The U.S. Food & Drug Administration (FDA) has accepted Byondis‘ submission of a Biologics License Application (BLA) for [vic-] trastuzumab duocarmazine (previously known as SYD985) in patients with HER2-positive unresectable locally advanced or metastatic breast cancer (MBC). The Prescription Drug User Fee Act (PDUFA) action date of May 12, 2023.
[Vic-]Trastuzumab Duocarmazine is an investigational next generation anti-HER2 antibody-drug conjugate (ADC) which 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).
Submission of the BLA followed positive results of phase III TULIP® Trial.
“Women with HER2-positive breast cancer generally have a more aggressive disease, greater likelihood of recurrence and poorer prognosis,” noted Byondis Chief Medical Officer Jan Schellens, M.D., Ph.D.
“Today’s [vic-]trastuzumab duocarmazine BLA acceptance by the FDA is an important step forward toward our goal of providing a much-needed alternative for these patients,” Schellens added.
HER2+ breast cancer
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.
“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,” explained Marco Timmers, Ph.D., Byondis’ Chief Executive Officer.
“[Vic-] trastuzumab duocarmazine combines a HER2-targeting antibody with a novel and potent cytotoxic drug in a way that limits damage to healthy tissue,” Timmers further added.
In preclinical studies [vic-] trastuzumab duocarmazine demonstrated to be highly effective in vitro in killing various types of cancer cells that express a variety HER2 levels, with IC50 values from 0.08 to 8.2 nM.
In addition, preclinical studies demonstrated that [vic-] trastuzumab duocarmazine mediates bystander killing of HER2-negative cells, indicating that active toxins are released after intracellular processing of of the investigational drug . Furthermore, study results from conventional and patient-derived breast cancer xenograft (PDX) studies confirm that a single injection of [vic-] trastuzumab duocarmazine at 1–3 mg/kg is sufficient to delay tumor growth, with growth inhibition of more than 50–95% and a long-lasting effect of up to 70 days duration, while increasing the dose to 10 mg/kg almost completely blocked tumor growth. 
Other preclinical in vivo studies demonstrated that [vic-] trastuzumab duocarmazine is superior to [ado-] trastuzumab emtansine (T-DM1; Kadcyla®; Genentech/Roche) and exerts significant cytotoxicity against cancer cells expressing low levels of HER2 3+, 2+, and 1+ models whereas [ado-] trastuzumab emtansine only showed significant anti-tumor activity in HER2 3+ breast cancer PDX models. Parallel comparison further demonstrated the superiority of [vic-] trastuzumab duocarmazine when compared to [ado-] trastuzumab emtansine, with the investigational gent showing a 10–70-fold increase in potency in breast cancer PDX models and in xenograft tumors from primary uterine serous carcinoma cell lines. 
TULIP study supports first regulatory submission
This is Byondis’ first regulatory submission for its lead program of [vic-] trastuzumab duocarmazine. The BLA is supported by data from the pivotal Phase III TULIP® multi-center, open-label, randomized clinical trial comparing [Vic-] trastuzumab duocarmazine to physician’s choice (PC) treatment in patients with pre-treated HER2-positive unresectable locally advanced or metastatic breast cancer (MBC) (SYD985.002/NCT03262935).
The TULIP study randomly assigned HER2-positive MBC patients with ≥ 2 previous MBC regimens or previous MBC treatment with [ado-] trastuzumab emtansine, 2:1 between [vic-] trastuzumab duocarmazine (1.2 mg/kg q three weeks) and physician’s choice (PC) chemotherapy.
In the trial, 437 patients from 11 countries were randomized to [vic-] trastuzumab duocarmazine (n=291) or physician’s choice (n=146). Median age was 56 years, median number of prior MBC treatments was 4 [range 1-16]. Centrally reviewed median PFS was 7.0 months [95% CI 5.4-7.2] for [vic-] trastuzumab duocarmazine and 4.9 mo [4.0-5.5] for physician’s choice (HR 0.64 [0.49-0.84]; p = 0.002).
Investigator-assessed PFS was also significantly improved (6.9 mo [6.0-7.2] vs 4.6 mo [4.0-5.6]; HR 0.60 [0.47-0.77]; p < 0.001). In the first analysis of OS the HR was 0.83 [0.62-1.09]; p = 0.153. No significant differences were observed in ORR or hrQoL.
Adverse events in TULIP
The most significant adverse events reported for [vic-] trastuzumab duocarmazine in the TULIP study were conjunctivitis (38.2%), keratitis (38.2%) and fatigue (33.3%), for physician’s choice, the significant adverse events included diarrhea (35.8%), nausea (31.4%) and fatigue (29.9%). Interstitial lung disease / pneumonitis was reported for 7.6% (5.2% grade 1-2) of patients treated with [Vic-] trastuzumab duocarmazine, including two grade 5 events. Adverse events leading to discontinuation ([Vic-] trastuzumab duocarmazine 35.4%, PC 10.2%) in the [Vic-] trastuzumab duocarmazine group were mainly related to eye disorders (20.8%) or respiratory disorders (6.3%).
The study results were presented at the 2021 Congress of the European Society for Medical Oncology (ESMO), and demonstrated that the trial met its primary endpoint of progression-free survival (PFS) by blinded central review and showed a statistically significant improvement of 2.1 months over physician choice. 
The trial was powered to detect a Hazard Ratio (HR) of 0.65 at the P < 0.05 significance level. Secondary endpoints were investigator-assessed PFS, overall survival (OS), objective response rate (ORR), and health-related Quality of Life (HRQoL).
Proprietary linker technology
[Vic-] trastuzumab duocarmazine, a Next Generation antibody-drug conjugate which incorporates Byondis’ distinctive, proprietary duocarmazine linker-drug 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.
While earlier generation antibody-drug conjugates 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.
The differentiating linker-drug, vc-seco-DUBA, owes its potent anti-tumor activity to a synthetic duocarmycin-based cytotoxin. Duocarmycins, a class of DNA minor-groove-binding alkylating molecules, were first isolated from Streptomyces bacteria in the 1970s, 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.
First-in-human Study With the Antibody-drug Conjugate SYD985 to Evaluate Safety and Efficacy in Cancer Patients – NCT02277717
Highlights of prescribing information
[Ado-] trastuzumab emtansine (T-DM1; Kadcyla®; Genentech/Roche) [Prescription information]
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