancers and autoimmune diseases. The company is developing new biological entities (NBEs) and new chemical entities (NCEs) and is differentiated by its patented molecular principles from other biopharmaceutical firms, such as its linker-drug (LD) and site-specific antibody-drug conjugate (ADC) conjugation technologies.
The large development portfolio of Byondis includes clinical programs in the preclinical and early and late stages, including the anti-HER2 ADC [vic-]trastuzumab duocarmazine (SYD985, Phase III). The company has a dedicated team of more than 350 workers employed at its state-of-the-art R&D and GMP production facilities in Nijmegen, the Netherlands, including highly trained scientists and qualified technicians. Byondis collaborates with major biotechnology and pharmaceutical firms and academic research institutions at home and abroad.

Research SYD985.003 is registered with identifier NCT04205630 in ClinicalTrials.gov.