- Ziihera is the first and only dual HER2-targeted bispecific antibody approved for HER2-positive BTC in the U.S.
- Ziihera received accelerated approval based on results including a 52% objective response rate and median duration of response of 14.9 months as determined by independent central review (ICR) from the HERIZON-BTC-01 clinical trial
- $25M milestone payment to be received from Jazz Pharmaceuticals in relation to the FDA approval; Zymeworks remains eligible for up to $500M in regulatory milestones
- Regulatory reviews of zanidatamab for BTC remain ongoing in China and Europe
- U.S. FDA approval of zanidatamab provides validation of the Company’s proprietary Azymetric™ technology and capabilities for design and development of novel medicines
- Zanidatamab continues to be investigated in a number of additional tumor types, including Phase 3 trials in gastroesophageal adenocarcinomas (GEA) and metastatic breast cancer (mBC)
VANCOUVER, British Columbia, Nov. 21, 2024 (GLOBE NEWSWIRE) -- Zymeworks Inc. (Nasdaq: ZYME), a clinical-stage biotechnology company developing a diverse pipeline of novel, multifunctional biotherapeutics to improve the standard of care for difficult-to-treat diseases, today announced, with Jazz Pharmaceuticals, that the U.S. Food and Drug Administration (FDA) has granted accelerated approval of Ziihera® (zanidatamab-hrii) 50mg/mL for injection for intravenous use for the treatment of adults with previously-treated, unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer (BTC), as detected by an FDA-approved test.1 Ziihera was approved under accelerated approval based on a 52% objective response rate (ORR) and a median duration of response (DOR) of 14.9 months as determined by independent central review (ICR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.1 The approval of Ziihera, which previously received Breakthrough Therapy Designation from the FDA for this indication, is an important advance and offers the first and only dual HER2-targeted bispecific antibody and chemotherapy-free treatment for patients living with BTC.
In late 2022, Zymeworks entered into a license and collaboration agreement with Jazz Pharmaceuticals Ireland Limited (a subsidiary of Jazz Pharmaceuticals plc, collectively referred to as Jazz), for the exclusive development and commercialization rights to zanidatamab across all indications in the United States, Europe, Japan and all other territories except for those Asia Pacific territories previously licensed by Zymeworks. This collaboration allowed the Company to leverage Jazz’s global commercial infrastructure, together with BeiGene’s complementary strengths in certain Asia Pacific countries, to enable the global, rapid advancement of zanidatamab in multiple tumor types with the potential to provide a foundational HER2-targeted therapy for patients with difficult-to-treat cancers and limited treatment options. Under the terms of the Jazz license and collaboration agreement, Zymeworks has earned a milestone payment of $25M based on the FDA approval in BTC. Zymeworks is also eligible to receive up to a further $500M in regulatory milestone payments and $862.5M in commercial milestone payments, as well as tiered royalties of 10% to 20% of net sales by Jazz.
This approval represents the first FDA-approved therapy in Zymeworks’ pipeline, and validates the Company’s novel Azymetric™ bispecific platform technology and internal research and development capabilities for novel multifunctional medicines.
“The FDA’s accelerated approval of Ziihera marks the culmination of more than a decade of research and development at Zymeworks, highlighting our deep scientific expertise in multifunctional biotherapeutics and unwavering commitment to innovation in drug development,” said Paul Moore, Ph.D., Chief Scientific Officer at Zymeworks. “This approval exemplifies our team’s exceptional scientific capabilities to translate from an initial hypothesis for dual-HER2 blockade to a breakthrough treatment that offers new hope for patients with unresectable or metastatic HER2-positive BTC with limited treatment options and few approved therapies.”
Through rigorous scientific investigation, innovative protein engineering, and proprietary Azymetric™ bispecific platform technology, Zymeworks developed the unique binding mechanism of zanidatamab-hrii, which enables it to bind to two extracellular sites on HER2. Binding of zanidatamab-hrii with HER2 results in internalization leading to a reduction of the receptor on the tumor cell surface. Zanidatamab-hrii induces complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). These mechanisms result in tumor growth inhibition and cell death in vitro and in vivo.
The FDA approval of Ziihera is based on compelling data from the HERIZON-BTC-01 trial, which included the evaluation of zanidatamab as a single agent in previously treated HER2-positive (as determined by Roche Diagnostic’s PATHWAY® anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody companion diagnostic) BTC and is the largest Phase 2b clinical trial to date specifically for this patient population. The trial achieved its primary endpoint of confirmed objective response rate (cORR) by independent central review (ICR) and results were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting 2023, published in The Lancet Oncology, and included in the 2023 Best of ASCO® program. Longer follow-up data showing improvement upon previously reported DOR were reported at the ASCO Annual Meeting 2024.1
The Phase 3 HERIZON-BTC-302 confirmatory trial is ongoing to evaluate zanidatamab in combination with standard-of-care therapy versus standard-of-care therapy alone in the first-line setting for patients with HER2-positive BTC. Zanidatamab is also being investigated in a number of additional tumor types, including Phase 3 trials in gastroesophageal adenocarcinomas (GEAs) and metastatic breast cancer (mBC). The HERIZON-GEA-01 trial is evaluating the potential of zanidatamab plus chemotherapy with or without tislelizumab as first-line treatment for patients with advanced/metastatic HER2-positive GEAs and top-line progression-free survival data from this study is expected to be available in Q2-2025. The EmpowHER-303 trial is evaluating the potential of zanidatamab in combination with physician’s choice chemotherapy for the treatment of HER2-positive mBC for patients who have progressed on, or are intolerant to, previous trastuzumab deruxtecan treatment.
“Our strategic collaboration with Jazz provided the optimal ‘partner of choice’ to continue the rapid advancement of zanidatamab, and we are extremely encouraged with Jazz’s continued investment in and dedication to the development and commercialization of this novel therapy within their geographic territories,” said Kenneth Galbraith, Chair and Chief Executive Officer of Zymeworks. “The combination of our strong balance sheet and anticipated revenue stream associated with zanidatamab positions us to accelerate the development of our wholly-owned R&D programs, while maintaining our projected cash runway into the second half of 2027.”
Zymeworks continues to advance a diverse pipeline of novel therapeutics targeting difficult-to-treat cancers and other serious diseases, with several product candidates in various stages of development. The Company’s in-house research and development capabilities, which were instrumental in zanidatamab’s success, remain focused on delivering the next generation of innovative treatments. Zymeworks will host an in-person and virtual R&D day in New York on December 12, 2024, which will feature updates on the Company’s portfolio of solid tumor targeting antibody-drug conjugates and T cell engager molecules, including preclinical progress supporting potential investigational new drug applications for multiple new product candidates in 2025, 2026 and beyond, and strategy and rationale for potential expansion into new therapeutic areas in hematological cancers and autoimmune and inflammatory diseases.
More information about Ziihera, the Full Prescribing Information, including Boxed Warning and Patient Information, is available here.
About Ziihera® (zanidatamab-hrii)
Ziihera (zanidatamab-hrii) is a bispecific HER2-directed antibody that binds to two extracellular sites on HER2. Binding of zanidatamab-hrii with HER2 results in internalization leading to a reduction of the receptor on the tumor cell surface. Zanidatamab-hrii induces complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). These mechanisms result in tumor growth inhibition and cell death in vitro and in vivo.1 In the United States, Ziihera is indicated for the treatment of adults with previously treated, unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer (BTC), as detected by an FDA-approved test.1 The U.S. Food and Drug Administration (FDA) granted accelerated approval for this indication based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).1
Zanidatamab is not approved anywhere else in the world.
Zanidatamab is being developed in multiple clinical trials as a targeted treatment option for patients with solid tumors that express HER2. Zanidatamab is being developed by Jazz and BeiGene, Ltd. (BeiGene) under license agreements from Zymeworks, which first developed the molecule.
The FDA granted Breakthrough Therapy designation for zanidatamab development in patients with previously treated HER2 gene-amplified BTC, and two Fast Track designations for zanidatamab: one as a single agent for refractory BTC and one in combination with standard-of-care chemotherapy for 1L gastroesophageal adenocarcinoma (GEA). Additionally, zanidatamab has received Orphan Drug designations from FDA for the treatment of BTC and GEA, as well as Orphan Drug designation from the European Medicines Agency for the treatment of BTC and gastric cancer.
More information about Ziihera, the Full Prescribing Information, including Boxed Warning and Patient Information, is available here.
Important Safety Information
| WARNING: EMBRYO-FETAL TOXICITYExposure to ZIIHERA during pregnancy can cause embryo-fetal harm. Advise patients of the risk and need for effective contraception. |
WARNINGS AND PRECAUTIONS
Embryo-Fetal ToxicityZIIHERA can cause fetal harm when administered to a pregnant woman. In literature reports, use of a HER2-directed antibody during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death.
Verify the pregnancy status of females of reproductive potential prior to the initiation of ZIIHERA. Advise pregnant women and females of reproductive potential that exposure to ZIIHERA during pregnancy or within 4 months prior to conception can result in fetal harm.Advise females of reproductive potential to use effective contraception during treatment with ZIIHERA and for 4 months following the last dose of ZIIHERA.
Left Ventricular Dysfunction
ZIIHERA can cause decreases in left ventricular ejection fraction (LVEF). LVEF declined by >10% and decreased to 2% of patients included biliary obstruction (15%), biliary tract infection (8%), sepsis (8%), pneumonia (5%), diarrhea (3.8%), gastric obstruction (3.8%), and fatigue (2.5%). A fatal adverse reaction of hepatic failure occurred in one patient who received ZIIHERA.The most common adverse reactions in 80 patients with unresectable or metastatic HER2-positive BTC who received ZIIHERA (≥20%) were diarrhea (50%), infusion-related reaction (35%), abdominal pain (29%), and fatigue (24%).
USE IN SPECIFIC POPULATIONS
Pediatric Use
Safety and efficacy of ZIIHERA have not been established in pediatric patients.
Geriatric Use
Of the 80 patients who received ZIIHERA for unresectable or metastatic HER2-positive BTC, there were 39 (49%) patients 65 years of age and older. Thirty-seven (46%) were aged 65-74 years old and 2 (3%) were aged 75 years or older.
No overall differences in safety or efficacy were observed between these patients and younger adult patients.
About Biliary Tract Cancer
BTC, including gallbladder cancer and intrahepatic and extrahepatic cholangiocarcinoma, account for