Trastuzumab duocarmazine

Dutch biopharma Byondis that the U.S. FDA issued a complete response letter for the company's lead asset, an anti-HER2 antibody-drug conjugate (ADC) for breast cancer treatment. With its BLA, Byondis sought approval for SYD985 in HER2-positive unresectable locally advanced or metastatic breast cancer — a disease with a high unmet medical need. According to Byondis, the agency requested additional information that "requires time and resources that extend beyond the current evaluation period." Byondis submitted its to the FDA back in July of last year, along with aMarketing Authorization Application to the . The EMA's decision is still pending, and is between April 2023 and October 2023. The BLA and MAA were supported by data from the phase 2 TULIP trial comparing SYD985 to physician’s choice (PC) treatment in patients with pre-treated HER2-positive unresectable breast cancer. The study met its primary endpoint of progression-free survival, demonstrating a statistically significant improvement of 2.1 months over PC. The trial also demonstrated supportive overall survival. Despite the CRL, Byondis remains optimistic about SYD985’s potential and is working with the FDA on next steps. “We continue to believe that SYD985 can present a meaningful treatment option for patients living with HER2-positive metastatic breast cancer,” said Byondis CEO Marco Timmers. HER2has become an increasingly popular target for drugmakers in the cancer space. Back in BioNTech signed a $1.5 billiondeal with China-based biotech DualityBio to co-develop and commercialize two cancer ADCs candidates, including DualityBio’s lead candidate, DB-1303, which is a topoisomerase-1 inhibitor-based ADC directed against HER2. Eisai and China-based Bliss Biopharmaceutical just a clinical trial collaboration agreement — with the option to license — for BlissBio's ADC candidate directed against HER2 for the treatment of cancers. SYD985 is also in for uterine cancer and solid tumors.

BYON3521 Targets c-MET, Widely Overexpressed in Solid Tumors Therapy Uses Proprietary Technologies Designed to Enhance Efficacy and Safety NIJMEGEN, Netherlands, Aug. 25, 2022 /PRNewswire/ -- Byondis B.V., an independent, clinical stage Dutch biopharmaceutical company creating precision medicines, today announced that the first cancer patients have been dosed with its investigational antibody-drug conjugate (ADC) BYON3521. The "First-in-Human Dose-Escalation and Expansion Trial With the Antibody-Drug Conjugate BYON3521 to Evaluate the Safety, Pharmacokinetics and Efficacy in Patients with c-MET-Expressing Locally Advanced or Metastatic Solid Tumors" (BYON3521.001/NCT05323045) is currently enrolling patients in leading oncology centers in Belgium, Italy, the Netherlands and the U.K. "The protein c-MET is widely overexpressed in a variety of solid tumors. Based on preclinical findings, we are keen to start the Phase I study of BYON3521, with the hope of finding another option for patients in need," said Byondis Chief Medical Officer Jan Schellens, M.D., Ph.D. c-MET (also called tyrosine-protein kinase MET [Mesenchymal Epithelial Transition] factor or HGFR [Hepatocyte Growth Factor Receptor]) is a proto-oncogene active in normal cell division, growth and differentiation. Mutations may cause it to become an oncogene, which can promote cancer cell growth and multiplication. "Preclinical data showed selective and potent killing of c-MET expressing tumors and a safety profile that indicated a favorable therapeutic index," said Byondis Chief Scientific Officer Wim Dokter, Ph.D. BYON3521 is the next Byondis ADC currently in the clinical trial phase. The company's most advanced ADC, [vic-]trastuzumab duocarmazine (SYD985), targets HER2-expressing cancers such as metastatic breast and endometrial (uterine) cancer. Following the release of positive results from its pivotal Phase III TULIP® trial of SYD985 in metastatic breast cancer, Byondis recently submitted the Biologics License Application (BLA) to the U.S. Food & Drug Administration and a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA). A current Phase II trial evaluates the safety and efficacy of SYD985 as a standalone therapy for HER2-expressing recurrent, advanced, or metastatic endometrial cancers. More About BYON3521.001 BYON3521.001 intends to evaluate the safety, pharmacokinetics and preliminary efficacy of BYON3521 in up to 150 patients aged 18 or over with histologically confirmed c-MET-expressing, MET-amplified or MET-mutated (except exon 14 mutated) locally advanced or metastatic solid tumors. Eligible patients are those who have progressed on standard therapy or for whom no standard therapy exists. The study is scheduled to be conducted in two parts: Dose Escalation and Dose Expansion. Part 1, the dose escalation phase, should enroll up to 30 patients with solid tumors to evaluate the therapy's safety and determine the Maximum Tolerated Dose (MTD) and Recommended Dose for Expansion (RDE). Part 2, dose expansion, should enroll up to 120 patients with specific solid tumors and documented c-MET pathway activation in four cohorts -- renal cell cancer, uveal (ocular) melanoma, head and neck squamous cell cancer and other cancers. These patients will receive the RDE determined in Part 1 to evaluate the objective tumor response rate (ORR) and safety of BYON3521 in these cohorts. All patients in both parts of the study will receive BYON3521 infusions every three weeks until disease progression or unacceptable side effects. BYON3521, a Next Generation Antibody-Drug Conjugate The ADC BYON3521 is comprised of the humanized IgG1 monoclonal antibody SYD2884, targeting c-MET, and a cleavable linker-drug called valine-citrulline-seco-DUocarmycin-hydroxyBenzamide-Azaindole (vc-seco-DUBA or SYD980). It employs site-specific conjugation to an engineered cysteine residue located on heavy chain position 41 of the antibody. The antibody part of BYON3521 binds to c-MET on the surface of the cancer cell and the ADC is internalized. After proteolytic cleavage of the linker in the lysosome, the inactivated cytotoxin is activated, binds to the DNA and DNA damage is induced, resulting in tumor cell death. Treatment with BYON3521 is considered a form of targeted therapy. Byondis' Distinctive, Proprietary Linker-Drug and Site-Specific Conjugation Technology While earlier generation ADCs improved targeting and cell killing, they can be 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 prematurely released, limiting damage to healthy tissue and improving the therapeutic window. Byondis' differentiating 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 subsequently leads to tumor cell death. BYON3521 incorporates Byondis' distinctive, proprietary duocarmazine linker-drug (LD) technology ByonZine® and its site-specific conjugation technology ByonShieLD®. 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 c-MET expression may improve the efficacy potential through the so-called bystander effect. The site-specific conjugation of the linker-drug results in enhanced in vivo antitumor activity, as was demonstrated in preclinical models. Furthermore, the manufacturing of BYON3521 relies on a single-step selective reduction of the engineered cysteines, instead of a two-step reduction/oxidation protocol that is commonly used for these types of site-specifically conjugated ADCs and that can lead to undesired side-products. The ByonShieLD® technology greatly improves manufacturability of ADCs and yields products with improved physicochemical properties. 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 production and conjugation facilities on its Nijmegen campus in the Netherlands. Byondis regularly collaborates with leading global biotechnology and pharmaceutical companies, as well as many academic research institutions. For more information, . Logo: SOURCE Byondis B.V.