寒冷的冬季，还是制药业的寒冬，从媒体再次转向实业，希望去探寻药物成功的奥秘，而不仅是开发结果的“评头论足”。一个正确的靶点、好的分子是药物成功的关键，什么转化医学发现新机制、什么临床开发新策略、什么药物新组合...，只是药物更加成功的助力，如果给你的分子就是一个“土坷垃”，来，你挖吧。
1. Keytruda王座难安
近期，MSD接连发布3条Keytruda临床研究不利消息，而其中最大的挫折来自 Keytruda与vibostolimab 的不同类型免疫疗法的联合制剂的肺癌试验，这种方法可以帮助默克公司在其主要 Keytruda 专利于 2028 年到期后抵御生物仿制药的竞争。
该试验名为 KeyVibe-002，旨在了解该组合是否可以改善已扩散到肺部以外的非小细胞肺癌患者的化疗治疗，这些患者在接受免疫疗法和化疗后病情出现进展。与单独使用多西紫杉醇相比，Keytruda-vibostolimab 组合与化疗多西紫杉醇相结合并没有显着延缓疾病进展。
今年早些时候，默克公司公布了另一部分试验的结果，该试验单独测试了 Keytruda-vibostolimab 组合与多西他赛的疗效。这些结果对于该组合也是负面的。
在欧洲医学会议上发布的 KeyVibe-002 试验结果可能会引发人们对 vibostolimab 类 TIGIT 抑制剂药物的持续怀疑。
TIGIT 抑制是一种新颖的方法，开发人员希望能够与 Keytruda、Opdivo 和该类药物（称为 PD-1 阻滞剂）携手合作。
百时美施贵宝、吉利德和罗氏的 TIGIT 药物都经历了临床挫折，尽管罗氏最近的数据呈现积极。
另外两项失败的试验涉及默克与其他制药商合作开发的上市药物。第一项是另一项针对非小细胞肺癌的试验，该试验将 Keytruda 与阿斯利康药物奥拉帕利 相结合，以在 Keytruda 与化疗相结合的初始治疗方案之后控制疾病。另一个就是大名鼎鼎的“可乐组合”，帕博利珠单抗和乐伐替尼的组合。
这项名为 KEYLYNK-008 的试验在中期分析中被终止，因为数据监测员发现 Keytruda-Lynparza 联合维持疗法无法比 Keytruda 加化疗维持疗法帮助患者延长寿命或延迟进展时间。
第三项试验试图扩大 Keytruda 与卫材 Lenvima 联合治疗子宫内膜癌的使用范围，该组合现已被批准用于携带一种名为“错配修复熟练”的突变的患者，这些患者在早期治疗中已取得进展，但目前尚未获得进展。适合接受手术或放射治疗的人。
LEAP-001 试验试图证明 Keytruda-Lenvima 作为一线治疗的效果优于化疗组合，但在总生存期和无进展生存期指标上均未达标。
值得注意的是，今年已经有多个LEAP系列试验宣告失败，除了LEAP-001，还有LEAP-006和LEAP-008，以及8月份的III期LEAP-010（一线治疗头颈部鳞状细胞癌，可乐组合 vs 帕博利珠单抗+安慰剂）、4月月份的III期LEAP-003（一线治疗黑色素瘤）和III期LEAP-017（既往接受过治疗的pMMR或非MSI-H结直肠癌）。此前，2022年8月LEAP-002（一线治疗晚期肝癌）也未达到OS主要终点。
默克报告称，截至 2023 年前 9 个月，Lynparza 合作收入为 8.84 亿美元，Lenvima 合作收入为 7.34 亿美元。
当然，帕博利珠单抗和Nectin-4 ADC维恩妥尤单抗提前近5个月获得FDA批准一线治疗局部晚期或转移性尿路上皮癌算是维护王座保卫的利好消息。然而，在GLP-1虎视眈眈之下，恐怕
帕博利珠单抗在短暂称王之后便需要拱手相让，继续演绎药界“五代十国”。
参考：https://www.biopharmadive.com/news/merck-keytruda-combination-trials-fail-patent-cliff/701975/
12月15日，BMS宣布终止一项评估
纳武利尤单抗（Opdivo，nivolumab）联合
relatlimab治疗微卫星稳定（MSS）转移性结直肠癌的III期
RELATIVITY-123研究。独立数据监测委员会计划分析后，认为该研究不太可能达到主要终点。
12月14日，
Reneo Pharmaceuticals宣布
，其mavodelpar针对成年原发性线粒体肌病（PMM）患者进行的关键性STRIDE研究（NCT04535609）未达到主要疗效终点或次要疗效终点。
Aadi Bioscience, Inc. (NASDAQ: AADI) reported data from its Phase 2 PRECISION1 trial of nab-sirolimus in patients with TSC1 or TSC2 inactivating alterations. Data reported a 26% Overall Response Rate (ORR) including 5 partial responses (PR) with 4 confirmed responses and 1 unconfirmed response (uPR). Shares closed down 56% at $2.34.
NextCure, Inc
. (NASDAQ: NXTC) announced that data from NC410 and NC525 trials are now expected in 2024, with the discontinuation of the development of NC762. Shares closed down 20% at $1.16.
Carrick Therapeutics today announced that the first patient has been dosed in its Phase 2b clinical trial evaluating the combination of samuraciclib (CT7001), an oral and first-in-class inhibitor of CDK7, and fulvestrant, an intramuscular injected selective estrogen receptor degrader (SERD), in women with HR+, HER2- advanced breast cancer previously treated with a CDK4/6 inhibitor.
The regulator placed the clinical hold on the Chinese biotech’s trio of CAR-T cell therapy candidates after an inspection of its Durham, North Carolina manufacturing facility.
The majority of patients with relapsed CLL treated with zanubrutinib or ibrutinib in the phase 3 ALPINE study did not acquire a BTK or PLCG2 mutation at the time of disease progression, indicating that these mutations may not be the primary drivers of resistance and relapse in this population.
百济神州也在ASH公布了BTK降解剂16673的首次临床数据，还有Nurix家的
NX-5948和
NX-2127
Agomab Therapeutics NV announced that it has dosed the first subject in a first-in-human Phase 1 clinical study of AGMB-447, an inhaled lung-restricted small molecule inhibitor of ALK5.
Revumenib demonstrated clinically meaningful activity, including high response and minimal residual disease negativity rates, in heavily pretreated patients with KMT2A-rearranged acute leukemia.
Cara
Therapeutics
,
Inc
.
(NASDAQ: CARA) announced the outcome from the dose-finding Part A of the KIND 1 study evaluating the efficacy and safety of oral difelikefalin as adjunct therapy to topical corticosteroids (TCS) for moderate-to-severe pruritus in adult patients with atopic dermatitis (AD). Oral difelikefalin as adjunct to TCS did not demonstrate a meaningful clinical benefit compared to TCS alone, resulting in the Company’s decision to discontinue its clinical program in pruritus associated with atopic dermatitis. Shares closed down 49% at $0.63
Structure Therapeutics Inc.
(NASDAQ: GPCR) reported data from its Phase 2a clinical trial of GSBR-1290 in T2DM patients. GLP-1 pill demonstrated a 1% lowering of blood glucose and slightly more than 3% weight loss relative to a placebo, however its data did not display better results than provided by
Eli
Lilly’s
(NYSE: LLY) drug. Structure shares closed down 43% at $33.83
Lantheus Holdings, Inc.
(NASDAQ: LNTH) and
POINT Biopharma Global
Inc
.
(NASDAQ:PNT) announced statistically significant topline results from the pivotal Phase 3 SPLASH study evaluating the efficacy and safety of 177Lu-PNT2002, a prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), in patients with metastatic castration-resistant prostate cancer (mCRPC) after progression on an androgen receptor pathway inhibitor (ARPI). The SPLASH trial met its primary endpoint. At the time of the analysis, interim overall survival (OS) results were immature, with only 46% of protocol-specified target OS events reached, and the HR was
1.11
.
由于令人失望的数据，Kronos 终止开发用于治疗 AML 的 larnarplenib 联合疗法
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