FDA Accepts Byondis' Biologics License Application for [Vic-] Trastuzumab Duocarmazine (SYD985) in HER2-Positive Metastatic Breast Cancer

Submission Follows Positive Results of Phase III TULIP® Trial

Next Generation HER2-ADC Uses Byondis Technologies Aimed at Improving Treatment Outcomes

NIJMEGEN, Netherlands, July 12, 2022 /PRNewswire/ -- Byondis B.V., an independent, Dutch clinical stage biopharmaceutical company creating precision medicines, announced today that the U.S. Food & Drug Administration (FDA) accepted the company's submission of a Biologics License Application (BLA) for [Vic-] Trastuzumab Duocarmazine (SYD985) in patients with HER2-positive unresectable locally advanced or metastatic breast cancer (MBC). The company has been given a Prescription Drug User Fee Act (PDUFA) action date of May 12, 2023.

SYD985 is an investigational next generation anti-HER2 antibody-drug conjugate (ADC) that was granted fast track designation by the FDA in January 2018 based on promising Phase I data involving heavily pretreated last-line HER2-positive MBC patients (SYD985.001/NCT02277717).

"Women with HER2-positive breast cancer generally have a more aggressive disease, greater likelihood of recurrence and poorer prognosis," said Byondis Chief Medical Officer Jan Schellens, M.D., Ph.D. "Today's SYD985 BLA acceptance by the FDA is an important step forward toward our goal of providing a much-needed alternative for these patients."

In HER2-positive breast cancer, overexpression of the human epidermal growth factor receptor 2 (HER2) protein causes out-of-control reproduction of breast cells. Less than 20 percent of all breast cancers are HER2-positive, with younger women being the most affected.¹

"With our proprietary technologies, we aim to offer antibody-drug conjugates with a novel mechanism-of-action, which are still efficacious when other ADC therapies have been exhausted," said Byondis CEO Marco Timmers, Ph.D. "SYD985 combines a HER2-targeting antibody with a novel and potent cytotoxic drug in a way that limits damage to healthy tissue."

This is Byondis' first regulatory submission for its lead program SYD985. The BLA is supported by data from the pivotal Phase III TULIP® multi-center, open-label, randomized clinical trial comparing SYD985 to physician's choice (PC) treatment in patients with pre-treated HER2-positive unresectable locally advanced or metastatic breast cancer (SYD985.002/NCT03262935). The study, of which the results were presented at the 2021 ESMO Congress, met its primary endpoint of progression-free survival (PFS), demonstrating a statistically significant improvement of 2.1 months over PC. TULIP also demonstrated supportive overall survival (OS) results.

[Vic-]Trastuzumab Duocarmazine (SYD985), a Next Generation Antibody-Drug Conjugate

[Vic]-trastuzumab duocarmazine (SYD985) incorporates Byondis' distinctive, proprietary duocarmazine linker-drug (LD) technology ByonZine®. The ADC is comprised of the anti-HER2 monoclonal antibody trastuzumab and a cleavable linker-drug called valine-citrulline-seco-DUocarmycin-hydroxyBenzamide-Azaindole (vc-seco-DUBA).

The antibody part of trastuzumab duocarmazine 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 is considered a form of targeted therapy.

ByonZine®, Byondis' Distinctive, Proprietary Linker-Drug Technology

While earlier generation ADCs improved targeting and cell killing, they were unstable in the bloodstream, leading to premature release of the cytotoxic payload, impacting healthy tissue and narrowing the therapeutic window. Byondis' next generation ADCs are highly stable in circulation and carry an intricate, inactivated and potent cytotoxic drug that rapidly self-destructs if 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 distinctive 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 Byondis

Driven to improve patients' lives, Byondis is an independent, privately held, Dutch clinical stage biopharmaceutical company creating innovative precision medicines targeting intractable cancers and autoimmune diseases. The company is developing next generation antibody-drug conjugates (ADCs) using its proprietary molecular concepts such as ByonZine®, its duocarmazine linker-drug (LD) technology, and ByonShieLD®, its site-specific conjugation technology. It is also creating monoclonal antibodies (mAbs) and new chemical entities (NCEs) that can stand alone or be incorporated in its ADCs.

Byondis' broad development portfolio comprises preclinical as well as early- and late-stage clinical development programs. The company has a dedicated team of about 400 employees, including highly educated scientists and skilled technicians working in state-of-the-art R&D and Good Manufacturing Practice (GMP) production and conjugation facilities on its campus in Nijmegen, the Netherlands. Byondis regularly collaborates with leading global biotechnology and pharmaceutical companies, as well as many academic research institutions. For more information, visit www.byondis.com.

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¹Cherney Kristeen. "What Is HER2-Positive Breast Cancer? Understanding Your Outlook." Healthline.com, 9 March 2022, accessed 15 June 2022 www.healthline.com/health/breast-cancer/her2-positive-survival-rates-statistics