brentuximab

2019年后，ADC药物如雨后春笋般接连获批上市，而2021年爱地希的获批上市标志着国产ADC创新药开发也迎来里程碑。广阔的治疗前景，庞大的市场规模，无不刺激着众多药企燃起对ADC药物的研发热情，行业进入快速发展阶段。虽然事物发展的总趋势是前进性的，但道路是曲折的。随着研究的趋之如骛，如何避免产品同质化，打破残酷的竞争格局，探索创新发展之路成为重中之重。下文从笔者浅显的认知出发，探讨了ADC药物的一些热门靶点为何脱颖而出，以及部分创新靶点的开发现状和挑战，最后展望了未来的创新之路。常见的肿瘤靶点目前，ADC药物开发的靶点包括靶向肿瘤细胞表面抗原和靶向肿瘤微环境抗原等。其中，以靶向肿瘤细胞表面抗原蛋白为主，通过识别高表达特异性标志物，将有效载荷递送至细胞内，发挥杀伤作用。回溯已获批上市的15款ADC药物，共有11个靶点，包括CD33、CD30、HER2、CD22、CD79b、Nectin-4、BCMA、EGFR、CD19、Tissue Factor和FRα（如图1）。其中，早期成功上市的ADC药物靶点主要针对血液瘤相关疾病，诸如CD22、CD30、CD33、CD79b、BCMA。而实体瘤领域的热门靶点HER2和Trop-2，在临床中也得到了很好的验证。此外，一些新兴靶点也吸引着国内外药企的开发兴趣，如CLDN18.2、EGFR、Nectin-4、HER3等（如图2）。图1 已上市ADC靶点汇总图2 主要的肿瘤表面靶点唾液酸结合Ig样凝集素2（CD22，Siglec-2），属于免疫球蛋白超家族和唾液酸结合Ig样凝集素家族。是一种I型跨膜蛋白，可特异性结合含唾液酸（Sia）的聚糖，并通过其免疫受体酪氨酸抑制性基序（ITIM）抑制B细胞受体（BCR）信号传导，发挥维持体液免疫稳态的作用。CD22主要位于于成熟B细胞的细胞膜上，并在大多数B细胞恶性肿瘤中表达，包括急性淋巴细胞白血病（B-ALL），非霍奇金淋巴瘤（NHL）和毛细胞白血病（HCL）。鉴于CD22是众多肿瘤细胞表面特异性抗原靶标，并具有胞吞内化的特性，因此成为开发最多的靶点之一。但因为CD22表位的糖基化严重影响了抗体药物的靶向结合力，所以限制了高亲和力抗体的开发。目前，全球有12个靶向CD22的在研ADC药物，以外企研发为主（如图3）。图3 anti-CD22 ADC药物汇总CD30是肿瘤坏死因子（TNF）受体超家族成员之一，可通过激活不同的信号通路促进细胞增殖或凋亡。其在健康细胞中不表达，在正常激活的T细胞和B细胞表面低表达，在肿瘤细胞（如霍奇金淋巴瘤和和间变大细胞淋巴瘤）表面高表达。这种差异化表达使得CD30成为肿瘤靶向药开发的理想靶点之一。虽然已有Brentuximab Vedotin获批上市，但该靶点的药物开发进程并不如人意，且主要集中在CAR-T领域。目前，除Brentuximab Vedotin获批上市外，大部分处于临床1期和临床前阶段（如图4）。图4 anti-CD30 ADC药物汇总CD33（Siglec-3）与CD22相同，也属于Siglecs家族，过表达于白血病原始细胞，以及髓细胞性白血病起始细胞，使其成为AML（急性髓细胞样白血病）免疫治疗的潜力靶点。与CD22相同，CD33也具有抑制细胞信号级联反应，以及内化特性，但CD33没有CD22保守，存在多种剪接变体。目前，全球有9个在研ADC项目（如图5）。图5 anti-CD33 ADC药物汇总CD79B是一种B细胞表面抗原，是BCR的组成部分，在几乎所有B细胞表面均有表达，对BCR的表达与转运至胞膜具有重要的作用。在多种B细胞NHL和慢性淋巴细胞白血病B细胞上也有较高表达，成为杀伤B细胞肿瘤的创新靶点之一。目前，针对该靶点，全球披露的在研ADC项目有5项。图6 anti-CD79B ADC药物汇总B细胞成熟抗原（BCMA），是肿瘤坏死因子受体超家族（TNF-receptor）成员，表达于成熟B细胞及浆细胞表面，在恶性增殖的B淋巴细胞（例如骨髓瘤细胞、白血病细胞）中高度表达。目前，有13个全球在研ADC项目（如图7）。图7 anti-BCMA ADC药物汇总人表皮生长因子受体-2（HER2），是EGFR受体酪氨酸激酶家族的成员，是迄今为止乳腺癌中研究较为透彻的基因之一。HER2基因的过表达，会导致异二聚体细胞质域内酪氨酸残基的自磷酸化并启动各种信号通路从而导致细胞增殖和肿瘤发生。从披露的信息看，作为竞争最激烈的靶点之一，靶向HER2的ADC项目已有130个。其中，已获批上市4个，申请上市2个，处于临床3期的也多达8个。适应症分布也很广，多用于乳腺癌、实体瘤、胃癌等疾病治疗（如图8-9）。除了HER2单靶点ADC，HER2结合Trop-2/PDL1/TOP1/STING的双靶点或多靶点ADC创新设计进入人们视野（如图10）。图8  HER2-ADC最高研发阶段图9  HER2-ADC排名前十的适应症图10  HER2-ADC排名前十的靶点人滋养细胞表面糖蛋白抗原2（TROP2），是一种细胞表面跨膜糖蛋白，介导细胞内钙信号传导。TROP-2在多种人上皮癌中高表达，如乳腺癌、肺癌、胃癌、结直肠癌等。目前，全球靶向TROP2的在研ADC项目多达59个，其中科伦博泰SKB264已申请上市，有望成为中国首个获批上市的国产创新TROP2-ADC（如图11-13）。图11  TROP2-ADC最高研发阶段图12  TROP2-ADC排名前十的适应症图13  TROP2-ADC排名前十的靶点CLDN18.2 (Claudin18.2)是一种胃特异性膜蛋白，是目前研究得最为透彻的Claudin家族蛋白，主要在胃癌和胰腺癌中表达上调。人CLDN18基因可产生2种蛋白异构体CLDN18.1和CLDN18.2，分别高表达于肺组织和胃组织。目前，该靶点全球共有28个在研ADC项目（图14，15），国内药企布局管线最多，其中康诺亚生物（CMG-901）、礼新医药（LM-302）和Innovent Biologics（IBI343）均已进展到临床3期。从临床结果看，Claudin 18.2靶点的ADC取得了卓有成效的进展。例如，2023年公布的CMG901临床结果显示8例接受CMG901治疗的Claudin 18.2阳性胃癌或胃食管结合部腺癌患者中，客观缓解率（ORR）为75%，疾病控制率（DCR）为100%，安全性和耐受性均良好。图14  CLDN18.2-ADC最高研发阶段图15  CLDN18.2-ADC排名前十的适应症肿瘤微环境靶点肿瘤微环境（TME）是肿瘤发生及生长的环境，主要由成纤维细胞（CAFs）、免疫细胞、脂肪细胞、血管内皮细胞和肿瘤细胞外基质（ECM）组成。通过靶向调节微环境细胞的代谢也可以有效促进抗肿瘤免疫，影响肿瘤的增殖转移。因此，肿瘤微环境（TME）靶点成为研究热点之一，例如作用于细胞外基质组分的ADC靶点：纤连蛋白（fibronectin）、细胞粘合度素（tenascin-C）、纤维蛋白（fibrin）和胶原蛋白（collagen IV）等。但目前肿瘤微环境靶点的ADCs在临床上还未取得成功，仍有很大的开发空间。碳酸酐酶Ⅹ（CAI Ⅹ）是一类金属酶，能在缺氧环境下催化二氧化碳水合生成碳酸氢盐，在90%以上的肾透明细胞癌中过表达，在正常组织中的几乎不表达。这一特点使得CAI Ⅹ成为很有吸引力的靶点之一。但目前针对该靶点的ADC项目尚无积极结果，例如BAY 79-4620分子虽然在体外药效检测中表现出良好的肿瘤杀伤效果，但是在临床中出现了严重的不良反应导致研究终止。成纤维细胞激活蛋白α（FAPα）是成纤维细胞分泌的一种丝氨酸蛋白酶，参与组织重塑和伤口愈合。研究发现靶向FAPα的单抗没有抗肿瘤活性，但是偶联美登素后具有显著抗肿瘤作用。根据已披露的信息显示，目前针对该靶点的在研ADC药物仅有一个，在研多肽偶联药物（PDC）和核素偶联药物分别有5个和41个。LRRC15（leucine rich repeat containing 15）是一种成纤维细胞表面富含亮氨酸的重复蛋白，在正常组织中低表达，多种实体瘤如乳腺癌、骨肉瘤、前列腺癌中高表达。目前，该靶点仅有1款ADC在研（Samrotamab vedotin），但研发处于临床1期且无进展。其他创新靶点除了上述靶点，一些创新靶点也具备一定的成药潜力，推动着XDC药物的发展，而适应症也不再局限于肿瘤治疗领域（如图16）。图16  XDC药物靶点促性腺素释放激素受体（GnRHR）是一种由下丘脑合成并分泌的作用于垂体的生殖激素。GnRH分子质量为1.181kDa，属于分泌型小分子半抗原，免疫原性很弱，通过改变GnRH的分子结构及将GnRH与大分子的载体蛋白偶联，可以提高免疫原性。目前，针对该靶点的在研多肽偶联药物仅有3个且开发现状不容乐观。进展最快的Zoptarelin Doxorubicin早已因严重的不良反应和高死亡率终止了临床3期（结构如图17），而另外2个项目也处于无进展状态。图17  Zoptarelin Doxorubicin结构癌胚抗原细胞粘附分子5 （CEACAM5）是一种参与肿瘤细胞粘附、分化、增殖和存活的生物标记物之一，在多种实体肿瘤表面过表达。目前，该靶点共有7款在研ADC。进展最快的是IBI-126（ImmunoGen），将tusamitamab抗体通过SPDB与美登素连接（如图18），但2023年12月公布的临床3期结果显示PFS及OS均未达到终点指标。图18  Tusamitamab ravtansine结构未来的创新之路一直以来，人们对ADC靶点的探索与开发从未停止，靶点的成药性也是ADC药物开发的难点。除了在肿瘤表面的特异性及丰度，是否具有内吞性也是靶点评估的重要标准。相比目前研发火热的内吞型ADC赛道，非内吞型ADC的开发尚且较少，但其在临床的疗效已经得到了充分验证，为未来ADC的开发提供了新机遇。除了对靶点的选择，基于靶抗原的抗体结构的设计也是另一创新点。鉴于良好的血清半衰期和较强的免疫激活能力，目前大部分抗体药物采用IgG1亚型，已上市ADC药物中仅有Mylotarg和Besponsa的抗体部分采用IgG4亚型。除了单抗形式，双抗、抗体片段、纳米抗体等形式为新型XDC药物的设计提供了方向。例如，靶向EGFR/HER3的双抗ADC（BL-B01D1）可杀伤EGFR依赖性的肿瘤并降低HER3引起的耐药性，且在肿瘤模型中的数据显示与HER3-ADC（U3-1402）相比，BL-B01D1具有更佳的抗癌活性。靶点的创新归根究底需要对疾病的发生、发展、靶点分布、作用机制等方面有更深入的研究，尽管任重道远，但21世纪是生物的时代，相信未来会涌现出更多更有效的ADC药物，为疾病治疗带来希望。参考来源：[1] 2023年华金证券研究报告《ADC药物：创新前行、出海扬帆》[2] 新药情报库https://synapse.zhihuiya.com/?csrfToken=识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

Driving clinical, regulatory, and operational excellence across five innovative platforms focused on immunology, neuroscience, and oncology: Portfolio targeting large indications including obesity, epilepsy, bipolar disorder, depression, obsessive-compulsive disorder (OCD), migraine, pain, Alzheimer's disease, Parkinson's disease, multiple sclerosis, rheumatoid arthritis, and cancer. Also advancing potential novel treatments for rare autoimmune and inflammatory diseases, including myasthenia gravis, cardiomyopathy, spinal muscular atrophy (SMA) and IgA nephropathy. Pivotal clinical data milestones expected across three distinct programs: First-in-human Phase 1 study with BHV-1300 initiated in 1Q 2024. Preliminary immunoglobulin G (IgG) lowering data from the single ascending dose (SAD) portion of the study expected in late 1Q 2024/early 2Q 2024. The MAD portion of the study is being planned in a relevant patient population with the possibility of benefit from BHV-1300. Phase 3 database lock for interim efficacy analysis with troriluzole in OCD remains on schedule for 1Q 2024, with results expected in 2Q 2024. Phase 3 topline data in ongoing fully enrolled SMA study with taldefgrobep expected 2H 2024. Multiple trial initiations and Investigational New Drug (IND) filings projected over next three years present potential for continued growth and value creation. NEW HAVEN, Conn., Feb. 29, 2024 /PRNewswire/ -- Biohaven Ltd. (NYSE: BHVN) (Biohaven or the Company), a global clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of life-changing therapies to treat a broad range of rare and common diseases, today reported financial results for the fourth quarter and full year ended December 31, 2023, and provided a review of recent accomplishments and anticipated upcoming developments. Vlad Coric, M.D., Chairman and Chief Executive Officer of Biohaven, commented, "We embarked on a bold execution plan after completing our spin-off, re-emerging as a separate entity focused on immunology, neuroscience, and oncology. In just over a year's time, we made tremendous strides in progressing our programs, providing impressive and supportive pre-clinical and clinical outcomes for our key stakeholders, including patients, who may gain access to differentiated drugs for difficult to treat medical conditions. Today we are focused on delivering outcomes across five platforms spanning inflammation and immunology, ion channel modulation, myostatin inhibition, glutamate modulation, and oncology. In the year ahead, we expect to deliver potentially groundbreaking data across three distinct programs. In the near-term, we expect to report first-in-human Phase 1 IgG lowering data with our pan-IgG degrader, BHV-1300, with broad potential application. Given the profoundly deep and rapid reduction in IgG levels observed in non-human primate studies, unique ability to co-administer with Fc-containing biologics, ease of self-administration, and favorable toxicology profile observed to date, we are eagerly awaiting the proof-of-concept human data. We also plan to report OCD Phase 3 topline data in the second quarter of 2024 from an interim analysis with our glutamate modulating agent, troriluzole. There has been little to no innovation in advancing treatments for this disorder in decades and a win in this Phase 3 trial would be a substantial clinical success for the three million patients across the OCD community, many of whom are plagued by debilitating intrusive thoughts and compulsions. And finally, we're expecting Phase 3 topline data in the second half of the year with our anti-myostatin compound, taldefgrobep alfa, for patients with SMA. Dr. Coric continued, "Beyond data expectations, we are excited with the progress made across the balance of our portfolio, starting with our Kv7 ion channel activation program, where we have operationalized over 110 clinical trial sites in our focal epilepsy trials and are advancing development programs in generalized epilepsy, bipolar disorder, and major depressive disorder. Excitement is also mounting for the potential of taldefgrobep alfa in weight loss, a compound that we believe will maintain and grow muscle mass as a means of helping to address the global obesity crisis. We also expect to deliver additional trial initiations across our broad IgG degrader program targeting both large indications and rare autoimmune/inflammatory diseases, TYK2/JAK1 inhibition in neuroinflammatory disorders, TRPM3 antagonism initially in migraine and neuropathic pain, and with our antibody drug conjugates program in an array of oncology indications. We are passionate about helping patients in need, and excited about our portfolio, the skilled drug development team we have in place, and the vast opportunity in the year ahead." Full Year and Recent Business Highlights Ion Channel Platform - Milestones and Next Steps: Kv7 Ion Channel Activation: Epilepsy & Neuropsychiatric Indications BHV-7000, the lead asset from the Kv7 platform, is a selective activator of Kv7.2/Kv7.3, a key ion channel involved in regulation of neuronal signaling and hyperexcitability. Reported BHV-7000 Phase 1 study results: In December 2023, the Company reported full results from the BHV-7000 Phase 1 SAD and multiple ascending dose (MAD) studies examining doses up to 120mg daily, demonstrating BHV-7000 was well-tolerated at all doses studied without the typical central nervous system (CNS) adverse effects associated with other anti-seizure medications (ASMs), such as somnolence and cognitive/mood disturbances. Results were consistent with previously reported preclinical data demonstrating BHV-7000's lack of GABAA receptor activation and lack of adverse impacts on neurobehavior in preclinical testing. Demonstrated CNS target engagement: In December 2023, the Company reported additional data from a Phase 1 electroencephalogram (EEG) biomarker study, where BHV-7000 demonstrated dose-dependent target engagement in the brain as shown by dose-dependent effects on EEG spectral power across all frequency bands. While changes in spectral power were observed across all frequency bands with BHV-7000, the minimal impact on slower frequencies (i.e., delta) is consistent with the low incidence of CNS adverse events observed in the BHV-7000 Phase 1 SAD/MAD studies. EEG delta activity is associated with somnolence, an undesirable CNS adverse event commonly reported with other ASMs. Developed once-daily formulation: In September 2023, the Company announced it had formulated an extended release, once-a-day tablet designed to achieve target therapeutic concentrations (25mg, 50mg and 75mg). This dosing approach with a Kv7 activator will allow for assessment of distinct target concentrations over a wide range, above and below projected efficacious EC50 drug concentrations, not previously feasible with drugs in this class. Sites operationalized: In January 2024, the Company completed its End-of-Phase 2 meeting with FDA to advance to Phase 3 trials and announced that more than 110 global clinical sites have been selected in the ongoing focal epilepsy trial, with enrollment planned for 1Q 2024. Upcoming trial initiations: The Company expects to initiate Phase 2/3 programs in focal epilepsy in 1Q 2024 and in generalized epilepsy in 2Q 2024; the Company also expects to initiate a Phase 2 study in major depressive disorder and a Phase 2/3 study in bipolar disorder in 1H 2024. TRPM3 Ion Channel Antagonism: Migraine & Neuropathic Pain BHV-2100 is an oral, selective TRPM3 antagonist offering a novel, non-addictive treatment for migraine and neuropathic pain. Phase 1 study data supports evaluation in acute migraine: In January 2024, the Company detailed preliminary pharmacokinetic (PK) and safety data from an ongoing Phase 1 study; in the study, BHV-2100 was rapidly absorbed, achieved 90% inhibitory concentrations within one hour, and was well tolerated at projected therapeutic concentrations Upcoming trial initiations: The Company expects to initiate a BHV-2100 Phase 2 study in acute migraine in 2H 2024 and conduct a POC study for neuropathic pain in 2H 2024. Inflammation and Immunology Platform - Milestones and Next Steps: Targeted Extracellular Protein Degradation: Molecular Degraders of Extracellular Proteins (MoDEs™) uniquely harness the hepatic ASGPR receptor for efficient and safe removal of circulating pathogenic targets; BHV-1300, is an IgG degrader. Reported on progress with BHV-1300: The Company has demonstrated the effect of a single dose of BHV-1300 in lowering IgG in nonhuman primates (NHPs), previously reporting over 75-80% reduction of IgG levels from baseline in three days. These data compare favorably to other IgG targeting agents, such as the FcRn inhibitor efgartigimod, where reduction of IgG levels, following a single dose, was shown to be approximately 50% in 5-7 days. In September 2023, the Company announced positive multiple dose, pharmacodynamic (PD) data from a NHP study with BHV-1300 demonstrating dose-dependent reductions of over 90% in IgG levels from baseline, suggesting the potential for achieving greater efficacy with finely calibrated, deeper IgG reductions as compared with existing standard of care FcRn targeting treatments. Demonstrated potential for same-day, co-administration with Fc-containing biologics: In January 2024, the Company presented new NHP data demonstrating that Biohaven's IgG degrader technology allows for co-administration with Fc-containing biologics; PK of Humira® was unaltered after being dosed 12 hours after BHV-1300 administration. Reported preclinical pharmacodynamic data with single dose of BHV-1310: In January 2024, the Company showed that a next generation and optimized IgG degrader, BHV-1310, allowed for much deeper 90% reductions in IgG after a single dose. Given the deep and rapid reductions observed, the Company believes BHV-1310 may have potential application in acute settings. Unveiled plans for BHV-1600: next-generation, selective degrader targeting β1-AR autoantibodies: In January 2024, the Company reported preclinical data demonstrating degradation of anti-β-1AR antibody in mice. The Company expects to file an IND application and initiate a first-in-human Phase 1 study in 2H 2024. BHV-1600 will initially be evaluated in patients with dilated cardiomyopathy. Near-term data expected: The Phase 1 SAD study examining BHV-1300 in healthy subjects was initiated in 1Q 2024 and the Company expects preliminary results in late 1Q 2024/early 2Q 2024. The FDA indicated that the MAD assessment of BHV-1300 should be performed in a relevant patient population. Upon completion of the SAD study, Biohaven is planning the MAD portion of the study in a relevant patient population with the possibility of benefit from BHV-1300. Upcoming trial initiations: A total of 4 INDs are expected for the degrader program in 2024. TYK2/JAK1 Inhibition: BHV-8000 is an oral, brain-penetrant, selective TYK2/JAK1 inhibitor with broad potential for neuroinflammatory and neurodegenerative disorders. Successfully completed single ascending dose cohorts; advanced multiple ascending dose cohorts in ongoing Phase 1 study of TYK2/JAK1 inhibitor, BHV-8000: In January 2024, the Company provided a program update for the ongoing Phase 1 study designed to evaluate the safety, tolerability, PK and PD of single and multiple ascending doses of BHV-8000 in healthy volunteers. The SAD cohorts have now completed dosing (10, 20 and 30 mg); in the MAD cohorts, the Company completed up to the 20 mg dose. Based on the preliminary data available, projected therapeutic concentrations of BHV-8000 were achieved and BHV-8000 was well tolerated with only mild adverse events reported. Upcoming trial initiations: The Company expects to initiate a Phase 2 study in multiple sclerosis in 2H 2024, a Phase 2a study in prevention of amyloid therapy induced ARIA in 2H 2024, and Phase 2/3 studies in early Parkinson's disease and early Alzheimer's disease in 2H 2024. Myostatin Platform - Milestones and Next Steps: Taldefgrobep alfa is a novel myostatin inhibitor optimized to target myostatin and associated signaling pathways of muscle growth. Taldefgrobep alpha also has promise as a potential treatment for obesity and, in preclinical models as well as preliminary healthy human studies, has demonstrated meaningful reductions in fat mass, the primary pathogenic tissue in obesity, while increasing lean mass. Biohaven is also studying taldefgrobep in a global Phase 3 study in Spinal Muscular Atrophy to enhance muscle mass and function in patients treated with standard-of-care gene therapy treatments. Preclinical data demonstrated taldefgrobep alfa reduces fat and improves lean mass: In October 2023, the Company presented preclinical data demonstrating the ability of taldefgrobep alfa to significantly reduce fat mass while increasing lean mass in an obese mouse model at The Obesity Society's annual ObesityWeek conference. Completed enrollment in pivotal Phase 3 study in SMA: In September 2023, the Company announced that it had completed enrollment in RESILIENT, a pivotal Phase 3 study designed to evaluate the efficacy and safety of taldefgrobep as adjunctive therapy to enhance muscle mass and function in SMA patients treated with standard-of-care treatments. In July 2023, the Company announced that taldefgrobep received orphan drug designation (ODD) from the European Commission for the treatment of SMA. Taldefgrobep previously received Fast-Track and ODD from the FDA. Topline data expected: The Company expects to announce Phase 3 topline data from the ongoing SMA study in 2H 2024. Upcoming trial initiation: The Company expects to initiate a Phase 2 study in patients with obesity in 2Q 2024. Glutamate Modulation Platform - Milestones and Next Steps: Troriluzole is a novel glutamate modulator currently being evaluated in Phase 3 trials for obsessive-compulsive disorder as an adjunctive therapy in patients with an inadequate response to existing standard-of-care treatment. Topline data from interim analysis in OCD expected in 2Q 2024: In January 2024, the Company shared an update on the ongoing Phase 3 trial in OCD. The Company remains on schedule for a database lock in 1Q 2024, with an interim efficacy analysis expected in 2Q 2024. Biohaven has also continued to have constructive dialogue with the FDA regarding its SCA development program and potential future data analyses to address regulatory concerns in the previously issued refuse-to-file decision on its NDA application for SCA3. Biohaven will provide further updates on the SCA development program as warranted by any continued positive progress from the outcome of future regulatory interactions on this topic. Next-Generation ADC Platform - Milestones and Next Steps: Biohaven's antibody drug conjugate (ADC) technology is focused on novel conjugation chemistry with the potential to be superior to the current industry standard maleimide and lipophilic click chemistry. BHV-1510 is a TROP2 directed ADC, with a highly differentiated efficacy and safety profile providing an opportunity to broaden therapeutic margin, increase time on treatment, and improve efficacy; BHV-1500 demonstrated superior efficacy to Adcetris® (brentuximab vedotin) and improved survival in a mouse xenograft model. Upcoming trial initiations: The Company completed its regulatory interactions to begin first-in-human studies with BHV-1510 (TROP2 directed ADC) and expects to initiate a Phase 1 trial in 2Q 2024. The company also expects to submit an IND for BHV-1500 (next-generation brentuximab ADC) in 2H 2024. Corporate Updates: Public offering: On October 5, 2023, the Company closed its previously announced underwritten public offering of 11,761,363 of its common shares, which included the full exercise of the underwriters' option to purchase 1,534,090 additional shares, at the public offering price of $22.00 per share. The net proceeds raised in the offering, after deducting underwriting discounts and estimated expenses of the offering payable by the Company, were approximately $242.4 million. As of February 26, 2024, we had 81,579,914 common shares outstanding. Expected Upcoming Milestones: We believe Biohaven is well positioned to achieve significant, value-creating milestones in 2024 across numerous programs: Selective Kv7 Activator: Initiate BHV-7000 Phase 2/3 program in focal epilepsy in 1Q 2024 Initiate BHV-7000 Phase 2/3 study in generalized epilepsy in 2Q 2024 Initiate BHV-7000 Phase 2/3 study in bipolar disorder in 1H 2024 Initiate BHV-7000 Phase 2 study in major depressive disorder in 1H 2024 Troriluzole: Database lock in 1Q 2024 and report troriluzole Phase 3 interim efficacy analysis topline results in OCD in 2Q 2024 Taldefgrobep alfa: Initiate taldefgrobep Phase 2 study in obesity in 2Q 2024 Report taldefgrobep Phase 3 topline results in SMA in 2H 2024 First-in-class TRPM3 Antagonist: Initiate BHV-2100 Phase 2 study in acute migraine in 2H 2024 Conduct BHV-2100 POC study for neuropathic pain in 2H 2024 TYK2/JAK1 Inhibitor: Initiate BHV-8000 Phase 2 study in Multiple Sclerosis in 2H 2024 Initiate BHV-8000 Phase 2a study in prevention of amyloid therapy induced ARIA in 2H 2024 Initiate BHV-8000 Phase 2/3 study in early Parkinson's disease in 2H 2024 Initiate BHV-8000 Phase 2/3 study in early Alzheimer's disease in 2H 2024 Extracellular protein degradation platform BHV-1300 first-in-human clinical data demonstrating IgG lowering expected late 1Q 2024/early 2Q 2024 A total of 4 INDs are expected for the degrader program in 2024 Next Generation ADC Platform: Initiate Phase 1 trial of BHV-1510 (TROP2 directed ADC) in 2Q 2024 File IND for BHV-1500 (next generation brentuximab ADC) in 2H 2024 Capital Position: Cash, cash equivalents and marketable securities as of December 31, 2023 was $385.5 million, which includes $3.7 million of restricted cash. Fourth Quarter 2023 Financial Highlights: Research and Development (R&D) Expenses: R&D expenses, including non-cash share-based compensation costs, were $134.8 million for the three months ended December 31, 2023, compared to $137.0 million for the three months ended December 31, 2022. The decrease of $2.2 million was primarily due to decreased non-cash share-based compensation expense during the three months ended December 31, 2023, and $5.2 million of one-time employee costs related to the Pfizer acquisition of Biohaven Pharmaceutical Holding Company Ltd. (the Former Parent) in the fourth quarter of 2022. This was partially offset by increased costs related to advancing additional clinical development program activities, including late Phase 2/3 studies and preclinical research programs, and recognition of one-time expenses of a $10.0 million cash payment and a $21.8 million non-cash issuance of common shares to acquire rights related to our agreement with Highlightll in the three months ended December 31, 2023, as compared to the same period in the prior year. Non-cash share-based compensation expense was $9.1 million for the three months ended December 31, 2023, a decrease of $60.3 million as compared to the same period in 2022. The decrease was primarily due to $61.7 million of expense allocated from the Former Parent recognized in connection with the settlement of outstanding Former Parent stock options and restricted stock units (RSUs) upon the effectiveness of the Former Parent's distribution to holders of all outstanding common shares of Biohaven and the spin-off of Biohaven from the Former Parent (the Separation) in the fourth quarter of 2022. General and Administrative (G&A) Expenses: General and administrative expenses were $18.9 million for the three months ended December 31, 2023, compared to $76.4 million for the three months ended December 31, 2022. The decrease of $57.5 million was primarily due to decreased non-cash share-based compensation expense during the three months ended December 31, 2023, and $8.2 million of transaction-related expenses and $8.9 million of one-time employee costs related to the Pfizer acquisition of the Former Parent in the fourth quarter of 2022. Non-cash share-based compensation expense was $6.8 million for the three months ended December 31, 2023, a decrease of $39.5 million as compared to the same period in 2022. The decrease was primarily due to $39.7 million of expense allocated from the Former Parent recognized in connection with the settlement of outstanding Former Parent stock options and RSUs upon the effectiveness of the Separation in the fourth quarter of 2022. Other Income (Expense), Net: Other income (expense), net was a net income of $7.7 million for the three months ended December 31, 2023, compared to a net expense of $1.8 million for the three months ended December 31, 2022. The increase of $9.6 million was primarily due to a $10.0 million impairment loss recognized during the fourth quarter of 2022 on our Artizan Series A-2 Preferred Stock Investment. Net Loss: Biohaven reported a net loss for the three months ended December 31, 2023, of $144.8 million, or $1.81 per share, compared to $201.1 million, or $3.32 per share, for the same period in 2022. Non-GAAP adjusted net loss for the three months ended December 31, 2023 was $128.9 million, or $1.61 per share, compared to $77.3 million, or $1.27 per share for the same period in 2022. These non-GAAP adjusted net loss and non-GAAP adjusted net loss per share measures, more fully described below under "Non-GAAP Financial Measures," exclude non-cash share-based compensation charges and transaction-related costs incurred relating to the Company's spin-off from Biohaven Pharmaceutical Holding Company Ltd. A reconciliation of the GAAP financial results to non-GAAP financial results is included in the tables below. Full Year 2023 Financial Highlights Note: As described in our Annual Report on Form 10-K, full year results for the year ended December 31, 2022 include direct and allocated expenses on a carve-out basis of accounting for the period prior to October 3, 2022, when the Company became a standalone public company. R&D Expenses: R&D expenses, including non-cash share-based compensation, were $373.3 million for the year ended December 31, 2023, compared to $437.1 million for the year ended December 31, 2022. The decrease of $63.8 million was primarily due to a decrease of $91.5 million in personnel related costs primarily due to decreased non-cash share-based compensation expense, and reduced program spend for discontinued programs in 2023 compared to 2022. R&D expenses for the year ended December 31, 2022 also included a one-time $93.7 million expense for our Kv7 Platform acquisition, and a $25.0 million milestone relating to BHV-7000. The decrease was partially offset by increases in direct program spend for additional and advancing clinical trials, including late Phase 2/3 studies and preclinical research programs, and recognition of one-time expenses of a $10.0 million cash payment and a $21.8 million non-cash issuance of common shares to acquire rights related to our agreement with Highlightll, as compared to the same period in the prior year. Non-cash share-based compensation expense was $16.0 million for the year ended December 31, 2023, a decrease of $100.4 million as compared to the same period in 2022. Non-cash share-based compensation expense for the year ended December 31, 2022 included $108.7 million of expense allocated from the Former Parent, including $61.7 million of expense recognized in connection with the settlement of outstanding Former Parent stock options and RSUs upon the effectiveness of the Separation in the fourth quarter of 2022. G&A Expenses: G&A expenses, including non-cash share-based compensation costs, were $62.8 million for the year ended December 31, 2023, compared to $130.9 million for the year ended December 31, 2022. The decrease of $68.1 million was primarily due to decreased non-cash share-based compensation costs. Non-cash share-based compensation expense was $12.8 million for the year ended December 31, 2023, a decrease of $64.4 million as compared to the same period in 2022. Non-cash share-based compensation expense for the year ended December 31, 2022 included $70.6 million of expense allocated from the Former Parent, including $39.7 million of expense recognized in connection with the settlement of each outstanding Former Parent stock option and RSU upon the effectiveness of the Separation in the fourth quarter of 2022. Other Income (Expense), Net: Other income (expense), net was a net income of $26.5 million for the year ended December 31, 2023, compared to a net expense of $1.9 million for the three months ended December 31, 2022. The increase of $28.4 million was primarily due to increased net investment income of $14.5 million and increased service revenue from the Transition Service Agreement we entered into with the Former Parent of $5.2 million in 2023, as compared to the same period in the prior year, as well as a $10.0 million impairment loss recognized during the fourth quarter of 2022 on our Artizan Series A-2 Preferred Stock Investment. Net Loss: The Company reported a net loss attributable to common shareholders for the year ended December 31, 2023 of $408.2 million, or $5.73 per share, compared to $570.3 million, or $12.75 per share for the same period in 2022. Non-GAAP adjusted net loss for the year ended December 31, 2023 was $379.4 million, or $5.33 per share, compared to $362.7 million, or $8.11 per share for the same period in 2022. These non-GAAP adjusted net loss and non-GAAP adjusted net loss per share measures, more fully described below under "Non-GAAP Financial Measures," exclude non-cash share-based compensation charges and transaction-related costs incurred relating to the Company's spin-off from Biohaven Pharmaceutical Holding Company Ltd. A reconciliation of the GAAP financial results to non-GAAP financial results is included in the tables below. Non-GAAP Financial Measures This press release includes financial results prepared in accordance with accounting principles generally accepted in the United States (GAAP), and also certain non-GAAP financial measures. In particular, Biohaven has provided non-GAAP adjusted net loss and adjusted net loss per share, which are adjusted to exclude non-cash share-based compensation, which is substantially dependent on changes in the market price of common shares, and transaction-related costs incurred relating to the Company's spin-off from Biohaven Pharmaceutical Holding Company Ltd., which are limited to a specific period of time and related to Biohaven Ltd. being established as a standalone public company. Non-GAAP financial measures are not an alternative for financial measures prepared in accordance with GAAP. However, Biohaven believes the presentation of non-GAAP adjusted net loss and adjusted net loss per share, when viewed in conjunction with GAAP results, provides investors with a more meaningful understanding of ongoing operating performance and can assist investors in comparing Biohaven's performance between periods. In addition, these non-GAAP financial measures are among those indicators Biohaven uses as a basis for evaluating performance, and planning and forecasting future periods. These non-GAAP financial measures are not intended to be considered in isolation or as a substitute for GAAP financial measures. A reconciliation between these non-GAAP measures and the most directly comparable GAAP measures is provided later in this news release. About Biohaven Biohaven is a biopharmaceutical company focused on the discovery, development, and commercialization of life-changing treatments in key therapeutic areas, including immunology, neuroscience, and oncology. The company is advancing its innovative portfolio of therapeutics, leveraging its proven drug development experience and multiple proprietary drug development platforms. Biohaven's extensive clinical and preclinical programs include Kv7 ion channel modulation for epilepsy and mood disorders; extracellular protein degradation for immunological diseases; TRPM3 antagonism for migraine and neuropathic pain; TYK2/JAK1 inhibition for neuroinflammatory disorders; glutamate modulation for OCD and SCA; myostatin inhibition for neuromuscular and metabolic diseases, including SMA and obesity; and antibody recruiting, bispecific molecules and antibody drug conjugates for cancer. Forward-looking Statements This news release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. The use of certain words, including "continue", "plan", "will", "believe", "may", "expect", "anticipate" and similar expressions, is intended to identify forward-looking statements. Investors are cautioned that any forward-looking statements, including statements regarding the future development, timing and potential marketing approval and commercialization of development candidates, are not guarantees of future performance or results and involve substantial risks and uncertainties. Actual results, developments and events may differ materially from those in the forward-looking statements as a result of various factors including: the expected timing, commencement and outcomes of Biohaven's planned and ongoing clinical trials; the timing of planned interactions and filings with the FDA; the timing and outcome of expected regulatory filings; complying with applicable U.S. regulatory requirements; the potential commercialization of Biohaven's product candidates; the potential for Biohaven's product candidates to be first in class therapies; and the effectiveness and safety of Biohaven's product candidates. Additional important factors to be considered in connection with forward-looking statements are described in Biohaven's filings with the Securities and Exchange Commission, including within the sections titled "Risk Factors" and "Management's Discussion and Analysis of Financial Condition and Results of Operations". The forward-looking statements are made as of the date of this news release, and Biohaven does not undertake any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law. MoDEs is a trademark of Biohaven Therapeutics Ltd. Investor Contact: Jennifer Porcelli Vice President, Investor Relations [email protected] +1 (201) 248-0741 Media Contact: Mike Beyer Sam Brown Inc. [email protected] +1 (312) 961-2502 SOURCE Biohaven Ltd.