BeOne Medicines AG (ONC) Earnings Call Transcript & Summary

Good day, and welcome to the BeiGene ASH 2022 ALPINE Late-Breaker Data Presentation. Today's conference is being recorded. [Operator Instructions] At this time, I would like to turn the conference over to Kevin Mannix, Investor Relations. Please go ahead.

Thank you, Sameera, and thank you, everyone, for joining us for this discussion that wraps up what has been a very exciting few days for BeiGene here at the ASH Conference in New Orleans. Before we get started, let me remind you that there may be forward-looking statements in today's presentation and our business carries certain risks. Some of these risks are discussed in our filings with the SEC, Hong Kong Stock Exchange and the Shanghai Stock Exchange. To begin today's presentation, our Co-Founder, Chairman and CEO, John Oyler, will open up with some introductory remarks. John will be followed by Dr. Jennifer Brown, who is here to walk us through a presentation of the ALPINE trial final PFS data from this morning's late-breaking session. We'll also hear from Dr. Mazyar Shadman, for additional clinical perspectives; and Dr. Mehrdad Mobasher, BeiGene's Chief Medical Officer, Hematology, will complete the presentation with key takeaways, before we then open the lines for a question-and-answer session. Also joining the question-and-answer session are Julia Wang, BeiGene's Chief Financial Officer; and Josh Neiman, BeiGene's Chief Commercial Officer, North America and Europe. And with that, I'll now turn it over to John Oyler, our CEO.

Thank you, Kevin, and thank you, everyone, for joining us to discuss the ALPINE trial final PFS data. We're really thrilled about this year's ASH meeting, culminating in today's late-breaker presentation and the simultaneous manuscript in the New England Journal of Medicine. We're very honored to have Dr. Brown and Dr. Shadman join us to discuss these important results. 12 years ago, we founded BeiGene and set out to build and grow an unique company. We strove to apply a thoughtful science-led approach to everything we did. We inspired not only to develop and deliver impactful medicines, but to do so differently, we were striving to make medicines more affordable and more accessible to patients here in the U.S., where 3 out of 8 patients have trouble affording their copayments, and also around the world where probably 2/3 of patients either don't have access to or cannot afford the latest medicines. Today, BeiGene is truly a global company. We're over 9,000 people strong, operating in 5 continents, and we've made tremendous progress on achieving our vision. We have one of the largest oncology research teams globally with more than 900 scientists, overseeing 50 -- 60 plus preclinical programs, the majority which have first-in-class potential. Our 3,300 plus internal clinical development and medical affairs colleagues have enabled us to work closely with oncologists and oncology centers around the world, predominantly done in a CRO free manner. We love BRUKINSA, but we're far more than this one medicine. Today, we have 50 potential medicines in either clinical or at the commercialization stage. And we've highlighted 2 other very exciting Heme-related programs at this meeting. Our BCL-2 inhibitor and our BTK protein degrader. We've been building a truly global commercial team and are very excited to bring BRUKINSA to the 60 plus regions across the world, where it has been approved. Although, there's many ways in which BeiGene is a unique global company, nowhere is this more apparent than one looks at our clinical trial footprint and our internalization of clinical trials. Clinical trials comprise the vast majority of the time and cost for developing medicines, which is why we focus on improving the way things are done in this area. Today, we're running trials in more than 45 countries and regions, and we've enrolled over 20,000 patients on trials. We've now run 15 global Phase III oncology trials, and we believe that we're now able to meaningfully reduce the cost and time without sacrificing quality. BRUKINSA is an affordable, accessible medicine that we believe will be a game changer for patients around the world. It's already approved, as I said, in 60 plus markets and we'll hear the insights shortly and walk through the data. But I do want to say that the data is not surprising to our team, it's consistent with the preclinical hypothesis that sustainable inhibition matters and the previous data from our 30 plus trials that have now enrolled over 4,700 patients and have exceeded our past expectations. Here to talk about these key data from BRUKINSA is Dr. Jennifer Brown.

Thank you, and hello, everyone. I'm Jennifer Brown, I was trained at Harvard Medical School and did my residency and fellowship in the Harvard System at Massachusetts General Hospital and Dana-Farber. And then joined the faculty of Dana-Farber in 2004. I'm now Director of the CLL Center and Institute position there, as well as the Worthington and Margaret Collette Professor of Medicine in the field of Hematologic Oncology at Harvard Medical School. And Market Collette Professor of Medicine in the field of hematological oncology at Harvard Medical School. My clinical interest is strongly focused on chronic lymphocytic leukemia and novel drug developments, and some of my translational research interest include resistance mechanisms and heritability of CLL. I'm very pleased to have the opportunity to present the final analysis of the ALPINE data at the late-breaking session today. Just to remind everyone, B-cell receptor signaling is required for tumor expansion and proliferation in CLL and B-cell lymphoma. And we know that B-cell receptor signaling is dependent on BTK or Bruton's tyrosine kinase. Ibrutinib, of course, is the first-in-class covalent BTK inhibitor that initially transformed CLL therapy. But it has properties that significantly limit its use. In particular, toxicities that lead to treatment discontinuation is 16% to 23% of patients. And exposure coverage between the dosing intervals falls below the IC50, as you can see in the blue curve on the right, and variable BTK occupancy at trough has been observed. Zanubrutinib is a second-generation Bruton's tyrosine kinase inhibitor, which is designed to have greater BTK specificity than ibrutinib and maintains exposure coverage above this IC50, again, as you can see in the panel on the right. This higher drug concentration to IC50 ratios are expected to lead to more sustained and complete BTK inhibition to improve efficacy, particularly in the setting where BTK may be regenerated during the dosing interval. Previously, zanubrutinib has demonstrated superior progression-free survival by independent review committee compared to chemoimmunotherapy in treatment-naive CLL/SLL patients without deletion 17p. This is the ALPINE study design. Patients with relapsed/refractory CLL or SLL with at least one prior treatment were enrolled. 600 patients were planned and 652 were actually enrolled. Key inclusion criteria included having measurable lymphadenopathy, while key exclusion criteria included prior BTK inhibitor therapy and treatment with warfarin or other vitamin K antagonists, although other anticoagulants were permitted. Patients were randomized 1:1 between zanubrutinib 160 milligrams twice per day and ibrutinib 420 milligrams daily. The randomization was stratified by age, geographic region, refractory disease and deletion 17p or p53 status. Treatment was until disease progression or unacceptable toxicity. The primary endpoint was overall response rate defined as partial and complete response, both noninferiority and superiority by investigator. Key secondary endpoints include progression-free survival and the incidence of atrial fibrillation. Overall response rate, noninferiority and superiority were demonstrated in the overall response rate, interim and final analysis. PFS is therefore now tested for noninferiority and superiority under hierarchical testing when 205 events had occurred, and the data cutoff was August 8, 2022. 652 patients were randomized, 327 to zanubrutinib and 325 to ibrutinib. Only 3 patients on the zanubrutinib arm and one patient on the ibrutinib arm were not treated. As of data cutoff, 86 patients to discontinue zanubrutinib, compared to 134 who have discontinued ibrutinib. 53 zanubrutinib patients discontinued for adverse events, compared to 74 ibrutinib patients. And 24 patients on the zanubrutinib arm discontinued for progressive disease, compared to 42 on the ibrutinib arm. As of data cutoff, 73 patients had ongoing treatment with zanubrutinib, compared to 58 patients on the ibrutinib arm. The disease characteristics at baseline were balanced with a median age of 67 to 68, male predominance, a median of one prior systemic therapy and less than 10% of patients with more than 3 lines of therapy. About 23% of patients had deletion 17p and/or p53 mutation, while 27% of patients had deletion 11q. 73% of patients had unmutated [ IGHV ] about 20% complex karyotype and 45% bulky disease. Here, you can see that zanubrutinib is significantly superior to ibrutinib for progressive-free survival with a median study follow-up of 29.6 months. The hazard ratio was 0.65 with a p-value of 0.0024. The 2 year landmark PFS estimate is 79% for zanubrutinib, compared to 67% for ibrutinib. And these results are by IRC, but the results are extremely concordant by investigator. Progressive-free survival favors zanubrutinib across all the subgroups of disease, age, sex, prior lines of therapy, baseline 17p or p53 mutation status. IGHV status and complex karyotype. In a pre-planned analysis, zanubrutinib improved progression-free survival in patients with deletion 17p and/or p53 mutations, with a hazard ratio of 0.52. The 2 year landmark estimate is 78% with zanubrutinib, compared to 56% with ibrutinib. And again, this is by IRC, but the results by investigator were extremely concordant. Zanubrutinib continues to show a higher overall response rate at 86%, compared to ibrutinib at 76%. And complete remissions are uncommon at 6.7% with zanubrutinib, and 5.8% with ibrutinib. Overall survival demonstrates fewer deaths with zanubrutinib at 48, compared to 60 with ibrutinib. These results are not statistically significant at present. Now in terms of safety, median treatment duration with zanubrutinib was 28 months, compared to 24 months with ibrutinib. Zanubrutinib was better tolerated than ibrutinib with fewer serious adverse events and fewer adverse events leading to dose reduction or interruption and fewer adverse events leading to treatment discontinuation. The most common adverse event leading to treatment discontinuation was infection, commonly COVID. Here, you can see the most common adverse events occurring in 15% or more of patients per arm. Neutropenia was the most common, Grade 3 or higher neutropenia was seen in 21% of zanubrutinib patients, compared to 18% of ibrutinib patients, but was only associated with Grade 3 or higher infection in 9% of zanubrutinib patients and 13% of ibrutinib patients. Next was COVID-19-related adverse events. This was the most common treatment-emergent adverse event leading to death at 4% on the zanubrutinib arm and 5% on the ibrutinib arm. And hypertension was similar in both arms at 23%. Zanubrutinib had a favorable cardiac profile with fewer cardiac adverse events and fewer serious cardiac adverse events. There are only 6 with zanubrutinib, 2 atrial fibrillation, 2 acute coronary syndromes and 2 congestive heart failure incidents. Cardiac adverse events leading to treatment discontinuation were only one with zanubrutinib, compared to 14 with ibrutinib. And notably, there were no fatal cardiac events with zanubrutinib, compared to 6 with ibrutinib, which is 1.9%. Looking at atrial fibrillation. The rate of atrial fibrillation is 5% with zanubrutinib, compared to 13% with ibrutinib. So in conclusion, zanubrutinib demonstrated superior progression-free survival over ibrutinib in patients with relapsed/refractory CLL/SLL, and the PFS benefit was seen across all major subgroups, including the deletion 17p, p53 mutated population. Zanubrutinib also has a favorable safety profile compared with ibrutinib with a lower rate of Grade 3 or higher and serious adverse events, as well as fewer adverse events leading to treatment discontinuation and dose reduction. Zanubrutinib has a better cardiac profile than ibrutinib with lower rates of atrial fibrillation, serious cardiac events, cardiac events leading to treatment discontinuation and fatal cardiac events. ALPINE is therefore the first study to demonstrate progression-free survival superiority in a head-to-head comparison with BTK inhibitors in patients with relapsed/refractory CLL/SLL. Zanubrutinib has now proven superiority to ibrutinib in both progression-free survival and overall response rate. Thank you. And I'll pass this to Dr. Shadman, who is going to comment.

Thank you. My name is Mazyar Shadman. I'm an Associate Professor of Medicine at the University of Washington and Fred Hutch Cancer Center in Seattle. I finished my training at Tehran University, Cleveland Clinic and University of Washington. I treat chronic lymphocytic leukemia and lymphoid malignancies, and my research is focused on therapeutics for B-cell malignancies using novel therapeutic agents and immunotherapy. It's my pleasure to join the discussion today, and we just heard a elegant presentation by Dr. Brown, and I was thinking that for a study like ALPINE, it's actually easy to make comments since the data speaks for itself. As a physician who treats patients with chronic lymphocytic leukemia and as one of the investigators on this study, I'm very excited to see these results. And I believe that ALPINE study is a unique study in that -- in showing for the first time in chronic lymphocytic leukemia that a novel BTK inhibitor is superior to ibrutinib, both for efficacy and safety. In this study, we saw an improved overall response rate and an improved progression-free survival, while the safety profile was also superior compared to ibrutinib. Importantly, this study was designed based on hypothesis. First, based on the specificity for BTK and lack of inhibition for off-target enzymes. And that, as we saw translated to clinical benefit in a lower rate of safety -- in lower rates of toxicities, including mainly cardiotoxicity in patients who were treated with zanubrutinib compared to patients who received ibrutinib. Also based on the pharmacology and information about the exposure coverage and BTK occupancy, it was expected to see an improved efficacy in zanubrutinib. And in fact, the primary endpoint of the study design with -- the primary endpoint of the study included a superiority in the study reset endpoint. The study showed both overall response and PFS superiority of zanubrutinib over ibrutinib. At the clinical level, this will be very helpful when we have discussions with the patient. Importantly, we try to cover 3 areas, efficacy, safety and issues related to the logistics and of administration. I think efficacy by far is one of the most important factors that patients care about and physicians care about. So I think, in my opinion, when we continue to have those conversations or start having conversations with our treatment, this data will be extremely important, and in my opinion practice changing given the improved efficacy and safety. With that, I would be happy to answer any questions during the Q&A. And again, thank you for giving me the opportunity, and congratulations to the study team and investigators on the ALPINE study.

Thank you, Dr. Shadman. This is Mehrdad Mobasher, I'm the Chief Medical Officer of Hematology at BeiGene. I'll walk you through the key takeaways. So BRUKINSA is designed to be a best-in-class BTK inhibitor, to improve efficacy through targeted and sustained BTK inhibition and improve safety by reducing inhibition of off-target tyrosine kinases. We have a broad clinical development program with more than 4,700 patients enrolled in several clinical trials in different geographies, with 3,700 patients enrolled outside China. Today, BRUKINSA is the only BTK inhibitor demonstrating PFS superiority versus IMBRUVICA in a head-to-head study. BRUKINSA has approvals in more than 60 markets and 4 indications. And sNDA in CLL based on ALPINE data or our superiority endpoint and SEQUOIA study in frontline CLL with PDUFA in January 2023.

Thank you, operator. We will begin question-and-answer session. Just a second, if you could remind everybody how to ask a question. Really appreciate it.

[Operator Instructions] And we'll take our first question from Andrew Berens with SVB Securities.

Congrats on the presentation and the publication. I appreciate you guys doing this call. Can you give us an update on some of the other opportunities like follicular lymphoma? And just want to know if there are plans to develop BRUKINSA for fixed duration therapy in CLL, maybe Dr. Brown can summarize, where she thinks the field is going in that regard for younger patients who may want to have limited therapy. And then also, I just wanted to know were the doctors think the non-covalent BTK agents are likely to fit into the treatment paradigm? Are they going to move to the frontline? Or will they be reserved for patients failing the covalent agents?

So this is Mehrdad Mobasher, maybe I'll start with answering the follicular lymphoma question. We presented the data on follicular lymphoma this summer. We are very excited that the combination of BRUKINSA and obinutuzumab is actually leading to great efficacy. So we are excited about those data and BRUKINSA is the only BTK inhibitor that has showed such efficacy and superiority to the comparators. So we are assessing those data, and we are assessing whether that can have potential next steps. And then on the rest of your questions, I'll pass it back on to Ms. Brown.

Right. I think the next question was about the potential for fixed duration therapies with BRUKINSA. And I'm actually running a study of BRUKINSA with venetoclax at my own institution at present, and we're in discussions hopefully developing additional larger frontline studies testing zanubrutinib with venetoclax. As you know, there are already data emerging on zanubrutinib and venetoclax in SEQUOIA R&D, which will hopefully be updated again soon. So definitely we'll be in that direction. Regarding the non-covalent inhibitors, personally, I am definitely reserving judgment about moving them before covalent inhibitors. We know that the benefit of covalent inhibitors is so strong and so -- and can extend for so many years. Until we fully understand the mechanisms of resistance and cross resistance with the non-covalent inhibitors, I'm very hesitant to move them before the covalent inhibitors. And so, I think we'll be keeping a close eye on those emergence patterns of resistance. We could hear a little bit more about it at the meeting the last week, but it's still not clear how sequencing would work with a non-covalent before that. And we certainly don't want to sacrifice the long-term benefit of the covalent inhibitors that we see with BRUKINSA in [ health resistance. ]

And if I may add from the company side, we also have a BCL-2 inhibitor, BGB-11417, Yesterday, we presented some data from the Phase I/II study of combination of zanubrutinib. One of our BCL-2 inhibitor, both in CLL, that was your question and also non-Hodgkin's lymphoma. And we are also assessing this combination for future that would be a potential for time limited therapy as opposed to treatment to progression.

So we also have some questions online. Next question comes from the line of Matthew Harrison from Morgan Stanley. Matthew writes for the physicians, doctors, all right. Can you comment on how you see these data cross-trial versus Calquence? And how do you think about using the 3 BTK inhibitors in your CLL patients?

I can start. So we try to follow the practice of not comparing different clinical trials. It's always difficult to look at studies that have different inclusion criteria and different patient populations. For example, in the case of ELEVATE-RR patients with 11q and 17p deletion included, enrolled and the median prior lines of therapy were different. So in order to answer the question, we would need a clinical trial looking at the 2 drugs head-to-head. But I would comment that at the practice level that I'm presenting different treatment options to the patient, explaining the current evidence and going through the clinical data from both ALPINE and ELEVATE and highlighting specifically the efficacy data. My expectation is that, that would be an important decision factor for most of the patients. And that's what I believe that this data will probably favor zanubrutinib for many patients with relapsed CLL. But to answer the general question about the best-in-class drug, we do the head-to-head clinical trial to answer that question.

I would agree. I would note that I don't use ibrutinib at all really anymore even prior to this trial. And this trial makes that even 100% more clear. And the superiority benefit for progression-free survival is really our gold standard, and we have that data with zanubrutinib. We don't have it with [indiscernible].

Next question comes from the line of Luisa Hector from Berenberg. We've got the first question. How much market share do you believe you can take in first-line CLL without head-to-head data against Calquence? And follow-up questions, do you expect patients established on IMBRUVICA to switch? And the third one, what advantages was your BTK degrader offer?

I'll start with the first question on market share. This is Josh Neiman. So I think it's important to think about these results in the context of the complete development program for BRUKINSA. And importantly across our breadth of indication. If I take the U.S. market as an example, we've been approved now for a few years in patients relapse [indiscernible]. We've had clinicians experience with BRUKINSA primarily across these indications. And that experience has been good. And it has translated to the belief in BRUKINSA as a strategy that they can employ when they think about [indiscernible] So as we now prepare for our first approval in CLL here in U.S., we expect that initial experience will translate into uptake across CLL, as the clinicians just walked us through -- clinicians making decisions for their patients. They're going to have to operate in a space in the head-to-head results with zanubrutinib, [indiscernible] result with ibrutinib. We believe that our data can come very favorably to the data that are out for these patients. Anecdotally, we've heard that most clinicians will extrapolate the results from relapsed refractory CLL to the following study. And so over time, our goal is certainly to expand through the market leader, we anticipate that over time that [indiscernible]. But when you consider the breadth of our data, the indications that we have, the differential indications as it relates to the other [ BTK ] 10% back. We do expect that the market improve over time.

Okay. Just a reminder, do you expect patients to establish IMBRUVICA to switch? And also what advantages with BeiGene's BTK is a greater offer?

So if some patients established on IMBRUVICA, they've been on it for a long time, and they're doing well. We'll tend to just let them stay on it. However, patients who are having toxicities and are having trouble with the drug, those are patients who we would potentially consider for transitioning. And I think zanubrutinib would be the drug of choice in that scenario.

And I'll take on the question about the BTK project degrader. As it was mentioned, we do have a protein degrader BeiGene that we believe that has the potential to be best-in-class as well. Just in general, BeiGene developed a lot of expertise in the target BTK. And we try to build on that and have a different approach in the addition of BTK. This time, we're degrading the protein as this mode of action is becoming more and more important. So our drug is in monotherapy Phase I dose escalation now. But with the data that we are accumulating, we think that it has the potential to approach BTK from a different approach, as I mentioned, and also overcome some of the known resistance mechanisms to covalent and non-covalent BTK. So we continue to keep our leadership in some detailed malignancies that we have now.

Okay. Operator, are there any additional questions?

There are no additional questions at this time.

All right. Thank you so much, Sameera. I'll turn the call back over to our CEO, John Oyler.

I just would like to thank everyone for attending the call, especially Dr. Brown and Dr. Shadman for their participation. And I wish you all a wonderful and happy holiday and look forward to seeing those of you who are coming to the JPMorgan meeting there in San Francisco in January. Happy holidays.

And this concludes today's call. Thank you for your participation. You may now disconnect.