Earlier this week Jazz Pharmaceuticals and Zymeworks confirmed that the companies have entered into an exclusive licensing agreement under which Jazz will acquire development and commercialization rights to Zymeworks’ zanidatamab (previously known as ZW25) across all indications in the United States, Europe, Japan and all other territories except for those Asia/Pacific territories previously licensed by Zymeworks.

“Zanidatamab is a novel human epidermal growth factor receptor 2 (HER2-) targeted bispecific antibody with biparatopic binding and the potential to transform the current standard of care in multiple HER2 expressing cancers,” said Rob Iannone, M.D., M.S.C.E., executive vice president, global head of research and development of Jazz Pharmaceuticals.

The investigational drug is based on Zymeworks’ Azymetric™ technology platform and can simultaneously bind two non-overlapping epitopes of HER2, which is known as biparatopic binding. This innovative design results in multiple novel mechanisms of action including dual HER2 signal blockade, enhanced binding and removal of HER2 protein from the cell surface, and potent effector function leading to encouraging anti-tumor activity in patients.

The Azymetric platform enables the transformation of monospecific antibodies into bispecific and multispecific antibodies, allowing simultaneous binding to several different disease targets. This unique technology enables the development of multifunctional therapeutics that can block multiple signaling pathways, recruit immune cells to tumors, enhance receptor clustering and internalization and increase tumor-specific targeting. These features are designed to enhance efficacy while reducing toxicities and the potential for drug resistance.

Compelling anti-tumor activity
Zanidatamab has demonstrated compelling anti-tumor activity in several HER2-expressing cancers, including biliary tract cancers (including including gallbladder cancer and cholangiocarcinoma) and gastroesophageal adenocarcinoma. In these studies zanidatamab was studies in both monotherapy and in combination with chemotherapy and other agents.

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Unmet medical need
Biliary tract cancers, account for approximately 3% of all adult cancers and are often associated with a poor prognosis. [1] Globally, more than 210,000 people are diagnosed with biliary tract cancers every year [2] and most patients (> 65%) are diagnosed with tumors that cannot be removed surgically.

HER2 is a well-validated target for anti-cancer therapy. About 5% to 19% of patients with BTC have tumors that express HER2 [3] and may be positioned for potential benefit from HER2-targeted therapy. Currently no HER2-targeted therapy has been approved for the treatment of BTC.

In addition, gastroesophageal adenocarcinoma, the fifth most common cancer worldwide and approximately 20% of patients, are HER2–positive. HER2–positive gastroesophageal adenocarcinoma has high morbidity and mortality, and patients are urgently in need of new treatment options.

Breakthrough Therapy
The Food and Drug Administration (FDA) has granted Breakthrough Therapy designation for zanidatamab in patients with previously treated HER2 gene-amplified biliary tract cancers, and two Fast Track designations for zanidatamab, one as a single agent for refractory biliary tract cancers and one in combination with standard of care chemotherapy, for first-line gastroesophageal adenocarcinoma.

These designations mean zanidatamab is eligible for Accelerated Approval, Priority Review and Rolling Review, as well as FDA guidance on an efficient drug development program. Zanidatamab has also received Orphan Drug designations from FDA for the treatment of biliary tract and gastric cancers, as well as Orphan Drug designation from the European Medicines Agency for the treatment of gastric cancer.

Clinical development
Zanidatamab is currently in pivotal trials as a second-line treatment for HER2-expressing biliary tract cancer and as a first-line treatment for HER2-positive gastroesophageal adenocarcinoma. In biliary tract cancer, where no HER2-targeted therapies are currently approved, the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation for zanidatamab, positioning it as a potential first-in-class therapy. In GEA, based on Phase 2 data, zanidatamab in combination with chemotherapy has the potential to be a best-in-class therapy.

“This agreement reflects Jazz’s strategic focus on opportunities where we can not only apply advanced technologies to address critical unmet patient needs, but where we can also leverage Jazz’s existing integrated capabilities and global infrastructure to commercialize efficiently,” Iannone added.

“Zanidatamab has the potential to deliver significant long-term value and meaningfully contribute to Vision 2025 as we aim to deliver at least five novel therapies to patients by the end of the decade. We are pleased to expand our growing oncology pipeline with a late-stage program, and today’s announcement further demonstrates our commitment to delivering novel oncology therapies,” he said.

Kenneth Galbraith as Chair and Chief Executive Officer (CEO) of Zymeworks. Photo courtesy: © 2022 Zymeworks. Used with permission.

“In partnering with Jazz, we are thrilled to be working with a leading global biopharmaceutical team that brings a wealth of development and commercial experience in oncology and shares our vision and passion for working hard every day to improve outcomes for cancer patients around the world,” said Kenneth Galbraith, Chair & CEO of Zymeworks.

“Zymeworks and Jazz are committed to advancing the development of zanidatamab as rapidly as possible, with the potential to provide a foundational HER2-targeted therapy for patients with difficult-to-treat cancers who currently have limited treatment options.”

Under the terms of the agreement, Jazz will receive an exclusive license to develop and commercialize zanidatamab in the United States, Europe, Japan and all other territories except for those Asia/Pacific territories that Zymeworks previously licensed to BeiGene, Ltd. Zymeworks is eligible to receive a US $50 million upfront payment, following receipt of the clearance relating to the United States Hart-Scott Rodino Antitrust Improvements Act of 1976 (such clearance, the “HSR Clearance”), and should Jazz decide to continue the collaboration following readout of the top-line clinical data from HERIZON-BTC-01, a second, one-time payment of $325 million. Zymeworks is also eligible to receive up to $525 million upon the achievement of certain regulatory milestones and up to $862.5 million in potential commercial milestone payments, for total potential payments of up to $1.76 billion. Pending approval, Zymeworks is eligible to receive tiered royalties between 10% and 20% on Jazz’s net sales.

Closing of the agreement is subject to expiration or termination of the waiting period under the Hart-Scott-Rodino Act of 1976. The transaction is expected to close within the 2022 calendar year.

Clinical trials
A Study of Zanidatamab (ZW25) With Evorpacept (ALX148) in Patients With Advanced HER2-expressing Cancer – NCT05027139
A Phase 2 Single-Arm Open-Label Pilot Trial Evaluating Zanidatamab (ZW25) in Patients With Early Stage HER2/Neu Positive (HER2+) Breast Cancer (BC) – NCT05035836
Study to Evaluate the Safety and Efficacy of Tislelizumab in Combination With Zanidatamab as a 2nd Line in HER2-Positive Advanced Gastric Cancer in K-Umbrella Trial – NCT05270889
A Study of ZW25 (Zanidatamab) With Palbociclib Plus Fulvestrant in Patients With HER2+/HR+ Advanced Breast Cancer – NCT04224272
A Study of ZW25 (Zanidatamab) in Subjects With Advanced or Metastatic HER2-Amplified Biliary Tract Cancers (HERIZON-BTC-01) – NCT04466891
Trial of ZW25 (Zanidatamab) in Patients With Advanced HER2-expressing Cancers – NCT02892123
A Safety and Efficacy Study of ZW25 (Zanidatamab) Plus Combination Chemotherapy in HER2-expressing Gastrointestinal Cancers, Including Gastroesophageal Adenocarcinoma, Biliary Tract Cancer, and Colorectal Cancer – NCT03929666

[1] Valle JW, Lamarca A, Goyal L, Barriuso J, Zhu AX. New Horizons for precision medicine in biliary tract cancers. Cancer Discov. 2017;7(9):943-962.
[2] GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1789-1858.
[3] Galdy S, Lamarca A, McNamara MG, et al. HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target? Cancer Metastasis Rev. 2017;36(1):141-157.

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