Jazz Pharmaceuticals, Inc. FDA announcement

Please go ahead. Thank you, operator, and thank you all for joining us.

We are excited to discuss the FDA approval and U.S. commercial launch of ZYHERA in first-line HER2-positive metastatic gastroesophageal adenocarcinoma, or GEA. The slide presentation accompanying this webcast is available on the investor section of our website, and you can also reference the press release we issued regarding the FDA approval of ZYHERA. Also on our website, you can find a link to the approved label. On slide 2, I would like to remind you that today's webcast includes forward-looking statements, such as those related to our future financial and operating results, growth potential, and anticipated development, regulatory, and commercial milestones, which involve risks and uncertainties that could cause actual events, performance, and results to differ materially from those contained in these forward-looking statements.

We encourage you to review the statements contained in our slide deck and the risks and uncertainties described in our SEC filings. We undertake no duty or obligation to update our forward-looking statements. Joining the call today are Dr. Rob Iannone, Global Head of R&D and Chief Medical Officer, who will discuss the approved label; Chumi Khurana, Head of our Oncology Franchise; and Sam Pearce, our Chief Commercial Officer, will discuss our commercial launch strategy. Then we will open up the call for Q&A. The approval of ZYHERA is a pivotal moment for Jazz and represents a paradigm shift for the treatment of first-line HER2 metastatic GEA. This approval is a powerful demonstration of our corporate strategy in action as we continue to transform Jazz into a highly innovative, rare disease-focused biopharmaceutical company.

ZYHERA demonstrated an unprecedented survival benefit, with median overall survival surpassing two years, and is the first and only bispecific HER2-targeted antibody combined with a PD-1 inhibitor and chemotherapy approved for all HER2-positive advanced GEA patients, regardless of PD-L1 status. These results give us high conviction that the ZYHERA combination is positioned to significantly improve outcomes and be established as the new standard of care for this patient population. Importantly, the approval marks a major step forward in establishing ZYHERA as a multibillion-dollar foundational asset in our oncology portfolio. Backed by robust clinical data and our plans to expand the zanidatamab development program, we are updating our view of the ZYHERA peak sales potential to a range of $3 billion-$5 billion.

This updated range reflects our confidence in ZEPZELCA's clinical profile, its potential as a foundational therapy across multiple HER2-expressing tumors, and supports our plans to expand zanidatamab's development into new tumor areas. With that, I'll turn the call over to Rob to discuss the approved ZEPZELCA label and the meaningful impact we believe ZEPZELCA can have for patients with GEA.

Thank you. I'll begin on slide 7. The FDA approval of ZEPZELCA represents a transformative shift in treatment options for patients with GEA and their families, who now have access to a therapy that delivers a median overall survival of more than 26 months when combined with tislelizumab and chemotherapy. These data from the HERIZON-GEA-01 trial demonstrates the remarkable advance in patient care and survival benefit that ZEPZELCA provides. It's based on these clinical outcomes, along with the FDA approval, that we believe every eligible HER2-positive first-line metastatic GEA patient should receive ZEPZELCA in combination with chemotherapy plus a PD-1 inhibitor, regardless of PD-L1 tumor status. These are the outcomes that drive our motivation and dedication at Jazz. I will now quickly speak to the label and supporting data.

ZEPZELCA is indicated irrespective of tumor PD-L1 status in combination with tislelizumab and fluoropyrimidine and platinum-containing chemotherapy as first-line treatment of adult patients with unresectable, locally advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma for patients with either IHC 3+ or IHC 2+ and ISH-positive disease, as detected by an FDA-authorized test. In addition, ZEPZELCA is indicated with fluoropyrimidine and platinum-containing chemotherapy for patients with HER2-positive IHC 3+ disease as first-line treatment of adult patients with unresectable, locally advanced, or metastatic GEA, as detected by an FDA-authorized test. ZEPZELCA is administered as an IV infusion in combination with chemotherapy, with or without tislelizumab. Dosing is weight-based, with patients weighing less than 70 kilograms receiving 1,800 milligrams of ZEPZELCA every 3 weeks or 1,200 milligrams every 2 weeks.

Patients weighing 70 kilograms or greater will receive 2,400 milligrams of ZEPZELCA every 3 weeks or 1,600 milligrams every 2 weeks. The optionality of Q2-week dosing aligns to FOLFOX administration, as the flexibility allows for physicians to choose the best chemotherapy for their patients. The efficacy results from the phase III HERIZON-GEA trial that appear in the label are outlined on Slides 8 and 9. Both investigational treatment arms containing ZEPZELCA demonstrated a statistically significant improvement in PFS, corresponding to a median PFS exceeding 12 months, reducing the risk of disease progression or death by 35% compared with the trastuzumab control arm. Likewise, both combinations containing ZEPZELCA exceeded 2 years of median overall survival, setting a new benchmark for survival in this disease.

The Ziihera, plus tislelizumab and chemotherapy arm demonstrated a clinically meaningful and statistically significant improvement in OS, with more than 7 months improvement in the median OS, reaching 26.4 months and a 28% reduction in the risk of death versus the trastuzumab control arm. Nearly 40% of patients treated with the triplet regimen were estimated to be alive after 3 years. The benefit was observed irrespective of tumor PD-L1 status. In the intention-to-treat population, and as published in the New England Journal of Medicine, Ziihera plus chemotherapy showed a clinically meaningful survival benefit with a median OS of over 2 years, with a strong trend towards statistical significance at the time of the first OS interim analysis. The top-line results from the second interim overall survival analysis from the HERIZON-GEA-01 trial doublet regimen are expected this quarter.

As outlined in the label, the subgroup of patients treated with Ziihera plus chemotherapy, whose tumors were IHC 3+ for HER2, showed a median overall survival of 25.5 months and a hazard ratio of 0.74, with an upper bound of the 95% confidence interval that did not cross one. We are very pleased with the approved label, and we believe the unprecedented survival benefit supports the use of Ziihera as the new HER2-targeted agent of choice in HER2-positive, first-line metastatic GEA. We expect that Ziihera in combination with tislelizumab and chemotherapy will become the new standard of care for these patients, irrespective of PD-L1 tumor status. Turning to Slide 10, I will review the important safety information. Ziihera has a box warning for diarrhea and embryo-fetal toxicity. Ziihera in combination with fluoropyrimidine and platinum-containing chemotherapy, with or without tislelizumab, can cause severe diarrhea, including life-threatening cases.

Physicians should prescribe antidiarrheal prophylaxis during the first cycle when Ziihera is given in combination with these drugs, and supportive measures should be implemented during treatment as clinically indicated. Before modifying the dose of Ziihera, it is recommended to evaluate, modify, or discontinue drugs contributing to diarrhea in accordance with their respective prescribing information. Treatment-related diarrhea that led to Ziihera discontinuation in the HERIZON-GEA-01 clinical trial was uncommon, occurring in less than 5% of patients across both experimental arms. Based on clinical trial experience and input from treating physicians and patients, we view these AEs as manageable with prophylaxis and active management, considering the significant antitumor and survival benefits of Ziihera. In addition, physicians have the option to use FOLFOX in combination with Ziihera, a chemotherapy regimen more widely used in the U.S. relative to CAPOX, which was primarily chosen as the chemotherapy backbone in the HERIZON clinical trial.

Other warnings and precautions related to Ziihera administration include left ventricular dysfunction and infusion-related reactions. The most common AEs with Ziihera in combination with tislelizumab and chemotherapy were diarrhea, nausea, decreased appetite, hypokalemia, vomiting, fatigue, peripheral neuropathy, rash, and infusion-related reactions. The most common adverse reactions with Ziihera in combination with chemotherapy were diarrhea, nausea, vomiting, peripheral neuropathy, decreased appetite, fatigue, hypokalemia, infusion-related reactions, and rash. I will cover zanidatamab's unique mechanism of action on Slide 11, which gives us conviction to expand our development program into areas where we think zanidatamab can outperform historical benchmarks for HER2-targeted agents. As described in the Nature publication illustrating zanidatamab's mechanism of action, we believe its design is fundamentally different from other HER2 antibodies. By binding 2 distinct sites on the HER2 receptor simultaneously, zanidatamab crosslinks neighboring HER2 proteins, leading to receptor clustering. The unique geometry and binding effectively blocks HER2-dependent cancer growth signaling.

Additionally, zanidatamab activates the immune system to attack the tumor, including activation of ADCC, ADCP, and CDC. We believe complement cascade activation is unique to zanidatamab among HER2-targeted therapies. Subgroup data from the HERIZON-GEA-01 trial presented at ASCO GI shows PFS and OS benefits were consistent in patients across PD-L1 positive and PD-L1 negative disease. We believe the complement and other immune activation induced by zanidatamab further enhances the efficacy of immunotherapy and explains the efficacy we see irrespective of PD-L1 status. We believe the combination of its unique mechanism of action, along with impressive clinical efficacy and a manageable safety profile for this molecule to date, are supportive of investing further in zanidatamab. Sam will discuss our expanded view on the value zanidatamab may offer to HER2-expressing cancer patients later in the call. I will now turn the call to Chumi for a discussion of our commercialization plans.