Full Press Release Details
FDA Grants U.S. Approval of Ziihera
(zanidatamab-hrii) for the Treatment of Adults with Previously Treated, Unresectable or Metastatic HER2-positive (IHC 3+) Biliary Tract Cancer (BTC)
Vancouver, British Columbia (November 21, 2024)
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
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.
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.
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.
WARNING: EMBRYO-FETAL TOXICITY
Exposure to ZIIHERA during pregnancy can cause embryo-fetal harm. Advise patients of the risk and need for effective
WARNINGS AND PRECAUTIONS
Embryo-Fetal Toxicity
ZIIHERA 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
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 <50% in 4.3% of 233 patients. Left
ventricular dysfunction (LVD) leading to permanent discontinuation of ZIIHERA was reported in 0.9% of patients. The median
time to first occurrence of LVD was 5.6 months (range: 1.6 to 18.7). LVD resolved in 70% of patients.
Assess LVEF prior to initiation of ZIIHERA and at regular intervals during treatment. Withhold dose or permanently discontinue ZIIHERA based on severity of
The safety of ZIIHERA has not been established in patients with a baseline ejection fraction that is below 50%.
Infusion-Related Reactions
infusion-related reactions (IRRs). An IRR was reported in 31% of 233 patients treated with ZIIHERA as a single agent in clinical studies, including Grade 3 (0.4%), and Grade 2 (25%). IRRs leading to permanent discontinuation of ZIIHERA were reported
in 0.4% of patients. IRRs occurred on the first day of dosing in 28% of patients; 97% of IRRs resolved within one day.
Prior to each dose of ZIIHERA,
administer premedications to prevent potential IRRs. Monitor patients for signs and symptoms of IRR during ZIIHERA administration and as clinically indicated after completion of infusion. Have medications and emergency equipment to treat IRRs
available for immediate use.
If an IRR occurs, slow, or stop the infusion, and administer appropriate medical management. Monitor patients until complete
resolution of signs and symptoms before resuming. Permanently discontinue ZIIHERA in patients with recurrent severe or life-threatening IRRs.
ZIIHERA can cause severe diarrhea.
reported in 48% of 233 patients treated in clinical studies, including Grade 3 (6%) and Grade 2 (17%). If diarrhea occurs, administer antidiarrheal treatment as clinically indicated. Perform diagnostic tests as clinically indicated to exclude other
causes of diarrhea. Withhold or permanently discontinue ZIIHERA based on severity.
Serious adverse reactions occurred in 53% of 80 patients with unresectable or metastatic HER2-positive BTC who received ZIIHERA. Serious adverse reactions in
>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
Safety and efficacy of ZIIHERA have not been established in pediatric patients.
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 <1% of all adult cancers globally and are often associated with a poor prognosis.2,3 The human epidermal growth factor receptor 2 (HER2) is a well-validated target for antitumor
therapy in other cancers. Across the U.S., Europe, and Japan, approximately 12,000 people are diagnosed with HER2+ BTC annually.4,5,6,7
Azymetric is a heterodimeric antibody technology that gives the ability to engineer, screen, and