On May 15, Byondis released a document on its official website, which showed that the FDA sent a complete response letter (CRL) regarding its biological license application of SYD985 to treat HER2-positive unresectable locally advanced or metastatic breast cancer (mBC).
The FDA stated in the CRL that more information is needed to support the approval decision, and additional time is also required for information review. While feeling regretful for FDA's decision, Byondis also presented its effort to keep advancing the marketing of SYD985 in the EU and England.
Innovative HER2 ADC has no advantages in therapeutic effects
To overcome the shortcomings of poor plasma stability and narrow treatment window of the previous generation of HER2ADC (T-DM1), SYD985 has made improvements in both linker and toxin payload. SYD985 is a next-generation HER2 ADC, which is developed by Byondis using its proprietary linker-drug technology platform, ByonZine, based on duocarmazine. It is composed of trastuzumab and cleavable linker-drug valine-citrulline-seco-Duocarmycin-hydroxyBenzamide-Azaindole (vc-seco-DUBA).
After binding to HER2 on the surface of cancer cells, SYD985 is internalized by the cells. Subsequently, the linker breaks under the action of proteases and releases the cytotoxic drug (CD), seco-DUBA, which can bind to DNA minor grooves and destroy cell and nucleic acid structures, ultimately leading to tumor cell death. SYD985, designed through the ByonZine technology platform, is highly stable in blood circulation. If the CD is released early, it will quickly start self-destruction, reducing the damage to normal tissues and expanding the treatment window.
To reduce side effects, the drug-to-antibody ratio (DAR) of SYD985 is set lower at only 2.8. Although it affects the striking effect, SYD985 has a bystander effect, which to some extent improves the therapeutic effect.
However, the marketing of the innovative HER2 ADC was rejected by the FDA. To investigate the reasons behind it, we shall look through the clinical data.
The Biologicals License Application (BLA) of SYD985 was mainly based on its critical phase III TULIP research results. It was a randomized, multicenter, open-label clinical trial (n=436), which compares the efficacy of SYD985 and the regimen selected by doctors (PC Regimen) in the treatment of patients with unresectable HER2+ locally advanced or metastatic breast cancer. The primary endpoint of the research was progression-free survival (PFS).
The results showed that compared with the PC group, the PFS of patients in the SYD985 group was significantly prolonged (7.0 months vs 4.9 months; HR=0.64; P=0.002), reaching the primary endpoint. In terms of the overall survival (OS), which was the secondary endpoint, the SYD985 group was 20.4 months, and the PC group was 16.3 months. Although SYD985 presented an improvement in survival for nearly four months, as the P value was 0.153, the OS improvement for patients from SYD985 was not significant compared to the PC group.
Regarding safety, 52.8% and 48.2% of patients in the SYD985 group and the PC group experienced level 3 and above adverse events, respectively. Three patients (1%) in the SYD985 group experienced any level of interstitial lung disease (ILD), with one patient experiencing level 3 and above adverse event.
Let's check the clinical data of DS-8201, which was regarded as the "ceiling" in the HER2 ADC field. In the DESTINY-Breast02 (DB02) trial targeted at patients with HER2-positive unresectable and metastatic breast cancer, the PFS (primary endpoint) of the DS-8201 group and the PC group was 17.8 months and 6.9 months, respectively; and the OS (secondary endpoint) of the DS-8201 group and the PC group was 39.2 months and 26.5 months, respectively.
After comparison, it is obvious that DS-8201 has almost changed the second-line and even the overall treatment pattern of HER2+ breast cancer. Therefore, if SYD985 wants to get a piece of the action, it is necessary to provide data with significant differences, which is apparently an unrealizable goal at pr...
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