ONC 百济神州 2024年第4季度财报电话会议文字稿中英文

Operator

各位好，欢迎参加百济神州2024年第四季度及全年业绩电话会议网络直播。所有线路已设为静音以防止背景噪音。演讲者发言结束后，将进行问答环节。现在，我将电话会议转交给公司。

Dan Maller

早上好，欢迎各位。感谢大家今天参加我们的会议。我是百济神州投资者关系负责人Dan Maller。在开始之前，请注意您可以在我们网站的投资者关系板块ir.beigene.com上找到包括今天网络直播回放和演示文稿在内的补充材料。我想提醒所有与会者，在本次电话会议中，我们可能会就公司未来前景和业务战略等方面做出前瞻性陈述。实际结果可能与前瞻性陈述中所示存在重大差异，原因包括我们在最近提交给SEC的定期报告中讨论的各种风险因素。请同时仔细审阅演示文稿中附带的前瞻性陈述免责声明。本次电话会议讨论的GAAP与非GAAP财务指标之间的调节表已在演示文稿附录中提供，该演示文稿与我们的业绩公告一同发布在我们的投资者关系网站上。本演示文稿中的所有信息截至演示文稿发布之日，除非法律要求，我们没有义务更新此类信息。现在转到今天的电话会议，如幻灯片3所示。我们的联合创始人、董事长兼首席执行官John Oyler将致开幕词并更新我们的血液学业务情况。我们的北美区总经理Matt Shaulis将介绍BRUKINSA在美国的商业表现。我们的全球研发负责人Lai Wang将讨论我们的研发和管线进展。我们的首席财务官Aaron Rosenberg将回顾第四季度财务业绩以及我们2025年的财务指引。随后我们将开放电话会议进行问答。现在我将电话会议转交给John。

John Oyler

谢谢Dan，大家早上好。2024年是真正非凡的一年，我们全年实现了38亿美元的收入，第四季度11亿美元，季度运营现金流为正，BTKi在美国所有治疗线和所有适应症的新患者启动方面处于领先地位。BRUKINSA美国收入在第四季度首次超过[听不清]。我们向临床引入了13个新分子实体，随着我们8亿美元美国旗舰制造设施的完工、股票代码变更为ONC（O-N-C）、提议更名为BeOne以及迁册至瑞士，我们已成长为一家全球性公司。我们相信我们已经达到了一个拐点，对未来感到非常兴奋。我们公司从创立之初就是为了解决我们行业中长期存在的投资回报挑战。正如您所知，每研发一美元的投资回报率越来越难实现。临床试验占开发和商业化一种肿瘤药物总成本的75%以上，目前估计每位患者需要25万至30万美元，且仍在上升。外部环境日益严峻，但我们从一开始就为预见这些挑战的世界构建了百济神州。我们真正全球化的、无CRO参与的临床团队近3700人，使我们能够以比行业同行更快的速度和更低的成本推进。结合我们内部研究和内部制造，我们实现了快速概念验证的方法，从早期开发阶段节省了大量时间。我们正有意识地创新，为患者建立具有更好疗效的最佳特许经营权，在日益激烈的商业环境中提供卓越回报。在CLL领域，我们相信我们正处于千载难逢的机遇之中，类似于吉利德在HIV领域和Vertex在囊性纤维化领域的机遇。我们2025年的重点是实现三大战略支柱：第一，巩固和深化我们的血液学特许经营权领导地位；第二，推进我们内部开发资产的管线；第三，推动卓越的财务表现。我今天将重点介绍我们的血液学特许经营权。当然，谈到特许经营权和我们的血液学领导地位，不能不从BRUKINSA开始。BRUKINSA从设计之初就旨在提供24/7的BTK抑制，覆盖所有疾病部位，并解决伊布替尼的疗效和毒性挑战。正如您在这里看到的，只有BRUKINSA维持血清暴露远高于其IC50，而伊布替尼的暴露在大部分时间内远低于其IC50。您不能兼职抗癌或仅在血液中抗癌。最近一篇同行评审的出版物分析了三种已批准共价BTK抑制剂在BTK占有率方面的差异。这些结果表明，就靶点结合而言，只有泽布替尼在所有相关疾病部位提供完全和持续的BTK抑制，且泽布替尼>伊布替尼>阿卡替尼。这些数据和此处展示的临床结果证明我们的假设是正确的。在ALPINE试验中，BRUKINSA与伊布替尼头对头比较，显示出持续优越的PFS疗效和更低的心脏毒性。左侧显示的是ALPINE在高风险del(17p)/TP53亚组中的数据。在42个月时，里程碑PFS泽布替尼为59%，而伊布替尼仅为32%。右侧是ELEVATE-RR研究，同样在高风险del(17p)/TP53患者中，据说风险比为1，但请注意早期分离可能是由于对伊布替尼不耐受所致。但更重要的是，阿卡替尼在刚过30个月时交叉，实际上在42个月时比伊布替尼差8%。在这个时间段，里程碑PFS仅为28%。是的，我说的是28%。这些令人信服的数据推动了BRUKINSA全球销售额的指数级增长。在我们首次在CLL获批后不到两年，尽管是第三个进入市场，BRUKINSA已成为BTKi类别中新患者启动的领导者。也许上述数据和真实世界经验的结合，正让患者和临床医生都理解在疗效上Z>I>A。我想花点时间谈谈固定疗程治疗格局，以及为什么我们将其视为扩大我们在CLL领域领导地位的关键机会。要创造有吸引力的固定疗程疗法，需要三个关键属性：第一，深度缓解；第二，与持续治疗相比，具有有竞争力和持续的PFS；第三，治疗期间的安全性，仅比持续BRUKINSA增加最小风险，而BRUKINSA始终表现出良好的安全性。近期竞争性治疗方案展示的数据确实不尽如人意。首先，AMPLIFY未显示深度MRD缓解。实际上，只有34%的AV患者达到MRD阴性，这在统计学上不仅劣于化疗，也明显差于类似PO和VI的3期试验的先例数据。相比之下，我们的BRUKINSA联合泽布替尼在健康状况差得多的全人群患者中显示了91%的MRD阴性率。其次，目前的固定疗程方案未显示出与持续使用BRUKINSA相匹配的持续PFS获益，尤其是在更长的随访期。AMPLIFY入组了高度筛选的年轻且体能状态良好的患者。该人群占真实世界CLL患者的不到25%。那么AV与先前类似体能状态的PO数据相比如何？简单来说差得多。A与I相比如何，当它们各自与V联合时？A联合方案在MRD和PFS方面都更差，尽管是在体能状态良好的人群中，而VI是在体能状态不佳的人群中。数值上，I联合方案>A联合方案，这与之前的所有数据一致。这一点更为显著，因为人们预期它在体能状态良好人群中应表现更好，那么能好多少呢？对于VO，数据就在这里，认识到交叉试验分析的局限性，比较体能状态良好与不佳人群时，PFS获益似乎有6%到7%的改善。当审视早期36个月时的实际PFS曲线时，AMPLIFY令人失望的疗效变得更加明显。BRUKINSA在体能状态不佳人群中为84%，而A+V在体能状态良好患者中仅为76.5%。还要注意，AV在那个时间点附近显示出进一步恶化。最后，与BRUKINSA相比，目前的固定疗程方案在最初60周治疗期间具有挑战性的安全性特征，这再次是在体能状态良好与高度筛选的健康人群之间比较。正如您所见，这些老年患者在最初60周内承受了相当大的额外毒性负担，却换来劣质的36个月PFS。这引发了一个问题：对于AV来说，值得吗？我们坚信固定疗程的前景。但不幸的是，目前的方案未能兑现这一承诺。这为一种最佳组合——sonro和泽布替尼——提供了重要机会，它满足所有条件：深度MRD缓解、在19个月时改善且持续的PFS曲线以及可接受的安全性。这种组合有可能使竞争性分子成为不可信的替代品。我们的3期关键性CELESTIAL CLL试验已完成入组，对照V+O（而非化疗），而V+O实际上是相关且广泛使用的标准治疗。我们还有正在进行的2期研究，在CLL、华氏巨球蛋白血症和MCL中具有早期注册潜力，并计划在今年上半年启动另外两项在CLL和MCL中的3期试验。另一个重大的血液学机会是我们的BTK CDAC。该项目已入组超过500名患者，是迄今为止最先进的BTK降解剂。我们在ASH上展示了在重度预处理人群中令人信服的早期疗效和安全性数据。正如您在这张幻灯片上看到的，我们数据相对于pirto的演变，加上KOL的反馈，使我们有信心在今年晚些时候启动一项针对二线治疗的与pirto头对头的3期试验。我们还有一项正在进行的针对复发/难治性CLL的2期扩展试验，可能支持注册，并且对早期治疗线（包括联合疗法）制定了积极的开发计划。我们对该项目感到非常兴奋。总之，我们的血液学特许经营权有望获胜，因为我们是唯一一家在最重要靶点和模式上拥有全资潜在最佳分子的公司。我们相信我们能够显著改善CLL所有治疗线的标准治疗。我们拥有千载难逢的机会，在120亿美元以上的CLL市场中建立改变生命的组合和卓越的特许经营权，并且我们相信我们的特许经营模式将有助于我们免受定价压力的影响。说到这里，我将把时间交给Matt。

John Oyler

Thank you, Dan, and good morning, everyone. 2024 was a truly remarkable year in which we achieved $3.8 billion in revenue for the full year, $1.1 billion in Q4, positive quarterly cash flow from operations, BTKi leadership in new patient starts across all lines and all indications in the U.S. BRUKINSA U.S. revenue exceeded [indiscernible] for the first time in the fourth quarter. We introduced 13 new molecular entities into the clinic, and we matured as a global company with the completion of our $800 million U.S. flagship manufacturing facility, our ticker change to ONC, O-N-C, and our proposed name change to BeOne and redomiciliation to Switzerland. We believe that we've reached an inflection point, and we're truly excited for the future. Our company was purpose-built to address the long-lived challenges of return on investment in our industry. And as you know, it's not getting any easier to generate ROI on each R&D dollar. Clinical trials represent more than 75% of the total cost to develop and commercialize an oncology medicine, and they're now estimated to be $250,000 to $300,000 per patient still rising. It's increasingly challenging out there, but we built BeiGene from inception for a world that envisioned these challenges. Our truly global CRO-free clinical team of nearly 3,700 allows us to move at a greater speed and a lower cost than our industry peers. Paired with our internal research and internal manufacturing, we've enabled a fast-to-proof-of-concept approach that shaves meaningful time from early stage development. We're innovating with intentionality and we're building best-in-class franchises with better outcomes for patients that will provide superior returns in the increasingly competitive commercial landscape. In CLL, we believe we're in the middle of a once-in-a-lifetime opportunity, which is akin to that of Gilead and HIV and Vertex in cystic fibrosis. Our focus for 2025 is to deliver upon three strategic pillars: first, solidify and deepen our hematology franchise leadership. Second, advance our pipeline of internally developed assets. And third, drive superior financial performance. My section today will focus on our heme franchise. And of course, we can't talk about the franchise and our heme leadership without starting with BRUKINSA. BRUKINSA was designed from inception to provide 24/7 inhibition of BTK in all disease compartments and to address efficacy and tox challenges of ibrutinib. As you can see here, only BRUKINSA maintains serum exposures well above its IC50, whereas ibrutinib and exposures are well below their IC50 for the majority of the period. And you can't fight cancer part time or only in the blood. A recent peer-reviewed publication analyzed the differences in BTK occupancy between the three approved covalent BTK inhibitors. These results indicate to us that with regard to target engagement, only zanub provides complete and sustained inhibition of BTK across all relevant disease compartments. And that zanubis greater than ibrutinib, which is greater than acalab. These data and the clinical results shown here proved our hypothesis was correct. In the ALPINE trial, BRUKINSA demonstrated sustained superior PFS efficacy and lower cardiac tox head-to-head against ibrutinib. On the left, the ALPINE data in the high-risk deletion 17p, P53 subpopulation is shown. At 42 months, milestone PFS was 59% for zanub and only 32% for ibrutinib. On the right is the ELEVATE-RR study, also in the high-risk deletion 17p, P53 patients, which is said to have a hazard ratio of one, but please note the early separation is likely due to lack of tolerance to ibrutinib. But more importantly, that acalab crosses at just over 30 months, and actually becomes 8% worse than ibrutinib at 42 months. And at this time period, the milestone PFS is only 28%. Yes. I said 28%. And this compelling data has led to exponential growth in BRUKINSA global sales. Less than two years from our first approval in CLL and despite being the third to market, BRUKINSA has become the BTKi class leader for new patient starts. Perhaps the combination of the aforementioned data and real-world experience are leading to both patients and clinicians understanding that on efficacy Z is greater than I, which is greater than A. I'd like to take a few moments to talk about the fixed duration treatment landscape and why we view it as a key opportunity to grow our CLL leadership. To create compelling fixturation therapy, three key attributes are required. First, deep response. Second, compressive and sustained PFS compared to continuous therapy. And third, safety during the treatment period that adds only minimal liability over a continuous BRUKINSA, which has consistently demonstrated a favorable safety profile. Recent data presented by competitive treatment options certainly leave a lot to be desired. First, AMPLIFY did not show a deep MRD response. Actually, only 34% of AV patients reached MRD negativity, which was both statistically inferior to chemo, and also dramatically worse than precedent data from similar Phase 3 trials of PO and VI. By comparison, our combination of BRUKINSA plus zanu has shown 91% MRD in a much less healthy all-comers population. Secondly, current fixed duration options do not show a sustained PFS benefit that matches continuous use BRUKINSA, particularly with longer follow-up. AMPLIFY enrolled a highly selected young and fit population. The population represents less than 25% of real-world CLL patients. So how did AV compare to the precedent similarly fit to PO data, it's simply much worse. How did A compare to I, when they each combined with V. The A combination was worse in both MRD and in PFS, despite being in a fit population versus VI's unfit population. Numerically in combination I was greater than A, which is consistent with all the previous data. And this is even more striking as one expects it to do better than unfit, how much better might one expect? For VO, the data is right here, recognizing the limitations of cross-trial analyses, there appears to be a 6% to 7% improvement in PFS benefit when comparing fit versus unfit. The underwhelming efficacy of AMPLIFY becomes even more evident when reviewing the actual PFS curves at the early 36-month period. No BRUKINSA in an unfit population at 84%, and A plus V in fit patients at only 76.5. Also notice, AV shows further deterioration around that time. And finally, current fixed duration options have a challenging safety profile during the first 60-week treatment period compared to BRUKINSA, and that's comparing again on fit to a highly selected healthy population. As you can see, there's a substantial additional tox burden placed on these elderly patients during the first 60 weeks, all for an inferior 36-month PFS. It raises the question for AV is the juice worth the squeeze. We strongly believe in the promise of fixed duration. But unfortunately, the current options don't fulfill this promise. This provides a significant opportunity for a best-in-class combination of sonro and zanub that checks all the boxes, deep MRD responses, improved and sustained PFS curves at 19 months and acceptable safety. This combination has the potential to render the competitive molecules as not credible substitutes. Our Phase 3 pivotal CELESTIAL CLL trial has completed enrollment against V + O, not chemo, and V + O is actually a relevant and widely used standard of care. We also have an ongoing Phase 2 studies with early registrational potential in CLL, Waldenstrom and MCL and we're planning to initiate two additional Phase 3 trials in CLL and MCL in the first half of this year. Another big heme opportunity is our BTK CDAC. This program has enrolled more than 500 patients and is by far the most advanced BTK degrader. We presented compelling early efficacy and safety data in a heavily pretreated population at ASH. As you can see here on the slide, the evolution of our data relative to pirto together with KOL feedback gave us confidence to initiate a head-to-head Phase 3 trial against pirto in the second line later this year. We also have an ongoing Phase 2 expansion trial in relapsed/refractory CLL that's potentially registration enabling and have an aggressive development plans for earlier lines of therapy, including combinations. We are really excited about this program. In summary, our heme franchise is poised to win as we are the only company with the wholly-owned potential best-in-class molecules across the most important targets and modalities. We believe that we can dramatically improve the standard of care across all lines in CLL. We have a once-in-a-lifetime opportunity to build life-changing combinations and the preeminent franchise in the $12 billion plus CLL market, and we believe our franchise model will help insulate us from pricing pressures. And with that, I'll pass it over to Matt.

Matt Shaulis

谢谢，John。接下来谈谈BRUKINSA在美国的表现。BRUKINSA的商业采用率非常出色，与一款具有明显差异化优势且同类最佳的药物所应有的表现一致。在BTK市场中，我们持续巩固BRUKINSA作为首选BTK药物的地位，这体现在其在一线治疗和复发/难治性CLL新患者启动方面的领导地位。总体CLL新患者份额已增长至超过50%，我们的实力和领导地位不仅限于CLL。在我们其他已获批适应症中，新患者份额甚至更高。新患者份额是价值份额的领先指标，我们可以看到CLL及其他已获批适应症中的领导地位在本幻灯片中得到了体现。第四季度，我们在美国的销售额达到6.16亿美元，同比增长97%。这一稳健表现为强劲的2024年画上了圆满句号，全年收入达19.5亿美元，较2023年增长106%。我们在第四季度在美国收入方面超越了Calquence，并且即将超越IMBRUVICA，这距离BRUKINSA获得CLL批准还不到两年时间。这证明了BRUKINSA的差异化特性以及我们强大的临床开发、医学和商业执行力。CLL领域竞争依然激烈，但进入2025年，我们处于极佳的位置。全球B细胞恶性肿瘤市场机会以及我们已获批适应症的规模庞大且不断增长，2024年总计约210亿美元。美国市场占全球市场的很大一部分，CLL在美国市场占比超过50%，同样增长强劲。就患者数量而言，BTK类药物约占美国CLL患者的50%。正如我们提到的，BRUKINSA在CLL新患者启动方面是BTK类药物的领导者。鉴于其差异化特性，我们相信BRUKINSA可以进一步扩大其在BTK类药物中的领先优势。考虑到BRUKINSA是一种持续治疗方案，重要的是要考虑持续接受治疗患者的叠加效应。2024年，约三分之一的BRUKINSA美国收入来自新患者，三分之二来自2024年初已在接受治疗的患者，这意味着我们不断增长的新患者份额水平将带来数年的收入增长。正如您在图表中所见，BTK之外的患者数量分布在固定疗程方案、BCL2 venetoclax和化疗之间。目前获批的基于事件的固定疗程方案并不适用于所有患者，超过一半的新诊断患者具有一个或多个高风险特征，而基于事件的方案治疗与较短的无进展生存期相关。AMPLIFY研究尽管入组了健康状况良好但不具代表性的患者群体，排除了具有这些风险因素的患者，但依然证实了这些较短的无进展生存期终点，显示出与持久缓解不相关的低MRD率，并带来了安全性挑战。鉴于当前固定疗程方案的挑战以及BRUKINSA同类最佳的特性，我们看到BRUKINSA单药疗法有更多机会继续从这些治疗方案中夺取份额。除了扩大BTK单药疗法外，我们相信我们有机会通过[indiscernible]和我们的BTK降解剂实施特许经营领导战略，这有潜力远超其他现有治疗方案，满足所有CLL患者的需求，无论其风险特征如何。说到这里，现在交给你，Lai。

Matt Shaulis

Thanks, John. Moving to BRUKINSA’s U.S. performance. BRUKINSA's commercial adoption has been remarkable and consistent with what you would expect to see with a clearly differentiated and best-in-class medicine. Within the BTK market, we continue to strengthen BRUKINSA's position as the BTK of choice, as demonstrated by its leadership in both frontline and relapsed/refractory CLL new patient starts. Overall CLL new patient share has grown to over 50%, and our strength and leadership extends beyond CLL. Our new patient share is even higher across our other approved indications. New patient shares leading indicator of value share, and we see the leadership in CLL and our other approved indications playing out on this slide. In Q4, we had $616 million of US sales, representing 97% growth compared to the prior year. This solid performance capped off a strong 2024, where we had $1.95 billion of revenue, representing growth of 106% versus 2023. We surpassed Calquence in US revenue in Q4, and we are close to overtaking IMBRUVICA, remarkably less than two years from BRUKINSA CLL approval. This is a testament to BRUKINSA's differentiated profile and our strong clinical development, medical and commercial execution. The CLL landscape remains competitive, but we are in an excellent position as we enter 2025. The overall global B-cell malignancy market opportunity and our approved indications is large and grown, totaling approximately $21 billion in 2024. The U.S. represents a significant portion of the global market, and CLL is over 50% of the market in the U.S. and similarly growing robustly. In terms of patient volumes, the BTK class represents about 50% of U.S. CLL patients. And as we've mentioned, BRUKINSA is the BTK leader in new patient starts in CLL. Given its differentiated profile, we believe BRUKINSA can further expand its lead in the BTK class. As we think about BRUKINSA as a continuous treatment, it's important to consider the stacking effect of patients that remain on therapy. In 2024, about one-third of BRUKINSA U.S. revenue came from new patients, and two-thirds came from patients that were already on therapy as we started 2024, which means we have several years of revenue growth from our increasing new patient share levels. As you can see on the chart, the remainder of patient volume beyond BTK is split between fixed duration regimens, BCL2 venetoclax, and chemo. Currently approved event-based fixed duration regimens are not for all patients, and over half of newly diagnosed patients have one or more high-risk features were event-based regimen treatment is associated with shorter PFS. AMPLIFY despite enrolling a fit non-representative patient population that excluded patients with these risk factors, nonetheless, confirm these shorter PFS endpoints, demonstrated low MRD rates that do not correlate durable remission and brought along safety challenges. Given the challenges with current fixed duration regimens and BRUKINSA's best-in-class profile, we see additional opportunity for BRUKINSA monotherapy to continue to take share from these treatment options. And beyond expansion of BTK monotherapy, we believe we have the opportunity for a franchise leadership strategy with [indiscernible] and our BTK Degrader that has the potential to far surpass the other existing treatment options and fulfill the needs of all patients with CLL regardless of risk profile. On that note, now over to you, Lai.

Lai Wang

谢谢Matt，我想花几分钟时间重点介绍一下我们投资组合的其他部分。回顾2022年，百济神州的增长主要由泽布替尼和替雷利珠单抗驱动。过去三年间，我们的产品组合经历了重大转型。在血液肿瘤领域，我们现在拥有三大基石资产，每项都具有数十亿美元的市场潜力。实体瘤产品组合已从广泛的免疫肿瘤学和泛肿瘤策略转向疾病聚焦的方法。我们的研发管线针对肺癌、乳腺癌和胃肠道癌症，专注于关键信号通路和靶点驱动的疗法，并得到多种技术平台的支持。我们的研发生产力非常出色，使我们区别于行业内的其他公司。仅在2024年，我们就将13个新分子实体推进到临床阶段，这超过了我们所有同行，甚至超过了行业内最大的制药公司，这些资产是肿瘤学领域最令人兴奋的一些项目。除了加强我们的药物发现能力外，我们还组建了一支内部全球临床开发团队，在37个国家设有临床研究中心，优化临床流程以实现卓越执行。我们的快速概念验证策略持续超越行业基准。例如，我们的CDK4抑制剂试验平均每个剂量水平仅需6.4周，并在14个月内入组了超过180名患者，这一显著成就在所有早期项目中都有体现。此外，我们也在提高后期试验效率。就在最近，我们完成了CELESTIAL-TNCLL研究的3期入组，在短短14个月内在20个国家、200多个研究中心招募了近700名患者。值得注意的是，这两项研究中超过75%的患者来自美国、欧洲、拉丁美洲、澳大利亚和日本。我们的速度和成本优势使我们能够推进行业内最有前景的研发管线之一。这张幻灯片重点介绍了一些科学上令人兴奋的项目，其中许多我们相信在重要市场中具有同类最佳或同类首创的潜力。我将在接下来的幻灯片中更详细地介绍这些资产。尽管CDK4/6抑制剂取得了成功，但其剂量限制性毒性凸显了未满足的宏观需求，CDK4特异性抑制剂可以避免CDK6相关的毒性。BGB-43395有潜力成为同类最佳的CDK4抑制剂，因为与[听不清]相比，它具有更优越的选择性和效力。我们观察到较低的血液学毒性，这与其更好的选择性一致，并且可能通过更高剂量实现更好的靶点抑制。如图所示，BGB-43395在剂量水平8实现了80%的TK1抑制，与替雷利珠单抗在RP2D时相似，而在剂量水平B-433955进一步将TK1抑制提高到95%。概念验证数据预计在今年上半年公布。KRAS突变存在于近五分之一的癌症患者中。与Revolution Medicine的RMC-6236等泛RAF抑制剂不同，泛KRAS抑制剂可能通过不抑制正常组织中的RAS通路而提供更好的治疗窗口。该分子于2024年11月开始临床试验。B7H4在多种实体瘤中表达，包括乳腺癌、卵巢癌和子宫内膜癌。超过70名患者已在七个剂量水平入组，在多种肿瘤类型和多个剂量水平显示出疗效。我们相信我们在这里有同类首创的机会。EGFR CDAC是一种同类首创的降解剂，具有更广泛的EGFR突变覆盖范围且不伤害野生型EGFR，在奥希替尼敏感和耐药的临床前模型中均显示出强大的疗效。它于2024年12月进入PINNACLE试验。需求路径相当直接，旨在作为第三代EGFR TKI的附加疗法，用于一线辅助和局部晚期非小细胞肺癌。MTAP缺失发生在七分之一的癌症患者中，PRMT5和MAT2A抑制剂都能在MTAP缺失的肿瘤中杀死细胞，并在临床前模型中显示出强大的协同作用。百济神州是唯一一家同时拥有这两种临床阶段资产的公司。我们的PRMT5抑制剂因其效力、选择性和脑渗透性而脱颖而出，我们的MAT2A抑制剂也能渗透到大脑中，并在临床前模型中显示出卓越的效力。[听不清]于2025年下半年开始了这两种分子的联合研究。IRAK4对于TLR和白细胞介素1受体通路至关重要。赛诺菲的KT-474在血液中实现了接近完全的IRAK4降解，但在皮肤中只有50%到70%。我们开发了BGB-45035以在靶组织中完全降解IRAK4并避免心血管风险，45035在血液中实现了完全的IRAK4降解。1期试验于2025年底开始，组织降解数据预计今年公布。最后，我想重点介绍我们关键研发管线的几个价值拐点。我们的后期血液肿瘤资产在2025年有几个重要里程碑，包括可能支持加速批准申请的2期试验结果，以及泽布替尼和我们的BTK降解剂的3期关键试验启动，包括计划中的头对头对比试验。转向我们的早期研发管线。正如您所听到的，我们预计早期研发管线在多种模式和治疗领域将有多个概念验证催化剂。我们期待在未来的更新中分享更多数据。说到这里，我想请Aaron来回顾一下财务情况。

Lai Wang

Thanks Matt, I would like to take a few minutes to highlight the rest of our portfolio. Back to 2022, BeiGene's growth was primarily driven by zanubrutinib and tislelizumab. Over the past three years, portfolio has ongoing significant transformation. For hematology, we now have three cornerstone assets, each with multibillion-dollar market potential. The solid tumor portfolio has transitioned from a broad immuno-oncology and pan-tumor strategy to a disease-focused approach. The pipeline targets lung, breast, and gastrointestinal cancers, focusing on critical segment pathways and TA-driven therapies supported by various technology platforms. Our R&D productivity has been remarkable and sets us apart from others in the industry. In 2024 alone, we put 13 new entities into the clinic, which is more than any of our peers above even the largest of pharma companies in the industry, and these assets are some of the most exciting ones in all of oncology. In addition to strengthening our drug discovery capability, we have assembled an internal global clinical development team with CIs in 37 countries, optimizing clinical process for superior execution. Our fast POC strategy consistently surpasses industry benchmarks. For instance, our CDK4 inhibitor trials achieved an average of just 6.4 weeks per dose level and they enrolled over 180 patients within 14 months, a remarkable feat mirrored across all early programs. In addition, we're enhancing late-stage trial efficiency as well. Recent today, we completed Phase 3 enrollment of the CELESTIAL-TNCLL study recording nearly 700 patients across 20 countries and 200-plus sites in just 14 months. It is worth noting that over 75% of our patients in these two studies were enrolled from United States, Europe, Latin America, Australia and Japan. Our speed and cost advantage have allowed us to advance one of the most promising pipelines in the industry. This slide highlights some of our scientifically exciting programs, many of which we believe have the best-in-class or first-in-class potential in significant markets. I will take you through each of these assets in a little bit more details in the following slides. Despite the success of CDK4/6 inhibitor, that dose-limiting toxicities highlight unmet macro need, a CDK4 specific inhibitor can border CDK6 related toxicities. BGB-43395 has the potential to be the best-in-class CDK4 inhibitor, due to its superior selectivity and potency compared to [indiscernible]. We are observing lower hematological toxicities aligned with its better selectivity and it might be dose higher to achieve better target inhibition, as shown in the graph, BGB-43395 achieved 80% TK1 inhibition at dose level 8, similar to a tislelizumab at RP2D and at dose level B-433955 further improved the TK1 inhibition to 95%. The proof concept data is expected in the first half of this year. KRAS mutations are funding almost one out of five cancer patients. Unlike pan-RAF inhibitors such as RMC-6236 from Revolution medicine, pan-KRAS inhibitors, spell, H-RAS and RAS possibly offering a better therapeutic window by not inhibiting the RAS pathway in normal tissues. This molecule began clinical trials in November 2024. B7H4 is expressed in several solid tumors, including breast, ovarian and endometrial cancers. Over 70 patients have enrolled across seven dose levels showing responses in various tumor types and at multiple dose levels. We believe we have a first-in-class opportunity here. EGFR CDAC, a first-in-class degraded with broader EGFR mutation coverage and sparing wide-type EGFR showed a strong efficacy in both osimertinib-sensitive and the resistant preclinical models. It entered the PINNACLE trial in December 2024. The demand pathway is quite straightforward, intent as add-on to the third-generation EGFR TKI for frontline adjuvant and locally advanced non-small cell lung cancer. MTAP deletions occurs in one of seven cancer patients, both PRMT5 and the MAT2A inhibitors called cells in MTAP-deleted tumors and show strong synergy in preclinical models. BeiGene is the only company with clinical stage assets for both. Our PRMT5 inhibitors stands out for its potency, selectivity and the brain penetration and our maturing inhibitor also penetrates the brain and demonstrates superior potency in preclinical models. [indiscernible] began the combination study of this two molecule in the second half of 2025. IRAK4 is essential for TLR and the interloping 1 receptor pathway. Sanofi KT-474 should near complete IRAK4 degradation in blood, but only 50% to 70% in skin. We developed BGB-45035 to fully degrade IRAK4 in target tissues and avoid cardiovascular risks and 45035 achieved a complete IRAK4 degradation blood. Phase I starts in late 2025, with tissue degradation data expected this year. And finally, I wanted to highlight a few of our key pipeline value inflection points. Our late-stage hematology assets have several significant milestones in 2025 including Phase 2 trial readouts that may support accelerated approval submissions as well as the initiation of Phase 3 pivotal trials for both zanu and our BTK degrader including the planned head-to-head versus product. Turning to our early stage pipeline. As you have heard, we have a number of proof-of-concept catalysts expected for our early-stage pipeline across multiple modalities and therapeutic areas. We look forward to sharing more data in future updates. With that, I'd like to pass it over to Aaron to review the financials.

Aaron Rosenberg

谢谢，Lai。2024年是增长的关键一年，也是对我们可持续发展道路的肯定。我们实现了强劲的营收增长，全年总销售额达到38亿美元，而2023年为25亿美元。与去年相比，营收增长了55%，其中产品收入增长了73%，所有关键产品和市场均呈现增长态势，这使我们在进入2025年时处于有利地位。聚焦第四季度业绩，本季度总收入为11亿美元，第四季度产品收入较去年同期增长77%。与近期趋势一致，我们的收入基础正在扩大。美国占本季度总收入的55%，欧洲贡献了另外10%。BRUKINSA在第四季度的销售额达到8.28亿美元，较2023年第四季度增长100%。在美国，BRUKINSA的增长得益于需求驱动，因为我们在新患者共享的CLL以及其他已批准的B细胞恶性肿瘤领域不断扩大领导地位，BRUKINSA在BTK抑制剂类别中仍拥有最广泛的适应症标签。请注意，该类别在美国确实存在季节性，第四季度和第二季度是季节性销售高峰期。此外，美国2024年第四季度的销售也受到客户订单时间安排的影响，约带来3000万美元的正面影响。在欧洲，BRUKINSA在第四季度继续保持增长轨迹，全年业务几乎翻了三倍。我们在欧洲的市场份额持续增长，与美国相比，我们在欧洲的产品上市周期更早。BRUKINSA在中国仍是领先的BTK抑制剂。正如我们之前强调的，我们在巴西和日本等具有巨大机会的关键全球其他市场仍处于上市早期阶段。我们期待继续执行计划，将BRUKINSA带给这些市场的患者。TEVIMBRA收入为1.54亿美元，较2023年第四季度增长20%。我们仍是中国市场的领导者，在该类别中拥有最广泛的NRDL标签覆盖范围。TEVIMBRA在其他市场的商业化工作正在进行中，包括近期获得监管批准的美国和欧洲市场。我们正以有针对性的方式在这些市场推出产品，并期待在2025年期间分享最新进展。安进授权产品也是业绩的重要贡献者，第四季度收入为1.01亿美元，较2023年第四季度增长98%。接下来看我们的运营损益表，我的评论将基于GAAP基础。第四季度产品毛利率为85.6%，较去年上升2.4个百分点，主要得益于BRUKINSA和TEVIMBRA的有利产品组合和销售成本效率提升。运营费用总计10亿美元，其中包括与12月宣布的MAT2A抑制剂授权相关的6000万美元研发费用。运营费用的增长支持了为近期和长期收入增长提供能力建设，并快速推进我们强大且差异化的创新管线。我们强劲的收入增长和以价值为中心的投资理念带来了显著的运营杠杆效应，第四季度产品收入增长速度比费用增长快5倍以上。这导致2024年第四季度GAAP和非GAAP运营业绩较去年同期显著改善，并实现了全年非GAAP盈亏平衡。第四季度调整后运营收入为7900万美元，实现了连续第三个季度的非GAAP运营收入。如前所述，这些结果包含了MAT2A抑制剂授权的6000万美元费用。我们对运营杠杆的关注已转化为连续第二个季度的正向运营现金流产生，从而改善了全年现金利用情况。这些是公司向自我维持型企业转型的关键指标。现在转向资本配置，我们遵循审慎的投资理念，以支持增长和可持续性的双重使命。核心是我们保守的财务政策，作为平衡我们作为领先的高增长创新生物制药公司所固有的风险承担。在我们行业中拥有强大的资产负债表是一种竞争优势，我们致力于继续优先保持其强度。我们在2024年底拥有26亿美元现金，处于极佳地位，同时朝着持续现金流产生迈进。我们将继续投资于差异化的商业资产和地域，以实现盈利增长，并将我们的创新药物带给更多患者。同时，我们将通过其在时间和成本方面的独特差异化优势，特别是通过概念验证，为我们的创新引擎提供动力。创造价值的业务发展在我们的战略中扮演重要角色，通过提供获取最佳外部科学的机会，特别是那些补充我们内部产品组合的资产。与以往合作一致，我们将积极探索能够加强我们业务的合作伙伴关系。现在转向我们的2025年指引，该指引基于1月底的汇率，且不考虑潜在的新业务发展活动。鉴于BRUKINSA的领导地位，我们预计收入将迎来又一个强劲增长年。我们预计美国将继续获得新患者份额，并受益于2024年新患者启动的同比基数效应。我们假设2025年BRUKINSA在美国的净定价相对稳定。这得益于我们被指定为小型制造商，该指定将医疗保险D部分福利重新设计带来的制造商责任增加分摊到五年期内。增长也预计来自欧洲和其他重要全球其他市场的持续全球扩张。我们预计收入将在49亿美元至53亿美元之间。在此水平上，外汇汇率预计全年带来约1%的逆风。在您的模型中考虑季度分布时，请注意我之前提到的季节性模式和客户订单时间安排。我们的GAAP毛利率百分比预计将在80%中段范围，并预计将继续受益于与2024年全年相比改善的产品组合和生产效率。该指引考虑了我们对当前形式的理解中，美国新进口关税的潜在影响。鉴于我们的利润率结构和BRUKINSA在美国进行的生产程度，这些关税带来的增量成本预计对我们来说是适度的。这未考虑未宣布的额外措施，这些措施可能会改变这一展望。GAAP基础上的运营费用预计在41亿美元至44亿美元之间。我们的投资支持商业和研发的关键增长，其速度继续带来有意义的运营杠杆。这体现在费用占销售额比例的显著降低上。非GAAP运营费用预计将与我们GAAP指引保持一致，调整项目与现有做法保持不变。最后，我们确认之前的承诺，即在2025年实现全年GAAP运营盈亏平衡，并在全年产生正向运营现金流。在此，我将把电话交还给Dan。

Aaron Rosenberg

Thanks, Lai. 2024 was a pivotal year of growth and an affirmation of our path to sustainability. We generated strong top line revenue growth with total sales of $3.8 billion for the year as compared to $2.5 billion in 2023. As revenue grew by 55% as compared to last year, with product revenues increasing by 73%, growth was seen across all key products and markets, which puts us in a position of strength as we enter 2025. Focusing on our fourth quarter results. Total revenue for the quarter was $1.1 billion with Q4 2021 product revenue growth of 77% compared to Q4 of last year. And consistent with recent trends, we see a broadening of our revenue base. The United States represented 55% of total revenues in the quarter, with Europe contributing another 10%. Sales of BRUKINSA totaled $828 million in Q4, representing 100% growth as compared to Q4 2023. In the United States, BRUKINSA growth was driven by demand given our expanding leadership in new patient shared CLL as well as other approved B-cell malignancies where BRUKINSA continues to have the broadest label in the BTK inhibitor class. Please note that this class does experience seasonality in the U.S. with Q4 and Q2 being quarters of seasonally high sales. In addition, the United States 2024 Q4 sales were also positively impacted by the timing of customer orders of approximately $30 million. In Europe, BRUKINSA continued its growth trajectory in Q4, culminating a full year where the business nearly tripled. We continue to grow share in Europe, where we are earlier in the product launch cycle as compared to the United States. BRUKINSA remains the leading BTKI in China. And as we've highlighted before, we are in the early stages of launch in key rest of world markets with large opportunities such as Brazil and Japan. We look forward to continuing to execute our plans to bring BRUKINSA to patients in these markets. TEVIMBRA revenue of $154 million resulted in 20% growth as compared to Q4 of 2023. We remain the market leader in China with the broadest NRDL label coverage in the class. Commercialization efforts for TEVIMBRA are ongoing in other markets, including the U.S. and Europe following recent regulatory approvals. We are launching in these markets in a targeted fashion and look forward to sharing updates over the course of 2025. Amgen in-license products were also strong key contributors to performance with $101 million of revenue in Q4, representing growth of 98% as compared to Q4 of 2023. Walking through our operating P&L and my comments will be on a GAAP basis. Product gross margin was 85.6% for Q4, an increase of 2.4 percentage points versus last year, largely due to favorable mix and cost of sales productivity for BRUKINSA and TEVIMBRA. Operating expenses totaled $1 billion and included $60 million in research and development expense associated with the in-license of our MAT2A inhibitor announced in December. The growth in OpEx supported capability built to deliver near and long-term revenue growth and to rapidly advance our robust and differentiated innovative pipeline. Our strong revenue growth and value-focused investment philosophy has resulted in significant operating leverage with product revenue growing more than 5x faster than expenses in the fourth quarter. This resulted in meaningful improvement in GAAP and non-GAAP operating results for Q4 2024, compared to Q4 of the prior year, and achievement of full year non-GAAP breakeven. Q4 delivered $79 million in adjusted income from operations, achieving our third consecutive quarter of non-GAAP operating income. And as mentioned, these results included the $60 million expense from the in-license of our MAT2A inhibit. And our focus on operating leverage has translated into a second consecutive quarter of positive operating cash flow generation, resulting in improved cash utilization on a full year basis. These are key metrics for the company as we transition to a self-sustaining enterprise. Now, turning capital allocation, where we follow a disciplined investment philosophy to support our dual mandate of both growth and sustainability. At the center, our conservative financial policies that serve as a balance to the inherent risk taking associated with being a leading high-growth innovative biopharmaceutical company. Having a strong balance sheet in our industry is a competitive advantage, and we are committed to continuing to prioritize its strength. And we are in an excellent position as we close 2024 with $2.6 billion in cash, while advancing towards sustained cash flow generation. We will continue to invest in our differentiated commercial assets and geographies to deliver profitable growth and bring our innovative medicines to more patients. At the same time, we will fuel our innovation engine with its unique and differentiated advantages in both time and cost, particularly through proof of concept. Value-creating business development plays an important role in our strategy by providing access to the best external science, particularly for assets that complement our internal portfolio. And consistent with previous collaborations, we will actively explore partnerships that strengthen our business. Now, turning to our 2025 guidance, which assumes late January exchange rates and no potential new business development activities. We expect another strong year of revenue growth given our leadership for BRUKINSA. We anticipate that the US will continue to gain new patient share and also benefit from year-over-year lapping of 2024 new patient starts. And we assume relatively stable net pricing for BRUKINSA in the US in 2025. This is supported by our specified small manufacturer designation which layers in the increases in manufacturer liabilities for Medicare Part D benefit redesign over a five-year period. Growth is also anticipated from continued global expansion in both Europe and other important rest of world markets. We project revenue to be between $4.9 billion to $5.3 billion. At these levels, foreign exchange represents an approximate 1% headwind for the year. And as you consider quarterly phasing in your models, please note the seasonal patterns and customer order timing that I previously mentioned. Our GAAP gross margin percentage is assumed to be in the mid-80% range, and it is anticipated to continue to benefit from improved mix and production efficiencies as compared to full year 2024. This guidance contemplates the potential impact in our understanding of current form from new U.S. tariffs on imports. Incremental costs from these tariffs are anticipated to be modest for us given our margin structure and the degree of manufacturing for BRUKINSA that is conducted in the United States. This does not contemplate unannounced additional measures, which may change this outlook. Operating expenses on a GAAP basis are forecast to be between $4.1 billion and $4.4 billion. Our investments support key growth in both commercial and research at a pace that continues to deliver meaningful operating leverage. This is demonstrated by significant reductions in expenses as a percentage of sales. Non-GAAP operating expenses are expected to track with our GAAP guidance with reconciling items remaining unchanged from existing practice. And finally, we are affirming our prior commitments to achieve full year GAAP operating breakeven in 2025 and generate positive cash flow from operations for the year. And with that, I will turn the call back to Dan.

Dan Maller

谢谢，Aaron。我们现在准备进入问答环节。我恳请各位参与者将问题限制在一个，以确保我们有时间听取尽可能多的与会者提问。接线员，我们准备好回答第一个问题了。

Operator

[接线员指示] 我们的第一个问题来自Jefferies的Kelly Shi。请取消静音并提问。

Kelly Shi

祝贺百济神州团队取得的令人印象深刻的进展，感谢回答我们的问题。对于2025年，全年收入指引为49亿至53亿美元。能否请您详细说明这一初步指引的关键假设？哪些关键因素将决定最终数字落在指引区间的哪个位置？另外，我想快速确认一下，现在B7-H4 ADC和CDK抑制剂的数据披露时间已提前到今年上半年，请确认这一点。非常感谢。

Aaron Rosenberg

谢谢Kelly，我是Aaron。我先回答您问题的第一部分，然后交给Lai。关于我们25%的收入指引，考虑到BRUKINSA的领导地位，我们预计收入将迎来又一个强劲增长年。我们预计在美国市场将继续获得份额。正如我在准备好的发言中所说，我们还将受益于2024年新患者启动的同比基数效应。这一增长是在美国净定价环境相对稳定的背景下实现的。我们预计全球扩张将继续带来强劲增长。我提到过，2024年在欧洲市场我们几乎实现了三倍增长。我们在其他重要的全球市场还处于早期阶段。例如，我们将在今年第一季度首次在日本上市，这对BRUKINSA来说是一个重要市场。我们不提供季度指引，但我确实提供了关于BTKi类药物季节性模式的评论，第二季度和第四季度通常是最强劲的，但总体而言，在经历了非常强劲的2024年之后，我们对进入新的一年充满信心。说到这里，也许我可以交给Lai。

Lai Wang

谢谢Kelly的提问。我们计划在ASCO上首次披露ADC和CDK2的数据。这将在今年上半年完成。

Kelly Shi

非常感谢。

Operator

我们的下一个问题来自摩根士丹利的Sean Laaman。请取消静音并提问。

Sean Laaman

大家早上好。抱歉，应该是大家下午好。感谢各位的演示。希望大家都安好。我的问题也与业绩指引相关。那么，在市场份额方面，你们现在已超越Calquence。你们的增长速度远快于他们，但他们仍在增长——仍在持续增长。过去几个季度，他们的增长节奏似乎略有放缓。我想在业绩指引的背景下了解，你们从临床医生那里获得的关于该药物长期可行性的反馈是怎样的？或许时间跨度更长一些，但对于潜在的双联疗法获批可能产生的影响，你们有何看法？

Matt Shaulis

是的。当然。很高兴回答这个问题。确实，当我们审视整体增长时，我们看到与2023年第四季度相比，我们的增长非常强劲。同时，2024年与2023年相比，我们的全年增长也非常强劲。关于Calquence的问题，我们看到在该特定时间段内，他们的增长率明显较弱。John，你能否就此补充一些看法？

John Oyler

是的。关于双药疗法，我认为，我们已经在此次电话会议中分享了很多数据。固定疗程治疗所需的条件在该研究中看起来并不十分出色。从研究设计来看，这是一项成功的研究——它在超健康人群中超越了化疗，这类人群可能代表了真实世界场景中较健康的四分之一患者，并且能够在36个月时在无进展生存期上优于化疗。这就是该研究显示的结果。正如我们在之前的幻灯片中展示的，微小残留病阴性率在统计学上更差，远低于以往任何现有数据，尽管研究对象是这种超健康、高度筛选的人群。安全性数据也不如预期。再看无进展生存期数据，同样，与现有数据相比并不占优。它不如现有数据，当然更不如连续BRUKINSA疗法。因此，从这个角度来看，这是一项达到了不相关主要终点的研究。我相信他们会尽可能地进行营销，并努力推动其商业销售——他们拥有非常强大且成功的营销组织。但我认为，最终数据本身已经非常清楚地说明了一切。当人们使用这种联合疗法时，他们的体验极有可能与这些数据一致。所以，我认为这与我们审视单药疗法时的情况类似——关于阿卡替尼的故事一直很精彩，但当我们审视单药疗法，当人们实际使用这些药物，随着数据成熟且使用越来越多，对我们来说就非常清楚了。在疗效方面，我们坚信我们在此阐述的观点：泽布替尼是一种卓越的药物，已在头对头试验中证明比伊布替尼更有效，即Z大于I。而伊布替尼曾针对A进行过研究，但在那项研究中未能显示优越性，风险比为1。此外，他们的里程碑无进展生存率比先前显示的数据差8%。综上所述，我们不认为这是一个重大的...

John Oyler

Yes. In terms of the doublet, I think, look, we've shared a lot of data earlier in this call. The things you need for a fixed duration treatment are things that don't look very impressive in that study. And it is a successful study in terms of beating in an ultra-fit population that represents maybe the healthier quarter of patients in the real-world scenario and it's able to beat chemo on PFS at 36 months. That's what that study shows. The MRD negativity is statistically worse, as we showed earlier in the slides and much lower than any present data that's ever existed before despite being in this ultra fit, highly selected population. The safety data is not what you'd hope to see. And then you look at the PFS data straight out, again, it doesn't compare favorably to present data. It doesn't compare favorably to the and it certainly doesn't compare favorably to a continuous BRUKINSA therapy. So, I think from that perspective, look, it's a study which has met a primary endpoint that is not relevant. And I'm sure that they will market as much as they can about it and try to do their best to drive their commercial sales that are very powerful and successful marketing organization. But I think, ultimately, the data speaks for itself very clearly. And when people use that combination, their experience is highly likely to be in line with that data. So, I think this is more of the same as we looked at monotherapy, the story has been great around acala, but as we look at monotherapy and as people actually are using the medicines and as the data matures and they use it more and more, it's very clear to us. On the efficacy story we have a strong belief that we've laid out here, Zanub is a spectacular medicine that's proven in a head-to-head trial that it's more efficacious than I, so Z is greater than I. And I has run a study against A. But in that study, they failed to show superiority. They have a hazard ratio of one. And again, there milestone BFS is 8% worse and the data that's previously shown. So with that said, we don't view this as a major.

LaiWang

约翰，如果我可以就我们听到的医生反馈补充一些背景说明，这与问题的这一部分相关。我认为，我们持续听到关于维奈托克的安全性和处理担忧，以及AV疗法（如果考虑三联疗法，还包括AVO疗法）患者管理的复杂性和负担性质。然后，当你查看将阿卡替尼加入AVO的数据时，结果在安全性方面并未显示出整体有利的特征。因此，我认为我们需要做的一件事，并且我们将继续听取医生的意见，就是关注该双药疗法的最终标签说明。这将是在所有其他因素的背景下进行的。

Sean Laaman

很好。谢谢。非常全面。我将回到队列中。非常感谢。

Operator

下一个问题来自Leerink Partners的Andrew Berens。请取消静音并提出您的问题。

Andrew Berens

您好。谢谢。祝贺你们在第一张幻灯片财报发布中取得的出色成绩。这是zanidutamab和tislelizumab在胃癌领域的重要数据读出。我想了解你们对ARM C[ph]的期望，这对产品线意味着什么？另外，公司对Jazz已开展的乳腺癌项目有何承诺？基于John关于squeeze a的评论，我知道你们目前尚未推广固定疗程的BRUKINSA，但你们是否看到或预期会看到BRUKINSA在固定疗程方案中的超适应症使用？在多项数据公布前，是否有机会获得认可？谢谢。

Aaron Rosenberg

非常感谢您的问题。我将回答关于zanidutamab问题的第一部分，然后请我的同事Matt回答第二部分。关于zanidutamab，正如您所指出的，这是设计的第三个治疗组，即tislelizumab加zanidutamab联合化疗方案。我们相信这将进一步扩大tislelizumab在一线胃癌中的适应症范围。目前，tislelizumab的标签是针对HER2阳性患者群体。如果这项试验成功，将进一步扩大适应症标签。如您所知，这项试验的数据读出将在2025年下半年进行。需要指出的是，这是事件驱动型试验，完全基于事件发生情况。关于乳腺癌方面的问题，我们正在与合作伙伴讨论zanidutamab在乳腺癌产品线中的开发。

Matt Shaulis

好的。接下来我可以谈谈BRUKINSA的自发性使用情况。考虑到我们BTK抑制剂的最佳疗效特征，我完全理解这个问题的性质。但同样重要的是要记住，目前我们在美国尚未获批BTK联合疗法。此外，当我们查看NCCN指南和药典时，BRUKINSA在该适应症中尚未被列入。另一方面，我们最近确实获得了BOVIN研究的数据。虽然那是MRD指导而非纯粹的固定疗程方案，但这肯定对未来意味着什么有所启示。

Andrew Berens

谢谢。

Operator

下一个问题来自JPMorgan的Jessica Fye。请取消静音并提出您的问题。

Jessica Fye

很好。早上好，祝贺强劲的业绩指引。关于即将公布的pirto数据读出，包括一线CLL数据以及针对IMBRUVICA生成的数据，你们如何看待？你们将关注哪些方面？BRUKINSA的交叉试验比较应该是什么，即投资者是否应该将这些其他试验的数据与你们的试验进行对比？为什么应该或为什么不应该？我知道你们正在推进降解剂与pirto的头对头研究，但考虑到潜在的近期竞争动态？谢谢。

Aaron Rosenberg

是的。非常感谢您的问题。Pirto确实有两项针对初治CLL的3期试验正在进行中，虽然第二项试验是混合人群，但我想您指的是313研究，这项研究将pirto与化学免疫疗法进行比较。我想强调的是，化学免疫疗法已不再是初治CLL的标准治疗方案。这项研究的结果公布并不一定意味着会改变临床实践。这项研究与[indiscernible]类似，是针对另一种标准疗法的研究。第二项研究的设计很有意思。这是一个混合人群研究，其中最多30%的患者是初治CLL患者，而其他患者则是复发难治性CLL患者。我想指出的是，这项研究实际上以ORR为主要终点，采用[Indiscernible]研究设计。即使这项研究获得阳性结果，我们也不认为这会改变临床实践。此外，这里的竞争对手是伊布替尼，而不是同类最佳的BTK抑制剂泽布替尼。因此，我们热切期待这些数据的公布。我们认为，pirto要在初治领域占据显著份额，需要与真正的标准疗法进行比较，并且需要更长时间的随访数据。因此，我们不相信短期内这会改变BTK抑制剂在初治领域的应用格局。Pirto可能更定位于患者完成共价BTK抑制剂治疗后的BTK抑制剂选择。我们对我们的BTK降解剂感到非常兴奋。根据我们在ASH上报告的数据，我们相信这种分子相比pirto展现出更好的安全性和疗效。这就是为什么我们要推进与pirto的头对头试验。我们期待启动这项试验，以及它为患者提供更好的治疗选择的潜力，特别是在完成共价BTK抑制剂治疗后。

Jessica Fye

好的。谢谢。

Operator

我们的下一个问题来自花旗集团的Yigal Nochomovitz。请取消静音并提出您的问题。谢谢。

Yigal Nochomovitz

关于强劲的季度业绩。希望您能听到我的声音。我有一个关于BRUKINSA专利和解评论的问题。首先，这是否符合您对2037年的预期？但更重要的是，假设您获得zanro联合疗法的数据并获得批准，是否有任何方式可以通过开发固定剂量口服联合制剂来保护您免受仿制药的冲击？您是否正在推进这一策略？谢谢。

Aaron Rosenberg

感谢您的提问，Yigal。我们确实已公开披露了关于BRUKINSA专利保护的情况。正如您所说，2037年是我们讨论的起点。就我们更广泛的产品组合而言，当我们考虑资产组合时，我们确实在寻求覆盖患者治疗旅程的所有维度，这是一个具有长期生命力的产品组合。除了BRUKINSA之外，我们其他仍处于开发阶段的资产显然拥有远超该时间点的专利保护。因此，我们认为这是一个持久、可持续的产品组合。最重要的是，它将满足市场上重大的未满足需求，为所有CLL患者提供医生认可的最佳治疗方案。感谢您的提问。

Yigal Nochomovitz

好的。好的。谢谢。

Operator

我们的下一个问题来自Citizens JMP的Reni Benjamin。请取消静音并提出您的问题。

Reni Benjamin

祝贺你们——2024年表现很棒。你们能听到我说话吗？

John Oyler

是的。

Reni Benjamin

哦，好的。谢谢。祝贺你们2024年的出色表现以及更加令人惊叹的2025年指引。我的问题是关于CELESTIAL研究完成入组的情况。能否谈谈您对未来事件发生率的看法？我们何时可以期待获得顶线数据以及潜在的NDA提交？谢谢。

John Oyler

是的。非常感谢您的提问。我们对这项研究能够在短短约14个月内完成入组感到非常兴奋。这再次证明了我们执行临床试验的能力。关于事件方面，我们并未提供指引，因为这项研究是以事件驱动的PFS为终点。我们和您一样热切期待研究结果。但由于对照组是VO，所以需要一些时间才能获得结果。

Reni Benjamin

谢谢。

Operator

我们的下一个问题来自Goldman Sachs & Co.的Ziyi Chen。请取消静音并提出您的问题。

Ziyi Chen

非常感谢您回答我的问题。2024年第四季度业绩非常出色。我的问题主要关于venetoclax，因为在一线CLL治疗中，您如何看待患者的潜在偏好？他们会更倾向于固定疗程治疗，还是会继续选择BTK单药疗法？我之所以这样问，是因为Matt展示的幻灯片显示，在BTK抑制剂处方约十年后，一线治疗中我们仍然看到只有约50%的患者实际使用BTKI，而另外50%的患者则采用其他治疗。因此我想知道，当固定疗程疗法进入市场时，患者和医生的偏好会如何？此外，考虑到固定疗程治疗肯定会比BRUKINSA本身的治疗时间更短，这对整个产品线的销售可能产生什么潜在影响？所以我在思考——当固定疗程疗法进入市场时，您如何看待对整个产品线的总体影响？或者您是否认为，我们可能会从固定疗程开始，然后患者会转回BRUKINSA进行长期维持治疗？谢谢。

John Oyler

感谢这个很好的问题。首先，我认为固定疗程意味着很多事情，化疗是固定疗程。我认为你有维奈托克组合疗法。然后我认为你有BI，它在美国未获批准，还有AAV，我们有一项研究将寻求批准，我们会看看结果如何。我认为我们向您展示的是，当你实际比较这些数据与持续使用BRUKINSA时，BRUKINSA对大多数患者来说看起来是更好的选择。我认为固定疗程也不应与间歇治疗混淆，这项研究中讨论的实际上是高度选择的超健康人群，只适用于约四分之一的患者，不包括预后较差的17p缺失患者，也不包括老年患者或健康状况较差的患者。在那个群体中，你仍然看到近四分之一的患者在三年内进展。记住，他们接受了14个月的治疗，对吧？那只有20个月没有治疗，就有四分之一的患者进展了。如果你看那条曲线的形状，你可以回头看看36个月后的情况。再次强调，这是高度选择性的，这已经是可能达到的最好结果了。真实世界的经验将是健康状况差得多的患者，结果也会差得多。你只需将其与持续治疗相比，就显得不够理想。所以我认为，如果你看这个门槛，你实际上是在VO（维奈托克+奥比妥珠单抗）之间做选择，VO有巨大的毒性负担，对患者是巨大负担。即使是这个VI（维奈托克+伊布替尼），当你实际看患者的治疗历程时，它并不更好，可能比化疗的负担更重，因为维奈托克相关的住院和监测。所以我们不预期这会显著改变固定疗程与持续治疗的比例，实际上我们认为持续治疗有机会更广泛地渗透到那些目前未接受持续治疗的患者中，即那50%的患者。当然，我们是这个领域的领导者。但更重要的是，正如我们展示的，Sonro加BRUKINSA最终看起来像是一个固定疗程方案，其中风险和收益是匹配的。这将是首创。我们确实相信，如果我们能继续完善这些数据并保持现状，对于接受固定疗程治疗的患者（约占患者的一半，无论是化疗还是其他基于维奈托克的疗法），这将是一个比所有现有方案都更好的选择。从这个角度来看，我们应该能够真正拓展到那个领域。尽管如此，我们仍然相信BRUKINSA单药治疗在这方面有重要作用。对于难治患者，你需要有很大的信心才能让患者停止治疗。每个人都喜欢这个想法，前景很好。但如果你没有达到MRD阴性，这样做是很冒险的。如果你的PFS看起来并不更好，这样做也很困难。我们认为，随着经验越来越多，我们对持续单药治疗的未来作用感到非常放心。我们相信联合疗法有巨大机会，目前我们确实没有覆盖到一半的患者。从另一个角度来看，简单来说，这个治疗领域将需要联合疗法，针对不同类型的患者，既有持续治疗也有固定疗程。正如我们所说，我们拥有的三种药物，无论是单药还是联合用药，我们可以覆盖整个领域，而且我们可能在每个治疗场景中都能为患者提供更好的结果，我们对此感到兴奋。即使是固定疗程，即使是zono加BRUKINSA，也不会是那种停止治疗后永远不会进展的固定疗程。仍然会有进展，会有复发/难治市场的再治疗，这个市场将是相当大的。这还不是治愈，远非如此。谢谢。

John Oyler

Thanks for the great question. I think, first of all, fixed duration means lots of things, chemos fixed duration. I think you have venetoclax combinations. And then I think you have BI, which is not approved in the U.S., and you have AAV, which has a study that we'll seek approval and we'll see how that plays out. I think that what we've laid out for you is when you actually look at this data versus continuous BRUKINSA, BRUKINSA looks like a better option for most patients. I think also fixed duration should not be confused with intermittent therapy really what you're talking about in this study, highly selected ultra-fit population, only relevant for a-quarter of the patients, not deletion 17p patients, which have a worse outcome, not older patients, not less healthy patients. In that population, you're still seeing close to a-quarter of the patient's progress within three years. Remember, they were on treatment for 14 months, right? That's only 20 months of being off treatment, and they progressed 1/4 of the patients. And if you look at shape of that curve, you can jump back to it, look at it right after 36 months. And again, highly selective, this is like as good as it could ever possibly get. The real-world experience is going to be much less healthy patients with much worse outcome. And you just compare that to a continuous therapy it's just underwhelming. So I think if that's the hurdle you're looking at, you really have a choice between VO, which is a huge tox burden, a huge burden on patients. And even this VI, when you actually look at the patient journey on it, it's no better, it's probably worse than chemo in the burden to a patient of the hospitalization and the monitoring associated with venetoclax. So we don't anticipate that to dramatically change this percentage of fixed duration versus continuous therapy and actually we think there's an opportunity for continuous therapy to try to work its way more broadly into some of those patients. The 50% that aren't on continuous therapy today. And of course, we're the leader in that space. But more importantly, as we've laid out Sonro, plus BRUKINSA finally looks like it's a fixed duration where the squeeze and juice make sense together. And that would be a first. And I think we do believe that, if we can continue to mature that data and it looks the way it is that for the patients that are on fixed duration, which is roughly half the patients whether it's chemo, whether it's other venetoclax-based therapies, this will stand out as a much better option than all of that. And from that perspective, we should really be able to expand into that area. All of that said, still, BRUKINSA monotherapy, we believe has a strong role in this. And for patients that are hard to treat, you have to have a lot of confidence to take people off and stop therapy. Everyone likes it. The promise is good. But if you don't have MRD negativity, that's a bold thing to do. And if you don't have PFS that really does look better, it's a hard thing to do. And I think that with more and more experience, we are very comfortable with the role of continuous monotherapy moving on. We believe with the combinations, there's huge opportunity and half of the patients were really not reaching right now. And I think from the other perspective, just simply put, this is a franchise that will require combinations that will have for different types of patients, continuous therapy and fixed duration. And the three agents we have, I think as we've said, single-agent combinations, we can cover this entire space and we probably can cover it with better outcomes for patients in every setting and we're excited about that. And even fixed duration, even with zono plus BRUKINSA, it's not going to be fixed duration where you stop and there's never any progression. There will be progression and there will be retreatment a relapsed/refractory market, which will be substantial. It's not yet a cure as far from that. Thank you.

Ziyi Chen

明白了。这一点非常清楚。谢谢，John。

Operator

我们的下一个问题来自Guggenheim Partners的Michael Schmidt。请取消静音并提出您的问题。

Unidentified Analyst

大家好，[听不清]代表Michael提问。祝贺2024年取得的进展，我们非常期待新的一年。关于CDK4，我想跟进一下。如果我听对了的话，您提到数据将在ASCO会议上公布。我想了解您对这次数据披露的预期如何设定？您希望看到哪些额外的疗效信号来进一步支持您计划的II期开发，并且与其他项目区分开来？谢谢。

John Oyler

我可以请您重复一下关于CDK4数据的问题吗？CDK4，好的。明白了。非常感谢您的问题。关于CDK4，我们已经从早期剂量递增中看到了非常有趣的数据。我们目前正处于安全性扩展队列阶段，试图确定我们将推进的剂量。正如我今天提到的，我们对这组数据感到非常兴奋，这与我们的假设一致——具有更好的选择性和更强的效力。现在看来这正在转化为临床方面的早期优势，即更少的血液毒性，同时我们也通过TK1检测看到了更好的靶向抑制效果。因此，随着数据的不断积累，我们将分析数据，并真正决定是否在今年晚些时候或明年初启动关键性试验。

Unidentified Analyst

好的。非常感谢大家。

Operator

我们的下一个问题来自TD Cohen的[听不清]。请取消静音并提出您的问题。谢谢。

Unidentified Analyst

您好。谢谢，我是[听不清]。感谢回答我的问题。祝贺出色的季度业绩和2025年指引。我有几个简短的问题。第一，对于TEVIMBRA在美国和欧盟的表现，您在2025年指引中有何预期？第二，关于您的降解剂，我知道您正在评估一些无化疗联合方案，例如与BRUKINSA、sonro或CD20双特异性抗体的组合。在这些方案中，您最看好哪一个？您有多大信心能将您的降解剂推进到CLL的更早期治疗线？非常感谢。

John Oyler

那么我先来回答这个问题。非常感谢。TEVIMBRA继续保持强劲的增长轨迹。您当然可以回顾我们2024年的表现。总体而言，我们显然继续是中国领先的PD-1药物。今年我们有多个新适应症符合国家医保目录（NRDL）资格，我们期待继续商业化这些适应症，并通过该类别中最广泛的NRDL报销覆盖范围来扩大我们的领导地位。我想指出，2024年确实存在价格影响，这一影响并非微不足道，但我们仍然展现出极其强劲的增长。2025年没有这种动态。考虑到我们在美国和欧洲的上市情况，正如我在准备好的发言中提到的，我们还处于非常早期的阶段，我们正在以有针对性的方式进行投资。我们对市场上看到的反响感到满意。但目前，随着我们在市场上获得更多产品经验，我们将在2025年继续向大家通报最新进展。那么，接下来我把话筒交给Lai。

A

是的。关于与降解剂平台试验相关的问题，实际上正如您提到的，我们对所有三种组合都感到兴奋，包括与sonro的组合，以及与BRUKINSA和CD20双特异性抗体的组合。原因在于它们可能用于不同的适应症。我们并不认为降解剂仅定位于慢性淋巴细胞白血病（CLL）。它在CLL之外肯定也有应用价值。在CLL方面，我们可能更期待看到与sonro以及BRUKINSA组合的数据，但在CLL之外，还有其他惰性淋巴瘤，BTK抑制剂在这些领域已明确显示出疗效。我们认为与CD20/CD3双特异性抗体（特别是针对滤泡性淋巴瘤和边缘区淋巴瘤）的组合将非常令人兴奋。因此，我们热切期待该平台试验的数据读出。

Unidentified Analyst

非常感谢。

Operator

没有更多问题了。我将把电话会议交给John Oyler进行结束发言。谢谢。

John Oyler

首先，我想感谢大家今天参与我们的会议并提出深思熟虑的问题。正如各位所知，我们公司的愿景是开展卓越的科学研究，开发真正能够帮助癌症患者的具有影响力的药物，并追求一种与众不同的商业模式。例如，我们拥有内部3,700人的全球临床团队，这使得我们能够比其他公司更快、更具成本效益地开发药物，从而让投资者能够从我们公司获得有吸引力且优先的回报。我认为，今天的目标还在于展示我们能够实现这一愿景，并以更可负担、更广泛的方式为美国乃至全球的患者提供药物。我们正在顺利实现这一目标，并且我们正在一个经济可行的框架内进行，正如我们所展示的，这一模式是有效的。无论是临床试验入组的速度，还是本次演示中数据的质量，我认为我们正在很好地践行我们这一非常大胆的使命和愿景。最后，我想感谢所有投资者和分析师对公司的帮助与支持，感谢我们团队的所有付出，感谢全球的临床医生和患者，正是他们真正推动了数据收集工作，帮助我们了解我们正在开发的哪些药物真正具有影响力，从而使我们能够集中资源，将这些药物带给患者。我们非常期待与各位继续这段旅程，感谢你们让我们得以实践这个我们正在经历的、充满乐趣的特权梦想。谢谢大家。