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At least for now, Jazz Pharmaceuticals isn’t angling Ziihera for a head-to-head showdown with Enhertu in HER2-positive breast cancer. A bispecific antibody has entered the HER2 fray with a differentiated profile from traditional agents and a chance to challenge AstraZeneca and Daiichi Sankyo’s star antibody-drug conjugate Enhertu.The new drug, Jazz Pharmaceuticals’ zanidatamab, has won an FDA accelerated approval for adults with previously treated HER2-positive biliary tract cancer. The drug, given as an intravenous infusion once every two weeks, will be available under the brand name Ziihera.With eyes on larger market opportunities in HER2-positive stomach cancer and breast cancer, Jazz has put Ziihera’s peak annual sales potential at more than $2 billion, CEO Bruce Cozadd told Fierce Pharma in an interview ahead of Wednesday’s approval.Jazz snatched up certain ex-Asian rights to Ziihera in 2022 through a licensing agreement with Zymeworks that included $50 million upfront and up to $1.76 billion in potential payments. Zymeworks will receive a $25 million milestone payment based on the FDA nod.In making that deal, Jazz was attracted by Ziihera’s bispecific construct. The drug binds two HER2 epitopes that are also separately targeted by Roche’s blockbuster HER2 antibodies Herceptin and Perjeta. Compared with the combination of Herceptin and Perjeta, Ziihera’s bispecific binding leads to unique clustering of the HER2 receptor, thereby more effectively interfering with the signaling of the cancer driver, Jazz’s R&D head Rob Iannone, M.D., explained in an interview.In the phase 2b HERIZON-BTC-01 trial, Ziihera induced a tumor response in 52% of 62 patients with previously treated HER2-positive biliary tract cancer, including two cases (3.2%) of complete response. The median duration of response reached 14.9 months.During an update in June, Jazz reported that Ziihera helped HER2-positive patients in the midstage study live a median 15.5 months. This data point is not included in the drug’s label. A phase 3 trial coded HERIZON-BTC-302 is evaluating Ziihera in combination with chemotherapy with or without a PD-1/L1 inhibitor as a first-line therapy for HER2-positive biliary tract cancer. The study is meant to serve as the confirmatory trial for Ziihera’s current accelerated approval.But rather than directly targeting Herceptin or Perjeta, Jazz is setting its sights on AZ and Daiichi’s Enhertu, a powerful player in the HER2 field. An FDA go-ahead in April made Enhertu the first HER2 agent that can treat certain HER2-positive solid tumors regardless of their location in the body. This indication naturally includes biliary tract cancer.In a subgroup of 22 biliary tract cancer patients enrolled in the DESTINY-PanTumor02 trial, Enhertu showed an overall response rate of 45.5%. The small size of the population makes it difficult to make a meaningful comparison with Ziihera’s data.Despite Enhertu’s forceful presence in the market, Cozadd argued that Ziihera has a compelling case in biliary tract cancer. He pointed to the number of patients who were evaluated in a trial specifically designed for the cancer type plus Ziihera's tumor response data and tolerability profile. Enhertu, as an ADC, carries a cytotoxic payload, whereas Ziihera is a pure antibody without any chemo component, Cozadd added.Jazz, for its part, has its own pan-tumor trial, having recently started the phase 2 DiscovHER-Pan-206 study for Ziihera in HER2-positive solid tumors.Nevertheless, with about 3,000 patients in the U.S., biliary tract cancer is a rather small indication in the HER2 world. The real battle is in breast cancer, where Enhertu already has a strong head start.At least for now, Jazz isn’t angling Ziihera for a head-to-head showdown with Enhertu in HER2-positive breast cancer. As Enhertu becomes "more and more accepted as a leading therapy in breast cancer, as it moves up in treatment toward potential front-line use, there’s a question" of how patients would be best served after progressing on Enhertu, Cozadd observed.After seeing some phase 2 activity in patients previously treated with HER2-targeted therapies, including Enhertu, Jazz in August advanced Ziihera, used in combination with chemotherapy, into phase 3 testing in post-Enhertu HER2-positive breast cancer. However, as Leerink Partners analysts highlighted in a March note, Jazz isn’t the only player that has recognized the huge post-Enhertu market opportunity. Ambrx, which was earlier this year acquired by Johnson & Johnson, previously laid out a plan to test its ADC candidate ARX788 in a post-Enhertu population. And, before the Pfizer buyout, Seagen also spotlighted disitamab vedotin’s potential in Enhertu-relapsed breast cancer.  Still, with a phase 3 already underway, Jazz aims to be the first company to have data in that space, Iannone said.“It’s a smart first step because in HER2-positive breast cancer, patients tend to do well enough to make it to the next line of therapy,” Iannone said. “We think we can still bring the benefit of zanidatamab to the great majority of breast cancer patients with the strategy that we have by sequencing rather than going head-to-head” against Enhertu, he explained.Jazz is already thinking about its next steps for Ziihera to potentially capitalize on its tolerability profile in early-stage breast cancer.Enhertu comes with the side effect of interstitial lung disease, which has raised some worries among industry watchers as the ADC moves into the first-line treatment setting. Doctors are less tolerant to potentially dangerous toxicities in earlier treatment settings.Ziihera is currently being evaluated in the platform I-SPY 2 trial, which is designed to evaluate multiple regimens as neoadjuvant therapy in breast cancer. The research group-sponsored study is currently not registrational, but it will give Jazz proof-of-concept data, Iannone noted. Beyond biliary tract and breast cancers, Jazz expects to read out progression-free survival data in the second quarter of 2025 from Herizon-GEA-01, for Ziihera, used with chemo with or without BeiGene’s PD-1 inhibitor Tevimbra, as a first-line treatment in HER2-positive gastric and esophageal cancers. BeiGene holds Ziihera rights in certain Asia-Pacific territories through a 2018 deal. Oncology is one of two pillars of Jazz’s business, the other being neuroscience. With blood cancer drug Rylaze and small cell lung cancer therapy Zepzelca, among other medicines, Jazz's oncology franchise surpassed $1 billion in sales last year. Cozadd said the company’s existing oncology sales team will be able to support Ziihera’s launch. 

Antibody-Drug Conjugates (ADCs), as a part of precision medicine, target tumor cells by combining the specificity of antibodies with the potent effects of cytotoxins. The design and manufacturing of ADCs pose multifaceted challenges, involving the selection and integration of antigens, antibodies, linkers, and active payloads. It is projected that by 2028, the revenue generated from approved ADCs and those in Phase III clinical development will reach 26 billion USD. According to the Synapse database, currently, there are over 1700 ADC therapeutics in the global pipeline, with nearly 200 of them in clinical research stages, and several are in the process of applying for market approval. Recently, John Wu from the Boston Consulting Group and colleagues published a review article titled "The antibody–drug conjugate landscape" in Nature Reviews Drug Discovery. The authors analyzed data on 168 antibody-drug conjugates (ADCs) currently in clinical development and found that approximately 85% of these assets are aimed at solid tumor indications, with breast and lung cancers being the most common. Among the ADCs in phase III clinical trials, about 60% are considered second-generation assets that utilize established target/cargo mechanisms of action (MoA) combined with novel delivery components to achieve best-in-class characteristics. In early-stage development, higher biological risks are more evident; approximately 75% of the phase I/II ADCs are categorized as first-generation assets, featuring new targets and/or payload mechanisms, demonstrating potential as first-in-class drugs. In 2000, the United States Food and Drug Administration (FDA) approved the first ADC (Antibody Drug Conjugate) drug, Gemtuzumab ozogamicin (brand name Mylotarg), for the treatment of adult patients with Acute Myeloid Leukemia (AML). Gemtuzumab ozogamicin combines a humanized anti-CD33 monoclonal antibody with the potent cytotoxic drug calicheamicin, delivering the drug directly to the leukemia cells expressing CD33. However, due to the emergence of severe side effects, including abnormal liver function and the so-called Veno-Occlusive Disease (VOD), it was voluntarily withdrawn from the market by the manufacturer in 2010. Nevertheless, considering its efficacy in certain AML patients, following further research and risk assessment, Gemtuzumab ozogamicin was re-approved by the FDA in 2017 for the treatment of newly diagnosed CD33-positive AML in adult patients, as well as in pediatric patients aged two years and older. Since 2011, there has been a significant increase in the number of ADCs (antibody-drug conjugates) approved by the FDA. According to the latest data, the FDA has approved 14 ADCs for the treatment of cancer. These ADCs target a range of cancer types including breast cancer, lymphoma, leukemia, and multiple myeloma. Development of ADCs continues, with a considerable number of such drugs currently in clinical trials. The FDA is also reviewing several new ADCs. In reviewing ADCs, the FDA takes a stringent approach, assessing the safety and efficacy of these drugs, while also paying attention to potential off-target effects. The figure below evaluates the antibody-drug conjugates in clinical development phases, showcasing specific design innovations utilized in clinical assets. Linkers play a crucial role in ensuring the overall stability of Antibody-Drug Conjugates (ADCs) and the timely release of payloads, having been refined to enhance the therapeutic index. The payload determines the ADC's capability to eliminate cancer cells while minimizing adverse reactions. The figure below presents statistics on linkers and payloads for FDA-approved drugs. Cleavable linkers utilize differences between the tumor microenvironment and normal physiological conditions to release their drug load. This release can lead to the "bystander effect," where the released drug also affects neighboring cells not directly targeted by the ADC. While this can amplify therapeutic effects, it also poses risks: cleavable linkers are more prone to off-target toxicity. Many clinical trials favor the use of dipeptide, disulfide, and enzyme-cleavable linkers. Enzyme-cleavable linkers, such as those targeting tissue proteases, are designed to be cleaved by enzymes overexpressed in tumor tissues. This specificity adds an extra layer of targeting, further ensuring that the drug is released only at the intended site. When an ADC binds to its target through antigen-antibody interaction, non-cleavable linkers require the antibody component to degrade before the drug is released. This mechanism can reduce the bystander effect. However, advantages of non-cleavable linkers include greater stability and reduced risk of unexpected side effects. The key challenge in ADC design lies in the antibody's internalization and lysosomal degradation, which are crucial for payload activation. Additionally, payloads linked to polar amino acid linkers require special transport mechanisms to transition from the lysosome to the cytoplasm. Researchers have been exploring new methods to enhance the efficacy and safety of ADCs (Antibody-Drug Conjugates). By developing novel linkers and potent payloads, researchers aim to create ADCs that more effectively kill cancer cells while exhibiting lower toxicity to healthy cells. The ideal payload should display high cytotoxicity at low concentrations, enabling effective targeting of tumor cells. The selection of payloads depends on several parameters, including solubility, hydrophilicity, permeability, and modifiability. The design process also needs to consider potential challenges such as aggregation, bystander effects, and stability in the bloodstream. To assess the potential impact of ADC innovations, the diagram below categorizes next-generation technologies and compares them to the characteristics of ADCs that are already on the market. Given their novelty and/or the encouraging preclinical and clinical data, certain designs may be particularly noteworthy. Next-generation payloads: Small molecule degraders as a payload category exhibit significant potential, as they possess high specificity, sub-nanomolar efficacy, and the ability to target an extensive range of intracellular proteins associated with cancer. For instance, Orum Therapeutics' ORM-5029 delivers a selective degrader payload targeting GSPT1, a GTPase overexpressed in multiple cancers including gastric, colorectal, and breast cancer. Next-generation carriers: Engineering antibodies to have variable antigen-binding affinity can reduce toxicity to non-target tissues and increase tumor-specific exposure. Strategies include masking the Fab domains with a peptide that is cleavable by proteases overexpressed in tumors, and engineering antibodies to optimize pH-sensitive binding characteristics. For example, Mythic Therapeutics’ MYTX-011 is designed to have lower antigen affinity at the pH of endosomes, enhancing payload escape from endosomes. Next-generation linkers: Emerging linker technologies focus on controlled payload release independent of endogenous enzyme-mediated cleavage. For example, TagWorks’ preclinical ADC TGW101 uses an exogenously administered chemical activator to induce payload release. Next-generation conjugation: Incorporating non-natural amino acids into antibody carriers facilitates site-specific conjugation through oxime linkages. For example, Ambrx's ARX788 is a HER2-targeted ADC where a non-cleavable PEG linker is attached site-specifically to a non-natural amino acid. Globally, the trend of regulating ADCs (Antibody-Drug Conjugates) as biologics is growing, yet there are still some differences in regulatory requirements across different countries. For instance, in the United States, ADCs are regulated by the FDA as combination products. This means that both the small molecule drug component and the monoclonal antibody must receive FDA approval before the ADC can be marketed. In the European Union, ADCs are regulated by the European Medicines Agency (EMA) as biologics. In China, ADCs are regulated by the NMPA (National Medical Products Administration) as biologics, and draft guidelines on ADC CMC (Chemistry, Manufacturing, and Controls), clinical, and non-clinical aspects have already been issued. How to obtain the latest research advancements in the field of biopharmaceuticals? In the Synapse database, you can keep abreast of the latest research and development advances in drugs, targets, indications, organizations, etc., anywhere and anytime, on a daily or weekly basis. Click on the image below to embark on a brand new journey of drug discovery!