Good day, welcome to the BeiGene ASH 2022 ALPINE Late Breaker Data Presentation. Today's conference is being recorded. If you would like to ask a question over the phone, you may press star one at any time. If you would like to ask a question via the webcast, please type your question in the Ask a Question box. At this time, I would like to turn the conference over to Kevin Mannix, Investor Relations. Please go ahead.
Thank you, Tamara, 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 that 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.
Mehrdad Mobasher, BeiGene's Chief Medical Officer, Hematology, will complete the presentation with key takeaways before we then open the lines for 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. 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 a unique company. We strove to apply a thoughtful, science-led approach to everything we did. We aspired 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 three out of eight patients have trouble affording their co-payments, 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 five 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+ preclinical programs, the majority which have first-in-class potential. Our 3,300+ 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 two 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+ 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; 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 gamechanger for patients around the world. It's already approved, as I said, in 60+ markets, we'll hear the insight shortly and walk through the data. 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. In the previous data from our 30+ 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. 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 in Dana-Farber, then joined the faculty of Dana-Farber in 2004. I'm now Director of the CLL Center and Institute Physician there, as well as the Worthington and Margaret Collette Professor of Medicine in the field of Hematologic Oncology at Harvard Medical School. My clinical interests are strongly focused on Chronic Lymphocytic Leukemia, Novel Drug Development, and some of my translational research interests include resistance mechanisms and heritability of CLL. I'm very pleased to have had 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 lymphomas.
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. It has properties that significantly limit its use, in particular toxicities that lead to treatment discontinuation in 16%-23% of patients. Exposure coverage between the dosing intervals falls below the IC₅₀, as you can see in the blue curve on the right. Variable BTK occupancy at trough has been observed. Zanubrutinib is a second-generation Bruton's Tyrosine Kinase inhibitor, which was designed to have greater BTK specificity than ibrutinib and maintains exposure coverage above its IC₅₀. Again, as you can see in the panel on the right.
These higher drug concentration to IC₅₀ ratios are expected to lead to more sustained and complete BTK inhibition to improve efficacy, particularly in a 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 del(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 including 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 one-to-one between zanubrutinib 160 mg twice per day and ibrutinib 420 mg daily.
The randomization was stratified by age, geographic region, refractory disease, and deletion 17p or TP53 status. Treatment was until disease progression or unacceptable toxicity. The primary endpoint was overall response rate defined as partial and complete response, both non-inferiority and superiority by investigator. Key secondary endpoints include progression-free survival and the incidence of atrial fibrillation. Overall response rate non-inferiority and superiority were demonstrated in the overall response rate interim and final analysis. PFS is therefore now tested for non-inferiority and superiority under hierarchical testing when 205 events had occurred. The data cutoff is August 8th, 2022. 652 patients were randomized, 327 to zanubrutinib and 325 to ibrutinib. Only three patients on the zanubrutinib arm and one patient on the ibrutinib arm were not treated.
As of data cutoff, 86 patients have discontinued zanubrutinib, compared to 134 who have discontinued ibrutinib. 53 zanubrutinib patients discontinued for adverse events, compared to 74 ibrutinib patients. 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 67-80, male predominance, a median of one prior systemic therapy, and less than 10% of patients with more than three lines of therapy. About 23% of patients had del(17p) and/or TP53 mutations, while 27% of patients had del(11q). 73% of patients had unmutated IGVH, about 20% complex karyotype, and 45% bulky disease.
Here you can see that zanubrutinib is significantly superior to ibrutinib for progression-free survival with a median study follow-up of 29.6 months. The hazard ratio is 0.65 with a P value of 0.0024. The two-year landmark PFS estimate is 79% for zanubrutinib compared to 67% for ibrutinib. These results are by IRC. The results are extremely concordant by investigator. Progression-free survival favors zanubrutinib across all the subgroups of disease: age, sex, prior lines of therapy, baseline 17p or TP53 mutation status, IGVH status, and complex karyotype. In a preplanned analysis, zanubrutinib improved progression-free survival in patients with deletion 17p and/or TP53 mutations with a hazard ratio of 0.52. The two-year landmark estimate is 78% with zanubrutinib compared to 56% with ibrutinib.
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%. 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. 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 three or higher neutropenia was seen in 21% of zanubrutinib patients compared to 18% of ibrutinib patients but was only associated with grade three 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. 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 were only six with zanubrutinib, two atrial fibrillations, two acute coronary syndromes, and two congestive heart failure incidents. Cardiac adverse events leading to treatment discontinuation were only one with zanubrutinib compared to 14 with ibrutinib.
Notably, there were no fatal cardiac events with zanubrutinib compared to six with ibrutinib, which is 1.9%. Looking at atrial fibrillation, the rate of atrial fibrillation is 5% with zanubrutinib compared to 13% with ibrutinib. In conclusion, zanubrutinib demonstrated superior progression-free survival over ibrutinib in patients with relapsed/refractory CLL/SLL. This PFS benefit was seen across all major subgroups, including the del(17p), TP53 mutated population. Zanubrutinib also has a favorable safety profile compared with ibrutinib, with a lower rate of grade three or higher in 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 of 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. I'll now pass this to Dr. Shadman, who's going to comment.
Thank you. My name is Mazyar Shadman. I'm an associate professor of medicine at the University of Washington and Fred Hutchinson 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. 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. We just heard an elegant presentation by Dr. Brown. 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.
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, lower rates of toxicities, including and 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.
In fact, the primary endpoint of the study design. The primary endpoint of the study included a superiority, and the study reached that 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 three areas: efficacy, safety, and issues related to the logistics and ease of administration. I think efficacy by far is one of the most important factors that patients care about and physicians care about. I think.
In my opinion, when we continue to have those conversations or start having conversations about 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. 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 Oncology at BeiGene, and I'll walk you through the key takeaways. 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 broad clinical development programs 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 four indications and an sNDA in CLL based on ALPINE data or our superiority endpoint. SEQUOIA study in frontline CLL has a PDUFA in January 2023.
Thank you. Operator, we will begin question and answer session in just a second. If you could remind everybody how to ask a question. Greatly appreciate it.
Thank you. If you would like to ask a question over the phone, please signal by pressing star one on your telephone keypad. If you are using a speakerphone, please make sure your mute function is turned off to allow your signal to reach our equipment. A voice prompt on the phone line will indicate when your line is open. Again, press star one to ask a question over the phone. To ask a question on the webcast, please type your question in the ask a question box. We'll pause for just a moment to allow everyone an opportunity to signal for questions. We'll take our first question from Andrew Berens with SVB Securities. Please go ahead.
Hi. Thanks, and congrats on the presentation and the publication. Appreciate you guys doing this call. Can you give us an update on some of the other BRUKINSA opportunities like follicular lymphoma? Just wanna 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 wanna have limited therapy. Then also just wanted to know where the doctors think the non-covalent BTK agents are likely to fit into the treatment paradigm. Are they gonna move to the front line, or will they be reserved for patients failing the covalent agents?
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. We are excited about those data, and BRUKINSA is the only BTK inhibitor that has showed such efficacy and superiority to the comparator. We are assessing those data, and we are assessing whether that can have a potential next step . Then on the rest of your questions, I'll pass it back on to Professor Brown.
Right. I think the next question was about the potential for fixed-duration therapy with BRUKINSA. I'm actually running a study of BRUKINSA with venetoclax at my own institution at present. We're in discussions, hopefully developing additional larger frontline studies testing zanubrutinib and venetoclax. As you know, there are already data emerging on zanubrutinib and venetoclax from SEQUOIA RMD, which will hopefully be updated again soon. Definitely moving 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 can extend for so many years that 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.
I think we'll be keeping a close eye on those emergent patterns of resistance. We did 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 beforehand. We certainly don't want to sacrifice the long-term benefit of the covalent inhibitors that we see with BRUKINSA in ALPINE, for example.
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 plus our BCL-2 inhibitor, both in CLL, if that was your question, and also non-Hodgkin lymphoma. We are also assessing this combination for future, that would be a potential for time-limited therapy as opposed to treatment to progression.
Okay.
Okay.
Thanks for answering all the questions.
Thanks, Berens. Okay. We also have some questions online. Next question comes from the line of Matthew Harrison from Morgan Stanley. Matthew writes: For the physicians, doctors, can you comment on how you see these data cross-trial versus CALQUENCE, and how you think about using the three BTK inhibitors in your CLL patients?
I can start. 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 were included and enrolled, and the median prior lines of therapy were different. In order to answer the question, we would need a clinical trial looking at the two drugs head-to-head.
I would comment that at the practice level, when I'm, when I'm presenting different treatment options to the patient, you know, 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. I think that's what I believe that this data will probably favor zanubrutinib for many patients with relapsed, CLL. To answer the general question about the best-in-class drug, I think we do need a 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. This trial makes that even 100% more clear. You know, 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 acalab.
Thank you, doctors. 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? The follow-up questions, do you expect patients established on Imbruvica to switch? A third one, what advantages would your BTK degrader offer?
I'll go. I'll start with the first question on market share. This is Josh Neiman. So, you know, I think it's important to think about these results in the context of the complete development program for BRUKINSA. Importantly, across our breadth of indications. You know, if I take the U.S. market as an example, we've been approved now for a few years for indications in relapsed or refractory mantle cell, Waldenström's, and relapsed marginal zone. What we've had is clinicians gaining experience with BRUKINSA primarily across these indications, and that experience has been good. It has translated to the belief in BRUKINSA as a strategy that they can employ when they think about each patient.
As we now prepare for our first approval in CLL here in the U.S., we expect that initial experience will translate into uptake across CLL. As the clinicians just walked us through, you know, a clinician making treatment decisions for their patients, they're gonna have to operate in a space in the absence of head-to-head results, which have been acalabrutinib, but they'll have head-to-head results with ibrutinib. We believe that our data compare very favorably to the data that are out there for these patients. Anecdotally, we've heard that most clinicians will extrapolate the results from the U.S. for factory CLL to the frontline setting. Over time, our goal is certainly to aspire to be the market leader. We anticipate that over time, zanubrutinib can become the standard of care inhibitor.
We, of course, need our frontline and relapsed approval in CLL to be able to drive that utilization. When you consider the breadth of our data, the indications that we have, the differentiated indications as it relates to other BTK inhibitors at that, we do expect to be the market leader over time.
Okay. Just a reminder, do you expect patients established on Imbruvica to switch? What advantages would BeiGene 's BTK degrader offer?
You know, if the patient's established on Imbruvica, if 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.
I'll take on the question about the BTK protein degrader. As it was mentioned, we do have a protein degrader at BeiGene that we believe that has the potential to be best in class as well. Just in general, you know, BeiGene develops a lot of expertise in this target BTK, and we try to build on that and have a different approach to inhibition of BTK. This time, we're degrading the protein as this mode of action is becoming more and more important. Our drug is in monotherapy phase I dose escalation now.
With the data that we are accumulating, we think that this 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. Continue to keep our leadership in some B-cell malignancy that we have now.
Okay. Operator, are there any additional questions?
There are no additional questions at this time.
Thank you so much, Tamara. 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, you know, wish you all a wonderful and happy holiday and look forward to seeing those of you who are coming to the JP Morgan meeting there in San Francisco in January. Happy holidays.
This concludes today's call. Thank you for your participation. You may now disconnect.