更新于：2024-12-12
MK-4830
更新于：2024-12-12
概要
基本信息
原研机构 |
非在研机构 |
最高研发阶段临床2期 |
首次获批日期- |
最高研发阶段(中国)临床1期 |
特殊审评- |
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关联
15
项与 MK-4830 相关的临床试验A Phase 1/2 Open-Label, Umbrella Platform Design Study of Investigational Agents With or Without Pembrolizumab (MK-3475) and/or Chemotherapy in Participants With Advanced Esophageal Cancer Previously Exposed to PD-1/PD-L1 Treatment (KEYMAKER-U06): Substudy 06B
This is a Phase 1/2, multicenter, randomized, open-label umbrella platform study to evaluate the safety and efficacy of investigational agents with or without pembrolizumab and/or chemotherapy, for the treatment of participants with second line (2L) esophageal squamous cell carcinoma (ESCC) who have previously been exposed to PD-1/PD-L1 based treatment.
开始日期2023-05-16 |
申办/合作机构 |
一项在既往接受过抗PD-1/PD-L1药物治疗的晚期食管癌受试者中评价试验用药物联合帕博利珠单抗（MK-3475）的I/II期开放性、伞式平台设计研究（KEYMAKER-U06）：子研究06B。
主要目的：
1.安全性导入阶段：评估尚未在单独子研究中评估的联合治疗的安全性和耐受性
2.BICR按RECIST 1.1评估的ORR
次要目的：
1.BICR按RECIST 1.1评估的PFS和DOR，及OS
2.评估联合治疗的安全性和耐受性
开始日期2023-05-16 |
申办/合作机构  默沙东研发（中国）有限公司 [+1] |
一项研究MK-4830单药治疗和与帕博利珠单抗联合治疗晚期实体瘤受试者的I期、开放性、多组、多中心研究
评估MK-4830联合帕博利珠单抗在中国晚期/转移性实体瘤受试者中的安全性和药代动力学特征。
开始日期2022-12-16 |
申办/合作机构 默沙东研发（中国）有限公司 [+2] |
100 项与 MK-4830 相关的临床结果
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100 项与 MK-4830 相关的转化医学
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100 项与 MK-4830 相关的专利（医药）
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4
项与 MK-4830 相关的文献（医药）2022-09-15·Clinical cancer research : an official journal of the American Association for Cancer Research
Correction: First-in-Class Anti-immunoglobulin–like Transcript 4 Myeloid-Specific Antibody MK-4830 Abrogates a PD-1 Resistance Mechanism in Patients with Advanced Solid Tumors
作者: Siu, Lillian L. ; Geva, Ravit ; Lunceford, Jared ; Perets, Ruth ; Markensohn, Julia F. ; Suttner, Leah ; Altura, Rachel A. ; Hilton, John ; Wang, Ding ; Rasco, Drew ; Maurice-Dror, Corinne ; Wilson, Douglas C. ; Siddiqi, Shabana ; Abraham, Anson K.
2022-04-14·Clinical cancer research : an official journal of the American Association for Cancer Research
Correction: First-in-Class Anti-Immunoglobulin–like Transcript 4 Myeloid-Specific Antibody MK-4830 Abrogates a PD-1 Resistance Mechanism in Patients with Advanced Solid Tumors
作者: Geva, Ravit ; Siu, Lillian L. ; Lunceford, Jared ; Perets, Ruth ; Markensohn, Julia F. ; Suttner, Leah ; Altura, Rachel A. ; Hilton, John ; Wang, Ding ; Maurice-Dror, Corinne ; Rasco, Drew ; Siddiqi, Shabana ; Wilson, Douglas C. ; Abraham, Anson K.
2022-01-01·Clinical cancer research : an official journal of the American Association for Cancer Research1区 · 医学
First-in-Class Anti-immunoglobulin–like Transcript 4 Myeloid-Specific Antibody MK-4830 Abrogates a PD-1 Resistance Mechanism in Patients with Advanced Solid Tumors
1区 · 医学
Article
作者: Geva, Ravit ; Siu, Lillian L. ; Lunceford, Jared ; Perets, Ruth ; Markensohn, Julia F. ; Suttner, Leah ; Altura, Rachel A. ; Hilton, John ; Maurice-Dror, Corinne ; Rasco, Drew ; Wang, Ding ; Siddiqi, Shabana ; Wilson, Douglas C. ; Abraham, Anson K.
Abstract:
Purpose::
In this first-in-human study (NCT03564691) in advanced solid tumors, we investigated a novel first-in-class human IgG4 monoclonal antibody targeting the immunoglobulin-like transcript 4 (ILT4) receptor, MK-4830, as monotherapy and in combination with pembrolizumab.
Patients and Methods::
Patients with histologically/cytologically confirmed advanced solid tumors, measurable disease by RECIST v1.1, and evaluable baseline tumor sample received escalating doses of intravenous MK-4830 every 3 weeks as monotherapy (parts A and B) and in combination with pembrolizumab (part C). Safety and tolerability were the primary objectives. Pharmacokinetics, objective response rate per RECIST v1.1, and molecular biomarkers were also evaluated.
Results::
Of 84 patients, 50 received monotherapy and 34 received combination therapy. No dose-limiting toxicities were observed; maximum tolerated dose was not reached. MK-4830 showed dose-related target engagement. Eleven of 34 patients in the dose-escalation phase who received combination therapy achieved objective responses; 5 previously had progressive disease on anti–PD-1/PD-L1 therapies. Exploratory evaluation of the association between response and pretreatment gene expression related to interferon-gamma signaling in tumors suggested higher sensitivity to T-cell inflammation with combination therapy than historically expected with pembrolizumab monotherapy, with greater response at more moderate levels of inflammation.
Conclusions::
This first-in-class MK-4830 antibody dosed as monotherapy and in combination with pembrolizumab was well tolerated with no unexpected toxicities, and demonstrated dose-related evidence of target engagement and antitumor activity. Inflammation intrinsic to the ILT4 mechanism may be facilitated by alleviating the myeloid-suppressive components of the tumor microenvironment, supporting the target of ILT4 as a potential novel immunotherapy in combination with an anti–PD-1/PD-L1 agent.
26
项与 MK-4830 相关的新闻（医药）2024-11-20
·肿瘤界
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毕雪瑾，谷俊杰，斯璐（北京大学肿瘤医院暨北京市肿瘤防治研究所 黑色素瘤暨肉瘤内科 恶性肿瘤发病机制及转化研究教育部重点实验室，北京 100142）
通信作者：斯璐 E-mail：silu15_silu@126.com
通
信
作
者
斯璐 教授
北京大学肿瘤医院 主任医师，教授，博士生导师
国家基金委首届临床杰青
北京大学杰出青年医师
中国临床肿瘤学会 常务理事
中国临床肿瘤学会黑色素瘤专家委员会 副主任委员
国家癌症中心国家肿瘤质控中心黑色素瘤专家委员会 副主任委员
中国临床肿瘤学会肉瘤专家委员会 常委
中国临床肿瘤学会免疫治疗专家委员会 常委
中国抗癌协会肉瘤专委会肿瘤多学科学组 副组长
《CSCO黑色素瘤诊治指南》 执笔人
《CSCO免疫检查点抑制剂相关毒性管理指南》执笔人
主要从事黑色素瘤、肉瘤、泌尿系肿瘤的临床和转化医学研究
发表J Clin Oncol、JAMA Oncol、Nature Commun等论文多篇，获得H1 connect的top 0.5%推荐
【摘要】黑色素瘤是一种常见的皮肤恶性肿瘤，其发病率在不同国家和地区存在一定的差异，总体呈现逐年增加的趋势，传统化疗治疗黑色素瘤的疗效不佳，且术后复发率较高，长期生存率较低。新辅助治疗是指在手术前给予药物治疗，近几年黑色素瘤领域最重要的进展均为新辅助治疗，多项临床试验显示出较好的结果，因此，新辅助免疫治疗的应用引起了临床广泛地关注。但对于新辅助免疫治疗的研究大多集中在皮肤黑色素瘤，而肢端黑色素瘤和黏膜黑色素瘤的临床研究较少。本文旨在回顾总结2024年度黑色素瘤及既往新辅助免疫治疗相关的临床研究，探讨与治疗效果相关的预测指标，阐明新辅助免疫治疗的生物学机制，以期为优化黑色素瘤的后续治疗提供参考。
【关键词】黑色素瘤；新辅助免疫治疗；预测指标；生物学机制；免疫检查点抑制剂
黑色素瘤是一类起源于黑色素瘤细胞的高度恶性皮肤肿瘤，是临床上常见的皮肤恶性肿瘤，具有较高的发病率及死亡率。根据世界卫生组织最新统计数据，目前世界范围内黑色素瘤年龄标准化发病率和死亡率分别为3.2/10万人和0.53/10万人，中国年龄标准化发病率和死亡率分别为0.04/10万人和0.02/10万人[1]。早期恶性黑色素瘤患者可通过外科手术切除的方式达到疾病治愈并获得长期的生存，而中晚期恶性黑色素瘤患者单纯手术切除的效果有限[2]。然而，对于存在卫星转移或淋巴结转移等高危患者术后复发风险仍较高，肿瘤厚度＞4 mm且伴随区域淋巴结转移的患者，5年总生存（overall survival，OS）率仅为30%～50%，术后复发率为50%～70%，仍处于较差的水平[3-5]。因此高危患者亟需在术后接受辅助治疗以降低复发或死亡的风险，但研究表明，仍有部分接受辅助治疗患者在短期内复发或转移，因此进一步探究新辅助免疫治疗黑色素瘤具有重要意义[6]。
黑色素瘤是一种免疫原性较高的恶性肿瘤，免疫检查点抑制剂（immune checkpoint inhibitor，ICI）治疗显著改善了黑色素瘤患者的预后，单药或联合用药，可持久改善Ⅲ期和Ⅳ期患者的生存率，甚至有可能治愈[7-8]。新辅助免疫治疗（主要指免疫检查点阻断）是在癌症患者接受手术前进行的治疗，旨在增强手术切除肿瘤的可能性，并激发患者的免疫系统攻击肿瘤[9]，其不仅可以在术前缩小肿瘤病灶、消除已经扩散的肿瘤细胞、降低肿瘤分期以减少术后复发风险，也可在新辅助阶段确定免疫治疗疗效并避免术后各种复杂情况导致的系统治疗的延迟[10]。
黑色素瘤依据病因和遗传学背景，可分为肢端型、黏膜型和皮肤型3个类型，其中黏膜黑色素瘤（占所有黑色素瘤的1%）和肢端黑色素瘤（占所有黑色素瘤的2%～3%）被定义为罕见类型的黑色素瘤[11]，然而，这2种类型在亚洲人群和其他非白种人群中发病率更高，且常规治疗对二者的效果有限[12]。同时，大多数研究集中于皮肤黑色素瘤，早期研究表明，对于肢端和黏膜黑色素瘤患者免疫疗法有益，且正在成为除手术之外的标准治疗方法，这也使新辅助免疫治疗的应用成为可能[13]。本文旨在回顾各项先前和2024年度正在进行的临床试验，并总结新辅助免疫治疗中的相关疗效预测指标，以及肢端黑色素瘤和黏膜黑色素瘤新辅助免疫治疗研究进展，以期为未来研究提供更清晰的参考和研究方向。
1
黑色素瘤新辅助免疫治疗
1.1 新辅助ICI治疗
1.1.1 新辅助ICI联合高剂量α-干扰素（high-dose interferon-α2b，HDI）治疗
研究表明，使用HDI治疗可以减少复发风险[14]，在一项Ⅰ期临床试验（NCT02339324）中，新辅助免疫检查点程序性死亡受体1（programmed death-1，PD-1）抑制剂（帕博利珠单抗）与HDI联合应用于晚期黑色素瘤患者，研究纳入30例患者，接受了2周期帕博利珠单抗以及HDI治疗后进行手术，术后帕博利珠单抗辅助治疗1年。结果显示，完成评估的26例患者的病理完全缓解率（pathologic complete response，pCR）为32%。在平均17.4个月的随访期中，所有患者均经历了3级不良事件（adverse event，AE），3例患者发生4级AE，其中1例患者发生Ⅴ级AE，这也大大限制了其后续应用[15]。
1.1.2 新辅助ICI单药治疗
既往研究已证实，PD-1抑制剂（帕博利珠单抗）单药在可切除黑色素瘤患者中有良好的治疗效果[16]。对于其应用于新辅助免疫治疗方面，一项随机Ⅱ期SWOG S1801临床试验（NCT03698019）的结果表明，新辅助治疗阶段使用PD-1抑制剂较辅助治疗阶段使用更有效。研究共纳入313例患有ⅢB～ⅣC期黑色素瘤的患者，分为新辅助-辅助治疗组和辅助治疗组。新辅助-辅助治疗组术前接受了3个周期帕博利珠单抗新辅助治疗，并在术后接受15个周期帕博利珠单抗辅助治疗；辅助治疗组仅术后接受18个周期辅助帕博利珠单抗治疗。在平均14.7个月的随访期中，新辅助-辅助治疗组患者的2年无事件生存（event free survival，EFS）率为72%，而在辅助治疗组患者中为49%。与此同时，新辅助-辅助治疗组患者≥3级AE发生率为12%，辅助治疗组14%[17]。基于该研究，2024年《中国临床肿瘤学会（CSCO）黑色素瘤诊疗指南》新增新辅助帕博利珠单抗治疗为Ⅲ期皮肤黑色素瘤辅助治疗的III级推荐[18]。
在一项单中心Ⅰb期临床试验（NCT02434354）中，研究纳入30例可切除Ⅲ～Ⅳ期黑色素瘤患者，接受1个周期新辅助帕博利珠单抗治疗并在3周后接受了手术，术后行辅助帕博利珠单抗治疗1年。在平均61.9个月的随访期中，10%的患者（3/30）达到了主要病理缓解（major pathologic response，MPR），16.7%（5/30）达到了pCR，这8例患者中5年无病生存率达到75.0%，高于未达到MPR和pCR患者（P＝0.41），5年总生存（overall survival，OS）率为100%，其中有25%（2/8）的患者复发，中位复发时间为3.9年，显著优于未达到病理缓解的患者（P＝0.044）[19]。
1.1.3 新辅助ICI联合治疗
多项关于ICI的联合使用的临床试验已经结束或正在进行，进一步证实了ICI新辅助治疗的疗效和安全性。免疫检查点PD-1/程序性死亡受体配体1抑制剂与细胞毒性T淋巴细胞相关抗原4（cytotoxic T lymphocyte antigen-4，CTLA-4）抑制剂的联合应用在包括黑色素瘤在内的多种肿瘤中显示出有良好的疗效[20]。一项随机Ⅱ期临床试验（NCT02519322）研究纳入23例患者，随机接受新辅助纳武利尤单抗单药（单药治疗组）或纳武利尤单抗＋伊匹木单抗（联合治疗组）治疗。单药治疗组患者的中位随访时间为15.0个月，联合治疗组为15.6个月。结果表明，联合治疗组患者的pCR为45%，单药治疗组为25%；联合治疗组和单药治疗组患者的客观缓解率分别为73%和25%，3级不良事件发生率分别为73%和8%[21]。
一项Ⅲ期NADINA试验（NCT04949113）共纳入423例患者，其中212例接受2个周期新辅助伊匹木单抗＋纳武利尤单抗治疗（新辅助治疗组），211例术后接受12个周期辅助纳武利尤单抗治疗（辅助治疗组），中位随访时间为9.9个月。新辅助治疗组中59%的患者达到MPR，47.2%的患者达到pCR；新辅助治疗组12个月EFS率显著高于辅助治疗组（83.7%∶57.2%，HR=0.32，P＜0.000 1）。在新辅助治疗组达到MPR的患者中，12个月无复发生存（relapse free survive，RFS）率为95.1%。新辅助治疗组患者≥不良事件发生率29.7%，辅助治疗组为14.7%[22]。该研究团队更新的数据中，新辅助治疗组18个月EFS率为80.8%，远处无转移生存率为85.7%[23]。
在SWOG S1801的Ⅱ期回顾性试验（NCT03698019）中，共纳入37例Ⅲ期黑色素瘤患者，接受新辅助纳武利尤单抗（3 mg/kg）＋伊匹木单抗1 mg/kg（N3+I1）（N3+I1为接受纳武利尤单抗3 mg/kg，伊匹单抗1 mg/kg，每3周1次）2个周期治疗，术后辅助帕博利珠单抗治疗。在平均16.1个月的随访中，MPR率为66%，2年EFS率为73%。达到MPR患者的2年RFS率为96%，3～4级不良事件发生率为30%（11/37）[24]。
LAG-3抑制剂与PD-1抑制剂的联合应用在新辅助免疫治疗领域也有尝试。一项Ⅱ期临床试验（NCT02519322）纳入30例患者，将relatlimab＋纳武利尤单抗联合应用于可切除的Ⅲ～Ⅳ期黑色素瘤患者中，结果表明，pCR率为57%，3～4级不良事件发生率为0，1年和2年RFS率分别为100%和92%，且与患者的病理缓解无关[25]。
目前更多样的新辅助治疗组合也正在尝试过程中。在Ⅰ/Ⅱ期KEYMAKER-U02试验（NCT04303169）的02C子研究中，患者分别接受了新辅助帕博利珠单抗＋vibostolimab（组1）、帕博利珠单抗＋gebasaxturev（组2）、帕博利珠单抗单药（组3）、帕博利珠单抗＋MK-4830（免疫球蛋白样转录子4阻滞剂）（组4）、favezelimab/帕博利珠单抗（组5），术后辅助帕博利珠单抗治疗。组1、组2、组3、组4、组5中位随访时间分别为29.9、29.7、34.3、15.2、9.4个月，MPR率分别为50%、40%、47%、32%和58%，pCR分别为38%、28%、40%、28%和38%，Ⅲ～Ⅳ不良事件发生率分别为8%、28%、7%、16%和15%[26]。
1.1.4 新辅助ICI联合BRAF/MEK抑制剂
BRAF突变在黑色素瘤患者中发生率为50%～60%，通常与不良预后相关，BRAF和MEK抑制剂已成为BRAF突变黑色素瘤的标准治疗方案[27-29]。在新辅助治疗领域，Ⅱ期NeoACTⅣATE临床试验（NCT03554083）中BRAF突变患者接受了新辅助维莫非尼＋cobimetinib＋阿替利珠单抗治疗，BRAF野生型患者接受了cobimetinib联合阿替利珠单抗治疗，BRAF突变组的MPR为66.7%，而BRAF野生型组为33.3%，提示靶免联合治疗在BRAF突变黑色素瘤的新辅助治疗中也有较好的疗效[30]。
一项随机Ⅱ期NeoTrio试验（NCT02858921）纳入60例患者，在BRAFV600突变的患者中使用帕博利珠单抗＋达拉非尼＋曲美替尼，并分为帕博利珠单抗单药治疗组、序贯治疗组（达拉非尼＋曲美替尼治疗1周后应用帕博利珠单抗）和联合治疗组（帕博利珠单抗＋达拉非尼+曲美替尼）。在平均24.5个月的随访中，单药治疗组、序贯治疗组和联合治疗组患者的病理缓解（pathological response，PR）率分别为55%、50%和80%，pCR率分别为30%、15%和50%，MPR率分别为40%、30%和55%，EFS率分别为45%、45%和30%，Ⅲ～Ⅳ不良事件发生率分别为5%、25%和55%。同时，联合治疗组也显示出最好的客观放射学反应和代谢反应，分别为70%和80%，以及最优的12、24个月OS率，均为95%[31]。
1.1.5 新辅助ICI联合其他治疗
在一项临床概念验证研究中，15例Ⅲ期黑色素瘤患者在第1天接受新辅助纳武利尤单抗治疗，第2天接受经皮影像引导的冷冻消融，第3天在病灶处注射10～20 mg伊匹木单抗，5～8周后行完整的淋巴结清扫，pCR＋near-PCR（n-PCR）率为53%（8/15），3～4级不良事件发生率为20%（3/15）[32]。
1.1.6 抗体-细胞因子融合蛋白治疗
瘤内注射疗法可实现较强的局部免疫反应且减少全身副作用的发生，III期PIVOTAL试验（NCT02938299）设置新辅助治疗组及对照组，治疗组允许患者试验前接受抗肿瘤治疗，纳入127例患者，行4周期抗体-细胞因子融合蛋白Daromun（L19IL2+L19TNF）瘤内注射后行手术。结果示治疗组pCR率为21%。治疗组中位无复发生存期为16.7个月，对照组为6.9月，RFS期间盲法独立中心审查结果HR为0.59（95%CI 0.41-0.86；P=0.005），治疗组的远处无复发生存期显著延长（HR：0.60；P=0.029），常见不良反应为低级别局部不良事件，全身不良事件较少也均低级别。可见Daromun具有较好的治疗效果及良好的安全性，也为围手术期二次新辅助治疗提供了新的选择[33]。
新辅助免疫治疗相关的各项已经完成或正在进行的临床试验汇总如表1所示。
1.2 新辅助免疫治疗在特殊人群中的应用
1.2.1 在肢端黑色素瘤中的应用
一项病例报告报道了1例患者接受了帕博利珠单抗的新辅助治疗。治疗后，可在影像学检查中观察到手指和淋巴结转移的肿瘤缩小，并成功帮助该患者避免了截肢。随访9个月未出现复发，耐受性良好[34]。
一项包含30例患者的Ⅰb期临床试验（NCT04197882）将溶瘤病毒OrienX010和PD-1抑制剂联合应用。术前使用8×107 pfu/ml的OrienX010 10 ml和3 mg/kg的特瑞普利单抗4～6个周期，以及辅助特瑞普利单抗3 mg/kg治疗，直至出现放射学缓解。在21例完成新辅助治疗并接受手术的患者中，PR率为81%，pCR率为14%，病理部分缓解率为67%。在平均8.9个月的随访后，无复发患者。Ⅲ～Ⅳ级不良事件发生率为10%[35]。
1.2.2 在黏膜黑色素瘤中的应用
一项Ⅱ期临床试验纳入29例可切除黏膜黑色素瘤患者，患者术前接受特瑞普利单抗及阿昔替尼治疗，术后辅助特瑞普利单抗治疗。在平均34.2个月的随访中，PR为33.3%（8/24），pCR为16.7%（4/24），中位EFS为11.1个月，3～4级不良事件发生率为27.5%（8/29）。在新辅助治疗后，特别是在达到PR患者中，CD3+和CD3+CD8+肿瘤浸润性淋巴细胞显著增加[36]。在另一项临床试验中，36例患者接受新辅助抗PD-1和CTLA-4抑制剂治疗，平均随访时间为37.9个月，中位EFS为9.2个月，3年EFS率为29%，3年OS率为55%。3级不良事件发生率为39%[37]。
一项Ⅱ期NeoPlus试验纳入19例患者可切除黏膜黑色素患者，患者接受2个周期仑伐替尼联合帕博利珠单抗新辅助治疗，术后辅助帕博利珠单抗治疗15个周期。中位随访时间为49周，共计15例患者完成手术，术后患者中40%（6/15）达到PR，pCR率为13.3%（2/15），达到病理缓解的肿瘤中可观察到CD8+T淋巴细胞的增加。常见的不良事件包括蛋白尿、甲状腺功能减退、发声困难，无患者发生4～5级不良事件[38]。
伊匹木单抗联合纳武利尤单抗作为新辅助治疗已经在皮肤黑色素瘤患者中展现出良好的效果。在黏膜黑色素瘤患者中，一项病例报告显示2例黏膜黑色素瘤患者接受了的每3周1次伊匹木单抗（1 mg/kg）联合纳武利尤单抗（3 mg/kg）新辅助治疗。结果表明，2例患者术后均达到肿瘤完全清除，且持续保持无病状态[39]。
1.3 正在进行的临床试验
截至2024年11月，通过临床试验资料库（https://clinicaltrials.gov/）检索黑色素瘤正在进行的新辅助免疫治疗相关临床试验发现，立项总数32项，其中14项正在进行中、13项仍在招募、5项未招募及状态未知（检索词包括“Melanoma” “Neoadjuvant immunotherapy” “Acral melanoma” “Mucosal melanoma”，排除非新辅助免疫治疗相关试验及结束、退出的相关试验）（表2）。
2
新辅助免疫治疗效果预测指标
新辅助免疫治疗在黑色素瘤患者中显示了良好的治疗效果，但仍有许多患者面临复发的风险，尽管病理反应可以帮助评估复发和进一步治疗，但仍然需要更多的生物标志物来预测治疗效果。一项基础试验招募了来自OpACIN-neo和PRADO临床试验的30例患者，并证明了细胞游离DNA（cell-free DNA，cfDNA）在预测新辅助免疫治疗后复发中的作用。基线cfDNA在50%（15/30）患者中可检测，其中2例在治疗前后cfDNA均为阳性的患者的复发率为100%。在平均47个月的随访中，9例复发患者中44.4%（4/9）可以检测到cfDNA的存在[40]。
研究表明，肿瘤微环境和病理反应之间相关。例如，NeoPele试验对20例可切除Ⅲ期黑色素瘤患者应用帕博利珠单抗联合仑伐替尼新辅助治疗，结果显示，55%（11/20）患者达到MPR。与未达到MPR的患者相比，MPR患者在基线时T淋巴细胞（11%∶3%，P=0.012 7）和滤泡辅助性T淋巴细胞（CXCR5+，29%∶9%，P=0.029 3）的比例更高。MPR患者在新辅助治疗后显示出肿瘤反应性T淋巴细胞（CD39+）、CD21+B细胞、成熟B细胞（CD21+CXCR5+）的增加，以及组织驻留干细胞样T淋巴细胞（CD103+TCF7+）的减少（P＝0.019 5），同时第6周在肿瘤微环境中也检测到淋巴样聚集物数量的增加（P＝0.015 6）[41]。另一项近期研究发现，在接受新辅助PD-1抑制剂治疗后，肿瘤坏死中发现更多CD3+及CD8+肿瘤浸润淋巴细胞，这些细胞与PR率、5年RFS率均呈正相关[42]。此外，趋化因子CTACK和CXCL9的表达以及外周血CD8+中央记忆性T淋巴细胞也与更有效的治疗反应相关，而PD-1、CD161、PD-L2+B淋巴细胞以及髓样细胞的比例则与患者预后呈负相关[30,43]。
3
总结与展望
2024年新辅助免疫治疗取得了显著进展，这些进展为黑色素瘤患者提供了更多治疗选择，并有望改善患者预后。尽管黑色素瘤新辅助免疫治疗为黑色素瘤患者带来了长期获益，然而新辅助免疫治疗仍面临许多新的挑战：①目前大多数研究仍处于Ⅱ期临床试验，仍然需要更长时间及更大样本的临床研究；②新辅助免疫疗法的机制尚未完全阐明，已有相关文献提示，在新辅助免疫治疗中局部免疫反应的增强、组织驻留记忆T淋巴细胞更有效的识别和攻击肿瘤细胞并通过组织迁移增强全身免疫反应可能是相关机制的一个方面，未来还需要进一步的详细研究[44]；③随着新辅助免疫治疗的广泛使用，免疫相关毒性及耐药性不可避免，因此，未来需深入地了解其所涉及的机制，并根据不同患者的个体情况制订个性化的治疗方案[45-47]。
黑色素瘤是一种危害人类健康的恶性肿瘤，新辅助免疫治疗相关研究不断得出可观的结论，对于皮肤及肢端粘膜亚型黑色素瘤患者的病理缓解及减少肿瘤复发风险有益。不同的疗效预测指标也在不断被发现应用，多种治疗手段的联合、不良反应的探讨及更深入的机制研究成为未来研究的思路之一，相信未来关于新辅助免疫治疗的相关研究能为患者带来更好的临床获益。
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免疫疗法CSCO会议
2024-05-07
Conference Call Begins at 4:30 p.m. Eastern Time Today
JUPITER, Fla.--(BUSINESS WIRE)-- Ligand Pharmaceuticals Incorporated (Nasdaq: LGND) today reported financial results for the three months ended March 31, 2024, and provided an operating forecast and business updates. Ligand management will host a conference call today beginning at 4:30 p.m. Eastern Time to discuss this announcement and answer questions.
“We are pleased to report another quarter of strong financial results driven by the performance of our commercial royalty portfolio. Simultaneously, we continue to build our portfolio of development stage royalty assets to deliver future growth,” said Todd Davis, CEO of Ligand. “We continue to originate a robust pipeline of royalty opportunities with our proactive business development efforts. This is evidenced by our most recent royalty financing agreement with Agenus which will add several new late stage oncology assets to our portfolio. As we look ahead to the near term, we have several important catalysts in our existing portfolio in 2024. This includes Verona Pharma’s ensifentrine and Merck’s V116, both of which have been assigned PDUFA dates in June, top-line Phase 3 data on Takeda’s soticlestat, expected in the third quarter, and the commercial launch of ZELSUVMI®, a much-needed treatment for molluscum contagiosum, in late 2024.”
First Quarter 2024 Financial Results
Total revenues and other income for the first quarter of 2024 were $31.0 million, compared with $44.0 million for the same period in 2023. Royalties for the first quarter of 2024 were $19.1 million, compared with $17.6 million for the same period in 2023, with the increase primarily attributable to Amgen’s (Nasdaq: AMGN) Kyprolis, Jazz Pharmaceuticals' (Nasdaq: JAZZ) RYLAZE, Merck and Co.’s (NYSE: MRK) VAXNEUVANCE and Travere Therapeutics’ (Nasdaq: TVTX) FILSPARI, partially offset by a decline in CASI’s (Nasdaq: CASI) EVOMELA. Captisol sales were $9.2 million for the first quarter of 2024, compared with $10.6 million for the same period in 2023, with the change due to the timing of customer orders. Contract revenue and other income was $2.7 million for the first quarter of 2024, compared with $15.7 million for the same period in 2023, with the difference driven by a $15.3 million milestone payment earned from Travere Therapeutics upon the FDA approval of FILSPARI in the prior year quarter.
Cost of Captisol was $2.9 million for the first quarter of 2024, compared with $3.7 million for the same period in 2023, with the decrease due to lower total Captisol sales. Amortization of intangibles was $8.2 million for the first quarter of 2024, compared with $8.5 million for the same period in 2023. Research and development expense was $6.0 million for the first quarter of 2024, compared with $6.7 million for the same period in 2023. General and administrative expense was $11.0 million for the first quarter of 2024, compared with $10.9 million for the same period in 2023.
Net income from continuing operations for the first quarter of 2024 was $86.1 million, or $4.75 per diluted share, compared with net income from continuing operations of $43.6 million, or $2.43 per diluted share, for the same period in 2023. The increase in net income from the prior year period is due primarily to realized gains from short-term investments associated with Viking Therapeutics (Nasdaq: VKTX) stock of $60.0 million. Adjusted net income from continuing operations for the first quarter of 2024 was $69.7 million, or $3.84 per diluted share, compared to $39.9 million, or $2.28 per diluted share, for the same period in 2023. Excluding the impact of gains from sales of Viking Therapeutics stock, core adjusted net income from continuing operations was $21.8 million, or $1.20 per diluted share, compared with $23.4 million, or $1.33 per diluted share, for the same period in 2023. The decrease in core adjusted net income is driven by the $15.3 million milestone payment earned from Travere Therapeutics in the prior year quarter. See the table below for a reconciliation of net income from continuing operations to adjusted net income from continuing operations.
As of March 31, 2024, Ligand had cash, cash equivalents and short-term investments of $310.6 million.
2024 Financial Guidance
Ligand is reaffirming its 2024 financial guidance. The Company expects 2024 royalties ranging from $90 million to $95 million, sales of Captisol to range from $25 million to $27 million, and contract revenue ranging from $15 million to $20 million. These revenue components result in total revenue forecast of $130 million to $142 million. Ligand notes that with total revenue of $130 million to $142 million, core adjusted earnings per diluted share are expected to range from approximately $4.25 to $4.75. This guidance excludes the $60 million gain from short-term investments on the sale of Viking Therapeutics stock.
First Quarter and Recent 2024 Business Highlights
On May 7, Ligand announced a $100 million royalty financing agreement with Agenus, Inc. Under the terms of the agreement, in exchange for an initial $75 million payment, Ligand will receive 18.75% of the royalties and 31.875% of the future milestones on six Agenus-partnered oncology programs including BMS-986442 (Bristol Myers Squibb), AGEN2373 (Gilead Sciences), INCAGN2385 and INCAGN2390 (Incyte), MK-4830 (Merck), and UGN-301 (UroGen Pharma). Ligand will also receive a 2.625% royalty on future global net sales of Agenus’ novel immuno-oncology botensilimab in combination with balstilimab (“BOT/BAL”) program. Agenus’ BOT/BAL program received Fast Track Designation from the U.S. FDA in April 2023 for patients with metastatic, refractory colorectal cancer that is not MSI-H/dMMR, who do not have liver metastases, and who failed first and second line standard of care treatments. The capital will support Agenus’ upcoming Phase 3 BOT/BAL colorectal cancer trial and other key commercialization activities. Ligand has an option to invest an additional $25 million to increase its economics on a pro rata basis for the additional investment.
On April 3, Ligand announced the creation of Pelthos Therapeutics under the leadership of Scott Plesha as Chief Executive Officer. Pelthos is focused on the commercialization of innovative, safe, and efficacious therapeutic products for patients suffering from conditions with limited treatment options. ZELSUVMI™ (berdazimer topical gel, 10.3%), its first product, is the first and only FDA-approved prescription medicine for the treatment of the highly transmissible molluscum contagiosum (molluscum) viral skin infection in adults and pediatric patients one year of age and older. It can be applied by patients, parents, or caregivers at home, outside of a physician's office, or other medical setting. ZELSUVMI received a Novel Drug designation from the U.S. FDA in January 2024 to treat molluscum viral skin infection. ZELSUVMI was developed using Pelthos' proprietary nitric oxide-based NITRICIL™ technology platform. Commercial availability of ZELSUVMI in the United States is expected by late 2024. The rights to ZELSUVMI and all assets related to the NITRICIL technology platform were acquired from Novan, Inc. in September 2023.
Portfolio Updates
On April 24, Travere Therapeutics and CSL Vifor (ASX: CSL), Travere’s commercial partner in Europe, gained European Commission conditional marketing authorization (CMA) for FILSPARI (sparsentan) for the treatment of adults with primary IgA nephropathy (IgAN). All member states of the EU, including Iceland, Liechtenstein, and Norway are included in the CMA. The European Commission's decision follows the Committee for Medicinal Products for Human Use (CHMP)'s positive opinion in February 2024, based on results from the pivotal Phase 3 PROTECT study of FILSPARI in IgAN. The PROTECT study met its primary endpoint at the pre-specified interim analysis with statistical significance.
On May 6, Travere Therapeutics announced the FDA granted Priority Review for its sNDA to convert FILSPARI® (sparsentan) from accelerated approval to full approval for the treatment of IgAN in the U.S. with a PDUFA target action date of September 5, 2024.
On April 24, Viking announced that in the first quarter this year they completed the 52-week biopsies for the Phase 2b VOYAGE study of VK2809 in biopsy-confirmed NASH and fibrosis. As we've previously mentioned, the study successfully achieved its primary endpoint after 12 weeks of treatment and affirmed VK2809's potent effect on liver fat, along with its favorable tolerability and safety profile. Viking plans to report data on histologic changes assessed after 52 weeks of treatment later in the second quarter of 2024.
On April 15, Marinus Pharmaceuticals provided an update on the Phase 3 RAISE trial evaluating the safety and efficacy of IV ganaxolone in patients with refractory status epilepticus. The trial did not meet pre-defined stopping criteria at the interim analysis; Marinus has completed RAISE enrollment at approximately 100 patients with topline results expected in the summer of 2024. Future development of IV ganaxolone in refractory status epilepticus will be assessed following review of the final RAISE results. Marinus remains blinded to the RAISE trial data.
Adjusted Financial Measures
Ligand reports adjusted net income and adjusted net income per diluted share in addition to, and not as a substitute for, or superior to, financial measures calculated in accordance with GAAP. The Company’s financial measures under GAAP include share-based compensation expense, amortization of debt-related costs, amortization related to acquisitions and intangible assets, changes in contingent liabilities, mark-to-market adjustments for amounts relating to its equity investments in public companies, excess tax benefit from share-based compensation, income tax effect of adjusted reconciling items and others that are listed in the itemized reconciliations between GAAP and adjusted financial measures included at the end of this press release. However, the Company does not provide reconciliations of such forward-looking adjusted measures to GAAP due to the inherent difficulty in forecasting and quantifying certain amounts that are necessary for such reconciliation, including adjustments that could be made for changes in contingent liabilities, changes in the market value of its investments in public companies, share-based compensation expense and the effects of any discrete income tax items. Management has excluded the effects of these items in its adjusted measures to assist investors in analyzing and assessing the Company’s past and future core operating performance. Additionally, adjusted earnings per diluted share is a key component of the financial metrics utilized by the Company’s board of directors to measure, in part, management’s performance and determine significant elements of management’s compensation.
Conference Call
Ligand management will host a conference call today beginning at 4:30 p.m. Eastern Time (1:30 p.m. Pacific Time) to discuss this announcement and answer questions. To participate via telephone, please dial (800) 715-9871 using the conference ID 8755336. Callers outside the U.S. may dial 1-(646) 307-1963. To participate via live or replay webcast, a link is available at .
About Ligand Pharmaceuticals
Ligand is a biopharmaceutical company enabling scientific advancement through supporting the clinical development of high-value medicines. Ligand does this by providing financing, licensing our technologies or both. Its business model seeks to generate value for stockholders by creating a diversified portfolio of biopharmaceutical product revenue streams that are supported by an efficient and low corporate cost structure. Ligand’s goal is to offer investors an opportunity to participate in the promise of the biotech industry in a profitable and diversified manner. Its business model focuses on funding programs in mid- to late-stage drug development in return for economic rights, purchasing royalty rights in development stage or commercial biopharmaceutical products and licensing its technology to help partners discover and develop medicines. Ligand partners with other pharmaceutical companies to leverage what they do best (late-stage development, regulatory management and commercialization) in order to generate its revenue. Ligand’s Captisol® platform technology is a chemically modified cyclodextrin with a structure designed to optimize the solubility and stability of drugs. Ligand has established multiple alliances, licenses and other business relationships with the world’s leading biopharmaceutical companies including Amgen, Merck, Pfizer, Jazz, Takeda, Gilead Sciences and Baxter International. For more information, please visit at . Follow Ligand on X @Ligand_LGND.
We use our investor relations website and X as a means of disclosing material non-public information and for complying with our disclosure obligations under Regulation FD. Investors should monitor our website and our X account, in addition to following our press releases, SEC filings, public conference calls and webcasts.
About Captisol®
Captisol is a patent-protected, chemically modified cyclodextrin with a structure designed to optimize the solubility and stability of drugs. Captisol was invented and initially developed by scientists in the laboratories of Dr. Valentino Stella, University Distinguished Professor at the University of Kansas' Higuchi Biosciences Center, for specific use in drug development and formulation. This unique technology has enabled several FDA-approved products, including Amgen's Kyprolis®, Baxter's NEXTERONE, Acrotech Biopharma's EVOMELA®, Sage Therapeutics' ZULRESSO®, Gilead’s VEKLURY®, and Merck's NOXAFIL®. More information is available at .
Forward-Looking Statements
This news release contains forward-looking statements by Ligand that involve risks and uncertainties and reflect Ligand's judgment as of the date of this release. Words such as “plans,” “believes,” “expects,” “anticipates,” and “will,” and similar expressions, are intended to identify forward-looking statements. These forward-looking statements include, without limitation, statements regarding: Ligand’s ability to expand its portfolio with life sciences royalty opportunities; the timing of clinical and regulatory events of Ligand’s partners, including the expected commercial launch of Zelsuvmi by Pelthos Therapeutics; the timing of the initiation or completion of preclinical studies and clinical trials by Ligand and its partners; the timing of product launches by Ligand or its partners; and guidance regarding the full-year 2024 financial results. Actual events or results may differ from Ligand's expectations due to risks and uncertainties inherent in Ligand’s business, including, without limitation: Ligand relies on collaborative partners for milestone payments, royalties, materials revenue, contract payments and other revenue projections and may not receive expected revenue; Ligand may not receive expected revenue from Captisol material sales; Ligand and its partners may not be able to timely or successfully advance any product(s) in its internal or partnered pipeline or receive regulatory approval and there may not be a market for the product(s) even if successfully developed and approved; Ligand may not achieve its guidance for 2024; Ligand faces competition in acquiring royalties and locating suitable royalties to acquire; Ligand may not be able to create future revenues and cash flows through the acquisition of royalties or by developing innovative therapeutics; products under development by Ligand or its partners may not receive regulatory approval; the total addressable market for our partners’ products may be smaller than estimated; Ligand faces competition with respect to its technology platforms which may demonstrate greater market acceptance or superiority; Ligand is currently dependent on a single source sole supplier for Captisol and failures by such supplier may result in delays or inability to meet the Captisol demands of its partners; Ligand’s partners may change their development focus and may not execute on their sales and marketing plans for marketed products for which Ligand has an economic interest; Ligand’s and its partners’ products may not be proved to be safe and efficacious and may not perform as expected and uncertainty regarding the commercial performance of such products; Ligand or its partners may not be able to protect their intellectual property and patents covering certain products and technologies may be challenged or invalidated; Ligand's partners may terminate any of its agreements or development or commercialization of any of its products; Ligand and its partners may experience delays in the commencement, enrollment, completion or analysis of clinical testing for its product candidates, or significant issues regarding the adequacy of its clinical trial designs or the execution of its clinical trials, challenges, costs and charges associated with integrating acquisitions with Ligand’s existing businesses; Ligand may not be able to successfully commercialize ZELSUVMI; the potential impact of six partnered programs, including BMS-986442 (Bristol Myers Squibb), AGEN2373 (Gilead Sciences), INCAGN2385 and INCAGN2390 (Incyte), MK-4830 (Merck), and UGN-301 (UroGen Pharma); the trial and regulatory success of Agenus’ upcoming Phase 3 trial of botensilimab in combination with balstilimab (“BOT/BAL”) for patients with metastatic, refractory colorectal cancer that is not MSI-H/dMMR and who do not have liver metastases; Ligand may not be able to successfully implement its strategic growth plan and continue the development of its proprietary programs; restrictions under Ligand's credit agreement may limit its flexibility in operating its business and a default under the agreement could result in a foreclosure of the collateral securing such obligations; changes in general economic conditions, including as a result of war, conflict or epidemic diseases and ongoing or future litigation could expose Ligand to significant liabilities and have a material adverse effect on the company. The failure to meet expectations with respect to any of the foregoing matters may reduce Ligand's stock price. Additional information concerning these and other risk factors affecting Ligand can be found in prior press releases available at as well as in Ligand's public periodic filings with the Securities and Exchange Commission available at . Ligand disclaims any intent or obligation to update these forward-looking statements beyond the date of this release, including the possibility of additional license fees and milestone revenues we may receive. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.
Other Disclaimers and Trademarks
The information in this press release regarding certain third-party products and programs, including ensifentrine, a Verona product candidate, V116, a Merck product candidate, Soticlestat, a Takeda product candidate, Kyprolis, an Amgen product, Rylaze, a Jazz Pharmaceuticals product, Vaxneuvance, a Merck product, FILSPARI, a Travere Therapeutics product, QTORIN, Evomela, a CASI product, and other programs described herein, comes from information publicly released by the owners of such products and programs. Ligand is not responsible for, and has no role in, the development of such products or programs.
Ligand owns or has rights to trademarks and copyrights that it uses in connection with the operation of its business including its corporate name, logos and websites. Other trademarks and copyrights appearing in this press release are the property of their respective owners. The trademarks Ligand owns include Ligand®, Captisol® and ZELSUVMI, a Novan product. Solely for convenience, some of the trademarks and copyrights referred to in this press release are listed without the ®, © and ™ symbols, but Ligand will assert, to the fullest extent under applicable law, its rights to its trademarks and copyrights.
LIGAND PHARMACEUTICALS INCORPORATED
CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS
(Unaudited, in thousands, except per share amounts)
Three Months Ended March 31,
2024
2023
Revenues and other income:
Revenue from intangible royalty assets
$
18,357
$
17,154
Income from financial royalty assets
738
493
Royalties
19,095
17,647
Captisol
9,212
10,622
Contract revenue and other income
2,671
15,710
Total revenues and other income
30,978
43,979
Operating costs and expenses:
Cost of Captisol
2,882
3,717
Amortization of intangibles
8,186
8,539
Research and development
5,971
6,663
General and administrative
10,951
10,855
Total operating costs and expenses
27,990
29,774
Income from operations
2,988
14,205
Gain from short-term investments
110,772
39,533
Interest income, net
1,879
1,195
Gain on derivative instruments
196
—
Other non-operating income (expense), net
(2,388
)
603
Total other income, net
110,459
41,331
Income before income taxes from continuing operations
113,447
55,536
Income tax expense
(27,308
)
(11,922
)
Net income from continuing operations
86,139
43,614
Net loss from discontinued operations
—
(1,665
)
Net income:
$
86,139
$
41,949
Basic net income from continuing operations per share
$
4.86
$
2.56
Basic net loss from discontinued operations per share
$
—
$
(0.10
)
Basic net income per share
$
4.86
$
2.46
Shares used in basic per share calculation
17,732
17,063
Diluted net income from continuing operations per share
$
4.75
$
2.43
Diluted net loss from discontinued operations per share
$
—
$
(0.09
)
Diluted net income per share
$
4.75
$
2.33
Shares used in diluted per share calculation
18,122
17,974
LIGAND PHARMACEUTICALS INCORPORATED
CONDENSED CONSOLIDATED BALANCE SHEETS
(unaudited, in thousands)
March 31, 2024
December 31, 2023
Assets
Current assets:
Cash, cash equivalents and short-term investments
$
310,593
$
170,309
Accounts receivable, net
28,435
32,917
Inventory
21,337
23,969
Income tax receivable
—
6,395
Prepaid expenses
1,237
1,182
Other current assets
7,311
2,657
Total current assets
368,913
237,429
Deferred income taxes, net
—
214
Goodwill and other identifiable intangible assets, net
396,670
402,976
Long-term portion of financial royalty assets, net
65,710
62,291
Property and equipment, net
15,135
15,607
Operating lease right-of-use assets
6,028
6,062
Financing lease right-of-use assets
3,219
3,393
Equity method investment in Primrose Bio
10,469
12,595
Other investments
36,500
36,726
Other assets
11,225
9,923
Total assets
$
913,869
$
787,216
Liabilities and Stockholders' Equity
Current liabilities:
Accounts payable and accrued liabilities
$
14,323
$
14,894
Income tax payable
1,138
—
Current contingent liabilities
127
256
Current operating lease liabilities
1,000
403
Current finance lease liabilities
3
7
Current deferred revenue
1,227
1,222
Total current liabilities
17,818
16,782
Long-term contingent liabilities
2,888
2,942
Long-term operating lease liabilities
5,191
5,755
Deferred income taxes, net
50,606
31,622
Other long-term liabilities
30,845
29,202
Total liabilities
107,348
86,303
Total stockholders' equity
806,521
700,913
Total liabilities and stockholders' equity
$
913,869
$
787,216
LIGAND PHARMACEUTICALS INCORPORATED
ADJUSTED FINANCIAL MEASURES
(Unaudited, in thousands, except per share amounts)
Three Months Ended March 31,
2024
2023(5)
Net income from continuing operations
$
86,139
$
43,614
Adjustments:
Share-based compensation expense
7,334
5,931
Non-cash interest expense (1)
84
95
Amortization related to acquisitions and intangible assets
8,186
8,539
Amortization of financial royalty assets (2)
3,262
(493
)
Change in contingent liabilities (3)
(33
)
(671
)
Novan operating loss
6,160
—
Gain from short-term investments
(110,772
)
(39,533
)
Realized gain from short-term investments
59,979
20,552
Provision for current expected credit losses on financial royalty assets
(2,841
)
—
Loss from equity method investment in Primrose Bio
2,352
—
Other
153
102
Income tax effect of adjusted reconciling items above
9,197
1,980
Excess tax benefit (shortfall) from share-based compensation (4)
465
(212
)
Adjusted net income from continuing operations
$
69,665
$
39,904
Realized gains from sales of VKTX stock, net of tax
(47,857
)
(16,548
)
Core adjusted net income from continuing operations
$
21,808
$
23,356
Diluted per-share amounts attributable to common shareholders:
Diluted net income per share from continuing operations
$
4.75
$
2.43
Adjustments:
Share-based compensation expense
0.40
0.34
Non-cash interest expense (1)
—
0.01
Amortization related to acquisitions and intangible assets
0.45
0.49
Amortization of financial royalty assets (2)
0.18
(0.03
)
Change in contingent liabilities (3)
—
(0.04
)
Novan operating loss
0.34
—
Gain from short-term investments
(6.11
)
(2.26
)
Realized gain from short-term investments
3.31
1.18
Provision for current expected credit losses on financial royalty assets
(0.16
)
—
Loss from equity method investment in Primrose Bio
0.13
—
Other
0.01
0.01
Income tax effect of adjusted reconciling items above
0.51
0.09
Excess tax benefit (shortfall) from share-based compensation (4)
0.03
(0.01
)
Adjustment for shares excluded using the if-converted method under ASU 2020-06 (6)
—
0.07
Adjusted diluted net income per share from continuing operations
$
3.84
$
2.28
Realized gains from sales of VKTX stock, net of tax
(2.64
)
(0.95
)
Core adjusted diluted net income per share from continuing operations
$
1.20
$
1.33
GAAP - weighted average number of common shares - diluted
18,122
17,974
Diluted effect of the 2023 Notes
—
(483
)
Adjusted weighted average number of common shares - diluted
18,122
17,491
(1) Amounts represent non-cash debt related costs that are calculated in accordance with the authoritative accounting guidance for our revolving credit facility and convertible debt instruments that may be settled in cash.
(2) Amounts represent the adjustments bridging the income from financial royalty assets to total contractual payments recorded in the period.
(3) Amounts represent changes in fair value of contingent consideration related to CyDex and Metabasis transactions.
(4) Excess tax benefits from share-based compensation are recorded as a discrete item within the provision for income taxes on the consolidated statements of operations as a result of the adoption of an accounting pronouncement (ASU 2016-09) on January 1, 2017. Prior to the adoption, the amount was recognized in additional paid-in capital on the consolidated statement of stockholders' equity.
(5) Q1 2023 numbers are adjusted to exclude after-tax impact from realized gain of Viking common stock.
(6) Excluding the impact from the adoption of accounting pronouncement (ASU 2020-06) on January 1, 2022 as the Company intended to settle the principal balance in cash. Under the standard, the Company is required to reflect the dilutive effect of the 2023 Notes by application of the if-converted method.
临床3期临床结果临床2期上市批准财报
2024-05-07
Capital infusion will support botensilimab and balstilimab (BOT/BAL) clinical development, confirmatory Phase 3 trial, and launch readiness activities
Ligand entitled to royalties and milestone payments on six Agenus-partnered programs as well as royalties on future global net sales generated by BOT/BAL
Transaction allows for a syndication of up to an additional $125 million in capital
JUPITER, Fla. and LEXINGTON, Mass.--(BUSINESS WIRE)-- Ligand Pharmaceuticals Incorporated (Nasdaq: LGND) and Agenus Inc. (Nasdaq: AGEN), a leader in discovering and developing novel immunological agents to treat various cancers, today announced that the companies have entered into a royalty financing agreement to support Agenus’ key development initiatives in the ongoing BOT/BAL clinical development program, including its planned confirmatory Phase 3 trial in its lead indication of patients with metastatic, relapsed/refractory colorectal cancer not microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR), who are without active liver metastases (r/r MSS CRC NLM), along with other launch readiness activities.
Under the terms of the agreement, Ligand will pay $75 million to Agenus at closing. In addition, Ligand has the option to invest an additional $25 million on the same terms on a pro rata basis. In return for the initial $75 million payment, Ligand will receive 18.75% of the future royalties and 31.875% of the future milestone payments related to six of Agenus’ clinical-stage partnered oncology programs, including BMS-986442 (Bristol Myers Squibb), AGEN2373 (Gilead Sciences), INCAGN2385 and INCAGN2390 (Incyte), MK-4830 (Merck), and UGN-301 (UroGen Pharma). Ligand’s portion of the milestones related to these six programs has the potential to exceed $400 million, with royalties in the low single digits. In addition, Ligand will also receive a 2.625% royalty on future global net sales generated by BOT/BAL. The royalties and milestone payments owed to Ligand could be adjusted up or down based upon pre-determined future events and achievements of certain milestones.
“This partnership with Agenus gives us an interest in multiple oncology products diversified across targets and indications, including royalties on BOT/BAL and several partnered oncology programs being developed by experienced biopharmaceutical companies,” commented Todd Davis, CEO of Ligand. “We are encouraged by Agenus’ progress to move BOT/BAL forward in the metastatic, relapsed/refractory colorectal cancer setting, in addition to other major indications, including pancreatic cancer, lung cancer, and melanoma. This demonstrates the potential value BOT/BAL could deliver to patients, as well as the significant revenue potential of this broad and highly differentiated program. Our seasoned investment team spent significant time and effort conducting diligence on each of these unique and valuable assets.”
As part of the agreement, the companies have also agreed to allow Agenus to syndicate up to an additional $125 million, potentially bringing the total capital infusion up to $200 million. This strategic collaboration will further validate BOT/BAL’s potential as a transformative treatment for patients with solid tumor malignancies and enhances Agenus’ ability to advance this promising therapy.
Garo Armen, Chairman and Chief Executive Officer of Agenus, commented, “We are pleased to partner with Ligand, a company that recognizes the paradigm-shifting potential of BOT/BAL in delivering benefit to patients across the solid tumor landscape. Ligand also recognizes the potential impact of our ongoing partnered programs, many of which are showing promise in the clinic. This collaboration enables both parties to benefit in the future potential success of these assets while simultaneously enabling Agenus to accelerate our efforts to bring BOT/BAL to patients in need.”
Over 900 patients have been treated with BOT/BAL in clinical trials across nine different difficult to treat solid tumor cancers. The novel therapeutic regimen has demonstrated the potential to be combined with chemotherapy and other standard of care therapies, and as an immunotherapy-only combo in CRC, one of the most prevalent solid tumors globally. In April 2023, Agenus was granted Fast Track Designation from the U.S. Food and Drug Administration (FDA) for the investigation of the BOT/BAL combination in patients with r/r MSS CRC NLM. Patients targeted with this designation are heavily pretreated with standard of care chemotherapy, anti-VEGF and anti-EGFR if RAS wild type.
About Agenus
Agenus is a leading immuno-oncology company targeting cancer and infectious diseases with a comprehensive pipeline of immunological agents. The company’s mission is to expand patient populations benefiting from cancer immunotherapy through combination approaches, using a broad repertoire of antibody therapeutics, adoptive cell therapies (through MiNK Therapeutics) and adjuvants (through SaponiQx). Agenus is headquartered in Lexington, MA. For more information, visit or @agenus_bio. Information that may be important to investors will be routinely posted on Agenus’ website and social media channels.
About Botensilimab
Botensilimab is an investigational multifunctional anti-CTLA-4 immune activator (antibody) designed to boost both innate and adaptive anti-tumor immune responses. Its novel design leverages mechanisms of action to extend immunotherapy benefits to "cold" tumors which generally respond poorly to standard of care or are refractory to conventional PD-1/CTLA-4 therapies and investigational therapies. Botensilimab augments immune responses across a wide range of tumor types by priming and activating T cells, downregulating intratumoral regulatory T cells, activating myeloid cells and inducing long-term memory responses.
Over 900 patients have been treated with botensilimab in phase 1 and phase 2 clinical trials. Botensilimab alone, or in combination with Agenus’ investigational PD-1 antibody, balstilimab, has shown clinical responses across nine metastatic, late-line cancers. For more information about botensilimab trials, visit with the identifiers NCT03860272, NCT05608044, NCT05630183, and NCT05529316.
About Agenus Partnered Programs
BMS 986-442 is a novel first-in-class anti-TIGIT and CD96 bispecific antibody engineered with an enhanced Fc region for high binding affinity and improved T and NK cell activation. MK-4830 is a potentially first-in-class human IgG4 monoclonal antibody targeting the immunoglobulin-like transcript 4 (ILT4) receptor. AGEN2373 is a fully human monoclonal antibody designed to boost the immune response to cancer cells by enhancing CD137 co-stimulatory signaling in activated immune cells. The unique binding properties of AGEN2373 are expected to limit its activity outside of the tumor site and mitigate toxicities that may be associated with systemic activation of CD137 in humans.UGN-301 (zalifrelimab) is a novel, fully human monoclonal immunoglobulin G1 (IgG1) designed to block CTLA-4 (cytotoxic T-lymphocyte associated antigen 4) from interacting with its ligands CD80 and CD86. CTLA-4 is a negative regulator of immune activation that is considered a foundational target within the immuno-oncology market. UroGen has a license to use zalifrelimab via intravesical delivery for treatment of cancers of the urinary tract. INCAGN2385, a novel human Fc silent IgG1 monoclonal antibody targeting LAG-3, blocking binding to MHC II. INCAGN3920, a novel recombinant human IgG1 monoclonal antibody targeting TIM-3.
About Ligand Pharmaceuticals
Ligand is a biopharmaceutical company enabling scientific advancement through supporting the clinical development of high-value medicines. Ligand does this by providing financing, licensing our technologies or both. Its business model seeks to generate value for stockholders by creating a diversified portfolio of biopharmaceutical product revenue streams that are supported by an efficient and low corporate cost structure. Ligand’s goal is to offer investors an opportunity to participate in the promise of the biotech industry in a profitable and diversified manner. Its business model focuses on funding programs in mid- to late-stage drug development in return for economic rights, purchasing royalty rights in development stage or commercial biopharmaceutical products and licensing its technology to help partners discover and develop medicines. Ligand partners with other pharmaceutical companies to leverage what they do best (late-stage development, regulatory management and commercialization) in order to generate its revenue. Ligand’s Captisol® platform technology is a chemically modified cyclodextrin with a structure designed to optimize the solubility and stability of drugs. Ligand has established multiple alliances, licenses and other business relationships with the world’s leading biopharmaceutical companies including Amgen, Merck, Pfizer, Jazz, Takeda, Gilead Sciences and Baxter International. For more information, please visit Follow Ligand on X @Ligand_LGND.
We use our investor relations website and X as a means of disclosing material non-public information and for complying with our disclosure obligations under Regulation FD. Investors should monitor our website and our X account, in addition to following our press releases, SEC filings, public conference calls and webcasts.
Forward-Looking Statements
This news release contains forward-looking statements by Ligand that involve risks and uncertainties and reflect Ligand's judgment as of the date of this release. Words such as “plans,” “believes,” “expects,” “anticipates,” and “will,” and similar expressions, are intended to identify forward-looking statements. These forward-looking statements include, without limitation, statements regarding: Ligand’s future royalty payments due under its agreement with Agenus, the potential impact of six Agenus-partnered programs with some of the leading biopharma companies in the world, including BMS-986442 (Bristol Myers Squibb), AGEN2373 (Gilead Sciences), INCAGN2385 and INCAGN2390 (Incyte), MK-4830 (Merck), and UGN-301 (UroGen Pharma), the trial and regulatory success of Agenus’ upcoming Phase 3 trial of botensilimab in combination with balstilimab (“BOT/BAL”) for patients with metastatic, refractory colorectal cancer that is not MSI-H/dMMR and who do not have liver metastases, the potential high patient impact, and revenue potential, of BOT/BAL program, the paradigm-shifting potential of BOT/BAL program in delivering benefits to patients across the metastatic solid tumor landscape and in generating significant revenues, Ligand may not receive expected revenue under this agreement or others, Ligand or its partners may not be able to protect their intellectual property, and patents covering certain products and technologies may be challenged or invalidated which could expose Ligand to significant liabilities and have a material adverse effect on the company. The failure to meet expectations with respect to any of the foregoing matters may reduce Ligand's stock price. Additional information concerning these and other risk factors affecting Ligand can be found in prior press releases available at as well as in Ligand's public periodic filings with the Securities and Exchange Commission available at . Ligand disclaims any intent or obligation to update these forward-looking statements beyond the date of this release, including the possibility of additional license fees and milestone revenues we may receive. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.
This press release contains forward-looking statements that are made pursuant to the safe harbor provisions of the federal securities laws, including statements relating regarding partnered programs, including BMS-986442, AGEN2373, INCAGN2385, INCAGN2390, MK-4830, and UGN-301 and to the use of botensilimab and balstilimab, for instance, statements regarding therapeutic benefit and efficacy, mechanism of action (including validation of mechanism of action), potency, durability, and safety profile (including the absence of specific toxicities) of the Company’s therapeutic candidates; and any other statements containing the words "may," "believes," "expects," "anticipates," "hopes," "intends," "plans," "forecasts," "estimates," "will," “establish,” “potential,” “superiority,” “best in class,” and similar expressions are intended to identify forward-looking statements. These forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially. These risks and uncertainties include, among others, the factors described under the Risk Factors section of our most recent Quarterly Report on Form 10-Q or Annual Report on Form 10-K filed with the Securities and Exchange Commission. Agenus cautions investors not to place considerable reliance on the forward-looking statements contained in this release. These statements speak only as of the date of this press release, and Agenus undertakes no obligation to update or revise the statements, other than to the extent required by law. All forward-looking statements are expressly qualified in their entirety by this cautionary statement.
View source version on businesswire.com:
Contacts
For Ligand:
Investors:
Michael Jeong
investors@ligand.com
(561) 214-4232
LifeSci Advisors
Bob Yedid
bob@lifesciadvisors.com
(516) 428-8577
Media:
Kellie Walsh
media@ligand.com
(914) 315-6072
For Agenus:
Investors:
(917) 362-1370
investor@agenusbio.com
Media:
(612) 839-6748
communications@agenusbio.com
Source: Ligand Pharmaceuticals Incorporated
View this news release online at:
免疫疗法引进/卖出临床2期快速通道临床3期
100 项与 MK-4830 相关的药物交易
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研发状态
10 条进展最快的记录, 后查看更多信息
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| 卵巢癌 | 临床2期 | 美国 | 2022-07-25 | |
| 卵巢浆液性肿瘤 | 临床2期 | 美国 | 2022-07-25 | |
| 卵巢浆液性肿瘤 | 临床2期 | 比利时 | 2022-07-25 | |
| 卵巢浆液性肿瘤 | 临床2期 | 加拿大 | 2022-07-25 | |
| 卵巢浆液性肿瘤 | 临床2期 | 智利 | 2022-07-25 | |
| 卵巢浆液性肿瘤 | 临床2期 | 以色列 | 2022-07-25 | |
| 卵巢浆液性肿瘤 | 临床2期 | 意大利 | 2022-07-25 | |
| 卵巢浆液性肿瘤 | 临床2期 | 波兰 | 2022-07-25 | |
| 卵巢浆液性肿瘤 | 临床2期 | 新加坡 | 2022-07-25 | |
| 卵巢浆液性肿瘤 | 临床2期 | 韩国 | 2022-07-25 |
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临床结果
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| 研究 | 分期 | 人群特征 | 评价人数 | 分组 | 结果 | 评价 | 发布日期 |
|---|
临床1/2期 | 117 | 壓築窪網網構齋餘鏇餘(膚糧製鏇積遞網醖蓋製) = 選襯壓網窪餘憲簾觸獵 壓壓餘襯遞觸鹽獵淵選 (齋選淵鬱範艱願繭鏇繭 ) 更多 | 积极 | 2024-09-14 | |||
壓築窪網網構齋餘鏇餘(膚糧製鏇積遞網醖蓋製) = 夢鹽憲窪網遞遞衊襯製 壓壓餘襯遞觸鹽獵淵選 (齋選淵鬱範艱願繭鏇繭 ) 更多 | |||||||
临床1期 | 93 | 鏇顧觸蓋鬱選憲獵醖醖(艱願憲齋蓋廠糧鹽選淵) = 網鏇鹽夢鬱糧簾襯窪蓋 壓淵鑰鬱膚憲壓膚選壓 (齋簾構鹹壓艱顧衊糧廠, 11 ~ 41) 更多 | 积极 | 2024-04-05 | |||
(NSCLC) | 鏇顧觸蓋鬱選憲獵醖醖(艱願憲齋蓋廠糧鹽選淵) = 襯範糧蓋憲壓夢範獵淵 壓淵鑰鬱膚憲壓膚選壓 (齋簾構鹹壓艱顧衊糧廠, 17 ~ 45) 更多 | ||||||
临床1期 | - | MK-4830 800 mg + pembrolizumab 200 mg (metastatic pancreatic adenocarcinoma) | 糧觸醖襯衊壓構構餘鑰(膚鬱積襯艱顧艱醖鏇積) = 積鹽衊簾淵顧願鏇夢餘 窪鑰夢淵夢壓觸餘醖衊 (襯鬱範遞蓋觸憲窪艱夢, 1 ~ 20) 更多 | 不佳 | 2024-04-05 | ||
MK-4830 800 mg + pembrolizumab 200 mg (unresectable glioblastoma) | 糧觸醖襯衊壓構構餘鑰(膚鬱積襯艱顧艱醖鏇積) = 窪選醖鹽窪遞窪範夢鹽 窪鑰夢淵夢壓觸餘醖衊 (襯鬱範遞蓋觸憲窪艱夢, 0 ~ 25) 更多 | ||||||
临床1期 | 84 | 範顧積顧艱醖夢鑰獵壓(獵築廠鹽壓鹹膚遞憲壓) = consistent with those common to pembro 糧獵積網選鹽廠窪蓋醖 (獵憲鏇醖襯廠艱糧壓衊 ) 更多 | 积极 | 2020-09-20 |
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