Jazz Pharmaceuticals plc (JAZZ) Earnings Call Transcript & Summary

Hello, and thank you for standing by. Welcome to the Zanidatamab KOL Investor Webcast. [Operator Instructions] Please be advised that today's conference is being recorded. It is now my pleasure to introduce Chairman and CEO, Bruce Cozadd.

Thank you, operator, and good evening, everyone. Earlier today, pivotal Phase IIb data from the HERIZON-BTC-01 clinical trial assessing zanidatamab in previously treated HER2 amplified biliary tract cancers or BTC, were featured in an oral session at this year's Annual Meeting of the American Society of Clinical Oncology. zanidatamab is one of several late-stage programs in our pipeline that we are advancing on behalf of patients in need of improved treatment options, and we're excited to share these impressive results with you today. I'd like to remind you that today's webcast includes forward-looking statements as outlined on Slide 2. These statements are subject to risks and uncertainties. If we refer to guidance, that's referring to our first quarter 2023 disclosure made on May 10. Please see our SEC filings for more information. There is a brief agenda for today's discussion on Slide 3. We are very pleased to welcome Dr. Shubham Pant from the MD Anderson Cancer Center to provide an overview of the trial findings. Following Dr. Pant, Jazz Chief Medical Officer, Kelvin Tan, will provide perspectives on how we use any data map development moving forward as well as how this novel therapy builds on our existing oncology franchise. We'll then open the call for questions. Abizer Gaslightwala, U.S. business unit head for Jazz Oncology will join our other speakers for the Q&A session. We are exceptionally pleased that the zanidatamab Phase IIb data from the HERIZON-BTC-01 trial were selected by ASCO to be featured in an oral presentation this afternoon. findings from the trial were also concurrently published in the Lancet Oncology. In addition, the presentation has been selected for the 2023 Best of ASCO program which will be held later this summer, following the ASCO annual meeting. Now I'm pleased to introduce our expert speaker, Dr. Shubham Pant. He is a professor in the Department of Gastrointestinal Medical Oncology at MD Anderson Cancer Center, serves on the ASCO GI Guidelines Committee and is a leading GI cancer researcher. Dr. Pant's is on Slide 5. Dr. Pant serves as an investigator for the zanidatamab HERIZON-BTC-01 trial and presented data from the trial at today's ASCO oral session. He is also a senior author of the Lancet Oncology manuscript on the Phase IIb data from the HERIZON-BTC-01 trial. Dr. Pant?

Thank you so much, Bruce. So I'm going to present the results from the pivotal Phase IIb HERIZON-BTC-01 study, zanitutumab in previously treated HER2-Amplified Biliary Tract Cancers, and that's the Slide 6. Next Slide. On Slide 7, you can see that this is a background of patients with biliary tract cancers. There are approximately 12,000 HER2-positive BTC cases annually in the U.S., Europe and Japan. And for patients with locally advanced or stage 4 metastatic BTC standard therapy, second line and beyond offers limited clinical benefit. Chemotherapy in the setting provides an overall response rate of 5% to 15% and a median progression-free survival of 4 months. And HER2 amplification or overexpression is observed in a subset of BTC and it's different in the different subsets, most commonly found in gall bladder cancer, where it can be found in 19% to 31% in extrahepatic cholangiocarcinoma. It can be overexpressed in 17% to 19%. And in 4% to 5% of intrahepatic cangiocarcinomas. And as we know, HER2-targeted therapies have clinical benefit in breast, gastric cancer and lung cancer but there are no approved HER2-targeted therapies for biliary tract cancers. On Slide 8, you can see the unique mechanism of action of zanidatamab, it simultaneously binds 2 domains in the HER2 protein, extra solar domain 2 and 4, and that binding is unique and results in multiple mechanisms of action preclinical studies, which were published recently demonstrated a greater activity in mouse models than trastuzumab as a single agent or trastuzumab in combination with pertuzumab and a Phase I trial basket trial, which was done, which was published before in Lancet Oncology. In that zanidatamab showed a manageable safety profile and encouraging antitumor activity in patients with HER2-expressing BTC. And we saw 22 -- we enrolled 22 patients in that cohort and seeing activity in that cohort led to this trial. On Slide 9, you can see the HERIZON-BTC-01 study design. The key eligibility criteria were locally advanced or metastatic BTC. Tissue was required to confirm HER2 status by central lab. Patients should have progressed after treatment with a gemcitabine-containing regimen or be intolerant to the same, no prior HER2-targeted therapies were allowed, and patients had to have an ECOG of 0 or 1. We did exclude patients with ampullary cancer. Now all patients who entered the study did have HER2 amplification by insight to hybridization. Cohort 1 was HER2-positive, which were IHC 2+ or 3+ and Cohort 2 were IHC 0 or 1 +. zanidatamab was given at the dose of 20-milligram per kilogram IV with mandatory premedication for infusion-related reaction for fylaxis. We scanned patients every 8 weeks. The primary end point was confirmed overall response rate by independent central review with key secondary endpoints being duration of response, disease control rate, progression-free survival, overall survival and frequency and severity of AEs. On Slide 10, you can see the enrollment. This was done during the pandemic September 2020 to March 2022, we enrolled in 32 sites across 4 continents: Asia, Europe, North America and South America. The data cutoff for the primary analysis was 10 October 2022, we enrolled 80 patients 80 in cohort 1 and 7 patients in Cohort 2. Now going forward, the focus of this presentation will be on HER2-positive BTC. That's cohort 1, IHC2+ and IHC3+ as Cohort 2 contained a small sample size of 7 patients and it did not reveal any responses nor any unique safety signals. These are the demographics and baseline characteristics. 65% of patients were Asian. Majority had an ECOG performance status or 1. As expected, the most common BTC subtype was gallbladder cancer, which was 51.3% of patients. About 77% of patients at IHC3+ disease with close to 90% of patients, 88.8% having Stage 4 disease or metastatic disease, 76% of patients received cisplatin and gemcitabine as frontline therapy and 26% patients received prior checkpoint inhibitor, they could either be a PD-1 or a PD-L1 inhibitor. On Slide 12, a you can see the disease response in patients with HER2-positive BTC. Now at the time of data cut off in October 2022, 16 patients had ongoing response. Now we assess response in 2 ways. By independent central review and by investigator assessment, and they were both the same 41.3% of patients had a confirmed overall response rate. One patient had a complete response, and these are patients in the independent central review that I'm mentioning. 32 patients had a partial response and 22 patients had a stable disease. The disease control rate was 68% and the clinical benefit rate. And that was defined as complete response, partial response and stable disease for greater than equal to 6 months of 47.5%. This is Slide 13. This is the waterfall plot. And as you can see, the majority of the evaluable patients, 80 -- sorry, 68.4% and had decrease in target lesions. The astric that you see are the patients who have HER2 2+ disease, the rest of the patients had HER2 3+ disease, and as you can see, majority all the BTC subtypes, which is gallbladder cancer, intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma seem to benefit from the therapy. Slide 14 shows you the same [swimmers] plot. The little green dots that you see are patients with an ongoing response at the time of data cut off. The median duration of response for the 33 patients who showed a response, PR or CR was 12.9 months, and the median time to first response was a relatively short 1.8 months. And this is a Kaplan-Meier curve for the progression-free survival in patients with HER2-positive BTC. The overall survival data has not yet matured. The progression-free survival median was 5.5 months. This is Slide 16 of adverse events. 96.6% of patients had any treatment-emergent adverse events with 72.4% of patients having treatment -- any treatment-related adverse events. However, there were 2 patients who had TRAEs treatment-related adverse event leading to treatment discontinuation, the most common side effects were diarrhea, infusion-related reaction, ejection fraction decrees, nausea and anemia, majority of a grade 1 and 2. There were no grade 4 TRAEs and no treatment-related deaths. And this is Slide 17. We did look at adverse events of special interest. Patients 33.3% of patients had infusion-related reactions. One of them had great 3 or higher infusion-related reaction. All the events resolved generally within one day and most occured within the first cycle of treatment and most at no recurrence. There were 5 patients who had confirmed cardiac events, which was decreased LVEF. Patients were clinically asymptomatic and the events were confounded by preexisting or current conditions. One patient had non-infectious pulmonary toxicity and 43.7% of patients had diarrhea with 6.9% of patients having grade 3 or higher diarrhea. All but 2 events were managed in the outpatient setting, typically with loperamide, which is commonly given for diarrhea, most events were resolved at the time of data cut off, and the median time to resolution was 2 days. Slide 18 is the conclusions. To conclude, zanidatamab demonstrated antitumor activity, including rapid and durable responses in patients with treatment-refractory HER2-positive BTC. The confirmed overall response rate for independent central review was 41.3%, and most responses were identified at first disease assessment. The median progression-free survival was 5.5 months and the median duration of response was 12 or 9 months. Zanidatamab demonstrated a manageable and tolerable safety profile, few events led to treatment discontinuation no grade for TRAEs, no debts for treatment related. And the most common AEs were IRRs and diarrhea, predominantly low-grade and reversible. And these results support zanidatamab having meaningful clinical benefit and potential as a future treatment option in HER2-positive BTC. And additional studies are both planned and active, including zani in combination with cisplatin and gemcitabine. On Slide 19, we sincerely thank all the patients and their caregivers and to all the investigators, clinical trial researchers and the research staff. On Slide 20 is a slide which has already shown, we were -- it's really -- it was great for us and the co-investigators that we had a simultaneous publication in the Lancet Oncology is published online today, June 2, 2023. With that, I want to thank you for listening.

Thank you, Dr. Pant, for reviewing the data that you presented earlier today at a packed ASCO session. This is very exciting news for the field and most importantly, for patients with BTC. Looking more broadly at the zanidatamab opportunity on Slide 21, we believe that Zane has the potential to transform the current standard of care in multiple HER2-expressing cancers. Given its monotherapy activity across multiple HER2-expressing tumor types, including cases resistant to prior HER2 therapies, we are committed to rapidly advancing our development program to unlock the potential of this molecule. Our initial focus is on BTC and gastroesophageal adenocarcinoma, or GEA. There are approximately 12,000 HER2 positive cases of BTC annually in the U.S., Europe and Japan. And as we've discussed today, these patients are in need of new therapeutic options. Currently, there are no HER2-targeted therapies approved for the treatment of BTC. The findings in the Phase IIb zanidatamab trial showed a significant improvement over the current standard of care in second-line BTC. In particular, I'd like to call out the compelling response rates and PFS data from this trial. Current standard of care for second-line advanced metastatic BTC includes 2 treatment regimens. One is the chemotherapy regimen Folfox which includes for [ feliinc ] acid, fluorourosol and oxaliplatin. Recent guidelines from the NCCN and ESMO recommend the protocol of FOLFOX Plus Advanced symptom control, or ASC for second-line BTC treatment. The other commonly used regimen is trastuzumab and pertuzumab. The literature indicates an overall response rate between 5% and 15% and a PFS for approximately 4 months for these regimens. As Dr. Pant noted in his presentation, patients treated with us zanidatamab in the HERIZON-BTC-01 trial had an overall response rate of 41% and a PFS of 5.4 9 months. In addition to these efficacy findings, zanidatamab demonstrated a manageable and tolerable safety profile. Based on its overall clinical profile, we believe zani has the potential to significantly advance the treatment of BTC. We are in dialogue with the FDA regarding the potential regulatory path forward for zani BTC, and we believe that the current body of data is sufficient to support a BLA submission. GEA is another area of unmet need and is a more frequently occurring cancer relative to BTC. In the U.S., Europe and Japan, there are approximately 63,000 HER2+ cases of GEA annually. At the January ASCO GI conference, the first zanidatamab overall survival data were presented from a Phase II trial evaluating zanidatamab in combination with chemotherapy in first-line patients with HER2-expressing metastatic GEA. The preliminary results show that the median overall survival had not yet been reached with an 18-month overall survival rates of 84%. The overall survival findings in this trial are compelling, given historically reported overall survival rate for the currently approved standard of care is a median of 14 months. These results shows any data potential as a foundational treatment for patients with HER2-positive GEA, and we look forward to additional data from the ongoing pivotal Phase III GEA trial expected to read out in 2024, which may support U.S. and global regulatory submissions. Now Slide 23. Slide 23 shows the breadth of our R&D programs, and I'll start by highlighting several programs in our oncology portfolio. Since we acquired development and commercialization rights to Zanidatamab last year, our confidence in this program has only grown based upon positive data in both BTC and GEA. And while our initial focus is on those 2 tumor types, we believe zanidatamab has the potential to transform the current standard of care in multiple HER2-expressing cancers. To that end, we're excited that zani was added to the I-SPY breast cancer platform this year. We also have multiple earlier stage trials assessing zanidatamab's clinical profile in a range of tumor types and are actively evaluating opportunities to pursue additional indications. In addition to zanidatamab, we have several other oncology programs in late-stage development. We are collaborating with Roche on a Phase III trial to evaluate Zepzelca as maintenance therapy in first-line small cell lung cancer, which is expected to complete enrollment by the end of the year. We also expect a response this year on our MAA submission for Rylaze. We also have multiple ongoing neuroscience programs with top line data readouts from our JZP-150 program in PTSD expected later this year and from our subacaltamide essential tremor trial expected in the first half of next year. In total, we expect at least 3 late-stage data readouts by 2024. Our efforts over the past several years to expand and enhance our R&D capabilities and productivity are being realized. And we're excited to reach these upcoming milestones on behalf of patients who are in need of new treatment options. This concludes the slide presentation. And now I'll turn it over to the operator to begin the Q&A.

And our first question comes from the line of Joe Thome with TD Cowen.

Maybe just for Dr. Pant, how quickly do you think this might be adopted in sort of the standard of care in second-line patients? It looks like the response rate, understandably so was much higher in the 3-plus IAC patients. But when you think about those that maybe R2, would you use this in everyone there too? Or how would you make that distinction? And I guess is there anyone that would not [indiscernible] at a 3-plus patient?

At least in the -- thank you -- the data that we've shown, it seems to benefit both HER2 3+ and 2s in totality. So I think that's what we would think about using it. Obviously, in the 0 and 1 plus, that's where we really did not see any responses. So that's a place where we would not be clinically -- I would not be using it. But plus and plus definitely based on the data.

And our next question comes from the line of Madhu Kumar with Goldman Sachs.

A question for Dr. Pant. When you look at the ORR kind of differences relative to the PFS differences versus standard of care, I guess one interpretation is that there's something about patients who respond to the drug leaves the real depth of response. And the kind of work you all have done from the HERIZON trial so far. Have you seen certain features of busier certain biomarkers that kind of predict this kind of depth of response that you don't necessarily that isn't on the bulk translate to changes in PFS to get that certain patients are getting a greater impact from Zanidatamab.

Yes. So we have not looked at kind of co-mutations, any other innate resistance mechanisms in the beginning. We've collected blood on these patients, tissue in these patients. So hopefully, we can look at that. Progression-free survival is really challenging in to interpret in the single-arm study because a lot of the patients who have HER2-positive disease are gallbladder cancer patients. Traditionally, those patients seem to have a more maybe aggressive disease. But -- so that's what -- so the progression-free survival only we can figure it out on a randomized trial. It's hard to interpret that in a single-arm study. As far as duration of response, yes, we were very -- that's what made the study important for us. One was the response rates, obviously, but the duration of response is more meaningful is more meaningful to me as a clinician. So that's what we were we happy about to see.

And our next question comes from the line of Ami Fadia with Needham & Company.

My question is for Dr. Pant. At ASCO [indiscernible] can you compare and contrast those data with these? And in the real world, how would you think about determining what patients to put on bed?

Thank you for that question. That presentation was right before mine. So that's when I got to see it. Differences are -- and there -- as Andrew Co, who discussed our session, said that they're being 3 or 4 trials which have been done mostly part of basket trials. So the difference is there were less patients. I don't remember how many, but like between 20 and 30 patients. And so it is part of a basket trial, I don't want to do is, but I don't think they had central read. So this was truly like a global trial. So more number of patients, obviously, 80 patients. where we did see the -- we see the benefit with the response rate of 42%. So it is more of a global trial, 4 continents. That's a different flavor than that trial, which was a basket study done in Japan. So at this time, the data has just come out, so it's kind of hard to compare and contrast, frankly, to see. But those are the 2 big differences, I think, which I caught when I was on the podium was smaller numbers, and this was global, that was more local. And I think the HER2 testing was central -- sorry, Central on this trial, and I think it was more local on the other trial.

Just add there was good data presented in both presentations on tolerability of the regimens and I'd look at that as well.

Good evening. This is Shah [indiscernible] for Balaji. Just a quick one on opportunities outside BTC and GEA in particular, HER2-expressing breast cancer which is a large indication with a lot of competition. Could you let us know what's the focus of your BD for breast cancer, given that it's a very competitive landscape, and then he is currently on trial for both first-line and third-line therapy. If I remember correctly, would it be safe to assume that third-line therapy would be more of a focus for zani for breast cancer.

This is Bruce. Maybe I'll start and then ask Kelvin to weigh in. And I'll just start by saying we haven't announced our specific development plans outside of BTC and GEA yet. But we have signaled that we have interest beyond those 2 initial indications with a real interest in breast cancer and Kelvin. Maybe you can talk about why we're headed that direction. Any color you might want to provide.

Yes. Thank you for that, Bruce. So what's clearly our focus right now is ensuring that we remain focused on BTC and GEA and in good time, we'll be thinking about where we need to progress next. Given that we know that HER2 is expressed widely particularly in breast, it is an area of interest for us. I'm very pleased to share that we have been invited by I-SPY to join their platform where they'll be looking at zanidatamab for HER2-expressing tumors in neoadjuvant treatment of locally advanced breast cancer. So we're excited about what that opportunity will look like, and we continue to explore other potential indications for any data knowing that the HER2 biomarker is expressed quite widely amongst other cancers as well.

To note on the timing of that, I-SPY we've been invited to participate in patient dosing has already, so it's moved quickly.

And our next question comes from the line of Daisy Lee with Stifel.

This is Stacy calling in for Annabel. One for Dr. Pant. So zani could be the first HER2 targeted treatment for BTC. But in this study, prior HER2 treated patients were explicitly excluded. Does that mean that HER2 agents are currently used off-label or with only NCCN guideline support? And how does this compare to those patients who have received HER2 with [indiscernible]? And I guess to that effect, if it is effective as combo therapy, then why has it ever been pursued as an actual indication?

Okay. So I think there were 2 parts to that question. One was what is being used outside off-label. So in NCCN guidelines be a trastuzumab and pertuzumab, which has been -- which is used off-label. In the HER2 pretreated, the 22 patients with biliary tract cancer who were enrolled in the Phase I trial. They were HER2 pretreated or at least a majority of them were HER2 pretreated. I don't have data in front of me. And we saw a response rate, I think, in that -- in BTC of about 38%. So there was also some response rates in that patient population of -- patient population HER2 pretreated. I'd have to look at the whole paper to exactly now, but that was the case. I think that was the case. The second part is, yes, I think it makes complete sense to combine an with chemotherapy. It's been combined in upper GI. Interestingly, the same regimen that we use in second line FOLFOX for biliary blue tract cancer is -- we have safety data with zani, so it does make sense to combine it. I think the challenge has been that the patients and kind of running these big trials in a rarer patient population. So that's what -- that's just my opinion on it.

And if I might just add, does any data has demonstrated compelling antitumor activity, both as monotherapy and in combination with chemotherapy. And we're pleased to also share that we have some Phase I monotherapy data in multiple HER2-positive solid tumors and in cases also resistant to prior HER2 therapies. I know that was a question that was raised.

Our next question comes from the line of Jeffrey Hung with Morgan Stanley.

This is Michael Riad on for Jeff Hung. These are for Dr. Pant. Looking at the waterfall plot for viable patients on Slide 13. It seems like patients with gall butter showed a better response versus ICC and ECC overall. Do gallbladder cancers have a higher HER2 expression level than ICC or ECC or do they tend to be more responsive. And I have a follow-up.

Yes. So I think if you look at it, I think all subtypes did get some kind of benefit in the trial. And if you look at the Asterix, the waterfall plots, obviously, the 3-plus patients seem to have a higher benefit than the 2-plus patients, but it's not that gallbladder cancers have more they can be scaled date cancers with 2-plus also. But I think it did -- mostly what it depends on is the oncogenic driver we think, have a potentially higher response rate than 2 plus, but the 2 plus also seem to respond maybe not as a high rate as the 3 plus.

I'll now hand the call back over to Chairman and CEO, Bruce Cozadd, for any closing remarks.

All right. Thank you, operator. Just in closing, we believe zanidatamab has the potential to transform treatment for a number of HER2-expressing cancers, and we are prioritizing its development. Zani is the newest program in our pipeline and exemplifies our approach to corporate development as we seek to identify and acquire on favorable terms differentiated therapies that improve patient care, enhance the value of our pipeline and are strategically aligned with our development and commercial capabilities. It also reflects our enhanced R&D capabilities. beyond the expanded breadth and depth of our pipeline with at least 3 late-stage readouts through 2024. I'm really proud of our expanded capabilities, including enhanced medicinal chemistry and translational biology and differentiated capabilities across cannabinoids and nanoparticle drug delivery. Our oncology franchise is a core component of our efforts to diversify our business, and we're excited about how zanidatamab may contribute to both patient care on our business. Thank you all for joining us today.

Thank you. This concludes today's webcast. Thank you for participating, and you may now disconnect.