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.