A Phase 2a, Randomized, Open-Label Study to Determine the Optimal Dose and Evaluate the Safety, Tolerability, and Pharmacokinetics of Progerinin in Patients With Hutchinson-Gilford Progeria Syndrome (HGPS)

Researchers will compare treatment with progerinin plus lonafarnib vs lonafarnib alone to assess optimal dosing, safety, tolerability, and pharmacokinetics in patients with Hutchinson-Gilford Progeria Syndrome (HGPS). Subjects in the randomized study arms will continue to take the standard of care (SOC), lonafarnib, and will be randomized to either take SOC alone or in combination with progerinin.

开始日期2025-01-13

申办/合作机构

PRG S&T Co., Ltd

NCT05953545

/ Withdrawn临床2期IIT

Open Label Phase 2 Clinical Study of Peginterferon Lambda and Lonafarnib Boosted With Ritonavir 48-Week Combination Therapy for Delta Hepatitis

Background:
Chronic hepatitis D is a serious liver disease caused by a virus. Currently, no medications are approved to treat chronic hepatitis D.
Objective:
To test a combination of 3 drugs in people with chronic hepatitis D.
Eligibility:
People 18 years or older with chronic hepatitis D.
Design:
Participants will be in the study about 2 years. They will have 3 inpatient stays of 3 to 5 days.
Participants will be screened. They will have a physical exam with blood tests. They will have a test of their heart function and an ultrasound: a wand that uses sound waves to create images of the liver will be rubbed over the skin on their torso.
Participants will stay in the clinic for a 3-day baseline visit. They will have imaging scans, an eye exam, and a visit with a reproductive specialist. They will have a liver biopsy: about 1 inch of liver tissue will be removed, either with a tube inserted through a vein in the neck, or with a needle inserted through the participant s side.
Participants will take the study drugs for 48 weeks. Two of them are tablets taken twice a day at home; 1 is a shot administered once a week. Participants will begin taking the drugs during a 5-day stay in the clinic. Then they will have 15 outpatient visits while taking the drugs and 7 more after they finish.
The last 3-day clinic stay will be 6 months after participants finish taking the drugs. The liver biopsy, imaging scans, and other tests will be repeated.

开始日期2024-05-22

申办/合作机构

National Institute of Diabetes & Digestive & Kidney Diseases

ChiCTR2100050052

/ Not yet recruitingN/AIIT

Observational study of Lonafarnib in Chinese patients with progeria and progeroid laminopathy

开始日期2021-08-18

申办/合作机构

浙江大学医学院附属儿童医院

100 项与洛那法尼相关的临床结果

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100 项与洛那法尼相关的转化医学

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100 项与洛那法尼相关的专利（医药）

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320

项与洛那法尼相关的文献（医药）

2026-12-01·MECHANISMS OF AGEING AND DEVELOPMENT

Hierarchical homeostatic failure in Hutchinson–Gilford progeria syndrome: From nuclear lesion to systemic decline

Article

作者: Djabali, Karima

Hutchinson-Gilford progeria syndrome (HGPS) is a fatal laminopathy caused by an LMNA mutation that generates progerin, a permanently farnesylated, truncated form of prelamin A. Although progerin's structural effects are well established, prior reviews have largely cataloged its downstream consequences, genome instability, proteostasis failure, inflammation, stem-cell dysfunction and matrix remodeling, as parallel, largely independent processes. Here, two decades of mechanistic evidence are reorganized into a single evidence-ranked hierarchy spanning four interconnected levels of homeostasis, nuclear, cellular, tissue and organismal, that explicitly separates established mechanisms from inferred cross-scale links. Progerin perturbs post-mitotic nuclear reassembly, but several defining abnormalities emerge or intensify during interphase and across successive cell generations, indicating progressive maintenance failure rather than a purely static structural model. Nuclear dysfunction is associated with impaired proteostasis, stress adaptation and lineage competence; these cellular defects can be amplified by extracellular-matrix remodeling, chronic inflammation, and reduced regenerative capacity. Evidence is strongest for nuclear and cellular mechanisms, whereas a continuous nucleus-to-organism sequence remains an integrative, testable model. When fragmented mechanisms are ordered across biological scales, this framework helps explain disease latency, tissue selectivity, partial reversibility, and the rationale for combination therapy. Lonafarnib, proteostasis-directed interventions, JAK-STAT inhibition and genome-, RNA-, and progerin-directed strategies are therefore considered complementary approaches acting at distinct levels of the hierarchy. HGPS is not a replica of physiological aging, but a genetically defined system that reveals how persistent nuclear stress can progressively erode conserved adaptive networks.

2026-11-01·PHARMACOLOGICAL RESEARCH

MT-Exo-derived miR-4651 and miR-6126 coordinately regulate the SRSF1–progerin and SP1–PrPᶜ axes to attenuate vascular aging in HGPS

Article

作者: Lee, Jaeyoung ; Kim, Su-Jin ; Song, Yun Seob ; Lee, Sang Hun ; Park, Ji Sun ; Jeong, Kyung Hee ; Jeon, Myung Shin ; Lee, Ji Eun ; Joo, Eun Young ; Choi, Gwang-Seong ; Yoon, Unyoung

Hutchinson-Gilford progeria syndrome (HGPS) is characterized by progressive vascular injury that remains incompletely controlled by therapies targeting progerin-associated pathology. Here, we investigated the therapeutic activity and molecular mechanisms of melatonin-preconditioned mesenchymal stromal cell-derived small extracellular vesicles (MT-Exo) using a patient-anchored translational framework integrating longitudinal vascular phenotyping and serial serum samples from an index patient with HGPS with independently sourced HGPS fibroblasts and endothelial-cell models. Serial HGPS serum samples exhibited increased progerin and cellular prion protein (PrPᶜ) signals, together with elevated troponin I, in the setting of progressive multisite vasculopathy. HGPS serum impaired endothelial morphology and angiogenic network formation, whereas recombinant PrPᶜ induced cellular-stress, inflammatory, chromatin, and nuclear-lamina abnormalities. MT-Exo attenuated HGPS serum-induced endothelial dysfunction and reduced progerin, PrPᶜ, p16, and γH2AX abnormalities and lamin A/C disorganization in HGPS fibroblasts. Mechanistically, MT-Exo-enriched miR-4651 directly targeted SRSF1 and attenuated progerin-associated nuclear-lamina abnormalities, whereas MT-Exo-enriched miR-6126 directly targeted SP1 and reduced PRNP/PrPᶜ expression. These two microRNAs therefore acted through distinct but complementary regulatory pathways involving SRSF1-progerin and SP1-PRNP/PrPᶜ signaling. A prespecified patient-informed virtual-cohort analysis of 15 treatment strategies further prioritized a cluster of lonafarnib-based combinations containing MT-Exo, dual miRNA, or miR-6126 for subsequent experimental evaluation, although no single regimen was consistently top-ranked across models. Collectively, these findings identify complementary miR-4651-SRSF1-progerin and miR-6126-SP1-PRNP/PrPᶜ regulatory axes in HGPS vascular aging and provide a mechanistic rationale for preclinical evaluation of MT-Exo- and miRNA-based combination strategies.

2026-11-01·JOURNAL OF PLANT PHYSIOLOGY

Thirty years of plant farnesylation research: Few substrates, many gaps, and a clear path forward

Review

作者: Sundaresan, Anjana P ; Distefano, Mark D ; Daszkowska-Golec, Agata

Protein farnesylation - the covalent attachment of a 15-carbon farnesyl isoprenoid to a C-terminal CaaX motif by protein farnesyltransferase (PFT, FTase) - is one of the most functionally important post-translational modifications in eukaryotic biology. In mammals, the biomedical significance of farnesylation is well established. The FTase inhibitor (FTI) lonafarnib treats Hutchinson-Gilford progeria syndrome. FTase remains an oncology target, and chemical proteomic strategies have mapped more than 100 farnesylated substrates at single-protein resolution. In plants, genetic evidence establishes that FTase governs abscisic acid (ABA) signalling, brassinosteroid (BR) homeostasis, cytokinin (CK) partitioning, meristem development, thermotolerance, innate immunity, nitrogen sensing, and drought resilience across Arabidopsis thaliana, barley (Hordeum vulgare), canola (Brassica napus), wheat (Triticum aestivum), soybean (Glycine max), and rice (Oryza sativa). Yet fewer than fifteen substrates have been biochemically confirmed in any plant species after nearly three decades of research, and no crop species has been subjected to prenylome-scale chemical proteomics. This review synthesizes the plant and animal farnesylation literature and argues that this disconnect is methodological rather than biological. We trace the arc from FTase enzymology through the emerging catalogue of confirmed plant substrates, exemplified by the HSP40 co-chaperones J2/J3, the cytokinin-biosynthetic enzyme AtIPT3, and plasmodesmal HIPPs, to crop engineering outcomes. We propose a spatial-switch model to organize the confirmed substrate data into a unifying mechanistic framework, while acknowledging that this model awaits systematic experimental testing. Finally, we outline the chemical biology tools - alkyne-isoprenoid probes, quantitative prenylomics profiling - that must be adapted for plant systems to close the gap between substrate prediction and biochemical validation. Farnesylation exemplifies how a conserved eukaryotic modification can be harnessed for crop improvement once the underlying substrate biology is sufficiently understood.

129

项与洛那法尼相关的新闻（医药）

2026-10-27

·BioSpace

EIT Pharma Appoints Dr. Joseph Toerner, M.D., M.P.H., as Chief Medical Officer

KIRKLAND, Wash. , Oct. 27, 2026 /PRNewswire/ -- EIT Pharma, Inc. ("EIT Pharma" or the "Company"), a biotechnology company focused on developing therapies for infectious diseases, today announced the appointment of Dr. Joseph Toerner, M.D., M.P.H., as Chief Medical Officer, effective immediately. Dr. Toerner brings 26 years of experience at the U.S. Food and Drug Administration (FDA), including leadership roles in hepatology, infectious diseases, and drug safety. As Chief Medical Officer, Dr. Toerner will provide medical and clinical leadership across EIT Pharma's development programs, including supporting the ongoing regulatory review of lonafarnib, its late-stage investigational first-in-class oral therapy for chronic hepatitis D (CHD), and peginterferon lambda, its Phase 2 investigational treatment for severe acute viral respiratory infections. "Dr. Toerner brings a rare combination of an infectious disease physician's perspective with more than two decades at the FDA, and few understand the path from clinical evidence to approved therapy as deeply as he does," said Dr. Leen Kawas, PhD, Chief Executive Officer of EIT Pharma. "We are delighted he has joined our team and his expertise will strengthen the clinical and medical foundation of our work as we advance our infectious disease pipeline and progress therapies toward the patients waiting for them." "People living with chronic hepatitis D have far too few treatment options, and I share EIT Pharma's conviction that no patient should be left behind," said Dr. Toerner. "My career has been defined by work where the unmet need is high and the science is rigorous, and EIT Pharma's programs reflect both. I am honored to join EIT Pharma and look forward to working with Dr. Kawas and the team to advance lonafarnib and lambda for patients." Dr. Toerner held several leadership positions at the FDA, most recently serving as Director of the Division of Hepatology and Nutrition from 2020 to 2024. His prior roles spanned antiviral drug development, vaccines, drug safety, and regulatory policy. Since leaving the FDA in 2024, he established Joseph Toerner, LLC to provide consulting services in drug development, including hepatology, nutrition, vaccines, and infectious diseases. Dr. Toerner received his B.S. from the University of Dayton, his M.D. from Case Western Reserve University School of Medicine, and his M.P.H. from Johns Hopkins Bloomberg School of Public Health. He completed his residency in internal medicine at Case Western and his fellowship in infectious disease at Georgetown University Medical Center. He holds Board Certifications in Internal Medicine and Infectious Diseases. About EIT Pharma, Inc. EIT Pharma is a biotechnology company focused on advancing therapies for infectious diseases with significant unmet medical needs. The company is developing a portfolio of programs designed to address serious infectious diseases through rigorous science, disciplined execution, and a patient-centered approach focused on translating scientific innovation into meaningful real-world impact for patients. About Lonafarnib Lonafarnib is an investigational oral therapy candidate being evaluated for the treatment of chronic hepatitis D. Lonafarnib is designed to target a key step in the hepatitis D virus lifecycle and is currently the only oral therapeutic candidate in late-stage clinical development for chronic hepatitis D. Lonafarnib has not been approved by the U.S. Food and Drug Administration or any other regulatory authority for the treatment of chronic hepatitis D. The safety and efficacy of lonafarnib have not been established. About Peginterferon Lambda-1a Peginterferon lambda-1a is an investigational therapy candidate being evaluated for the treatment of Acute Respiratory Infection. Peginterferon lambda-1a is designed to act as an antiviral to enhance innate immunity by inducing interferon-stimulated genes in immune cells. Peginterferon lambda-1a has not been approved by the U.S. Food and Drug Administration or any other regulatory authority for the treatment of Acute Respiratory Infection. The safety and efficacy of peginterferon lambda-1a have not been established. Forward-Looking Statements This press release contains forward-looking statements regarding regulatory review timelines, anticipated milestones, potential product characteristics, and future development plans. These statements are based on current expectations and assumptions and are subject to risks and uncertainties that could cause actual results to differ materially. Lonafarnib is an investigational product candidate and has not been approved by the FDA. There can be no assurance that the FDA will approve the NDA or that the product will become commercially available. EIT Pharma undertakes no obligation to update forward-looking statements except as required by law. Media Contact: Reevemark Jacqueline Zuhse/Jamie Olensky EITPharmaTeam@reevemark.com 212-433-4600 View original content to download multimedia: SOURCE EIT Pharma

临床2期高管变更上市批准

2026-10-20

·PRNewswire

EIT Pharma Presents New Lonafarnib Analyses at the 2026 Delta Cure International Meeting

FDA Previously Accepted the New Drug Application for Lonafarnib, an Investigational First-in-Class Oral Therapy for Chronic Hepatitis D KIRKLAND, Wash., Oct. 20, 2026 /PRNewswire/ -- EIT Pharma, Inc. ("EIT Pharma" or the "Company"), a biotechnology company focused on developing therapies for infectious diseases, today highlighted three presentations at the 5th Edition of the Delta Cure International Meeting in Milan, Italy. The Company presented new analyses from its lonafarnib development program for Chronic Hepatitis Delta (CHD), covering the durability of response after treatment ends, histologic improvement and the clinical significance of alanine aminotransferase (ALT) dynamics following treatment cessation. Lonafarnib is an investigational first-in-class oral CHD therapy candidate with a unique mechanism of action. The New Drug Application for Lonafarnib for the treatment of CHD is under review by the U.S. Food and Drug Administration. "Delta Cure has become one of the most important forums bringing together the global hepatitis D community, and we are proud to support this year's meeting and share new analyses from the lonafarnib development program," said Dr. Leen Kawas, Chief Executive Officer of EIT Pharma. "The findings presented at Delta Cure explore important questions regarding durability of response, liver health, and clinical outcomes following treatment and we believe continued research in these areas is essential as the hepatitis D community works toward better solutions for patients." Key findings from each of the presentations include: Histologic improvement and reduction in necroinflammation with lonafarnib-based therapy in chronic hepatitis delta: phase 3 D-LIVR trial • Presented by Dr. Nancy Reau • Read the selected Oral poster presentation here Post-treatment response following 48 weeks of lonafarnib therapy: analysis of 24-week follow-up in the phase 3 D-LIVR trial in chronic hepatitis delta • Presented by Dr. Saeed Hamid • Read the poster here Clinical significance of ALT dynamics following lonafarnib treatment cessation in the phase 3 D-LIVR trial • Presented by Dr. Ohad Etzion • Read the poster here About Lonafarnib Lonafarnib is an investigational oral therapy candidate being evaluated for the treatment of chronic hepatitis D. Lonafarnib is designed to target a key step in the hepatitis D virus lifecycle and is currently the only oral therapeutic candidate in late-stage clinical development for chronic hepatitis D. Lonafarnib has not been approved by the U.S. Food and Drug Administration or any other regulatory authority for the treatment of chronic hepatitis D. The safety and efficacy of lonafarnib have not been established. About EIT Pharma, Inc. EIT Pharma is a biotechnology company focused on advancing therapies for infectious diseases with significant unmet medical needs. The Company is developing a portfolio of programs designed to address serious infectious diseases through rigorous science, disciplined execution, and a patient-centered approach focused on translating scientific innovation into meaningful real-world impact for patients. Forward-Looking Statements This press release contains forward-looking statements regarding regulatory review timelines, anticipated milestones, potential product characteristics, and future development plans. These statements are based on current expectations and assumptions and are subject to risks and uncertainties that could cause actual results to differ materially. Lonafarnib is an investigational product candidate and has not been approved by the FDA. There can be no assurance that the FDA will approve the NDA or that the product will become commercially available. EIT undertakes no obligation to update forward-looking statements except as required by law. Media Contact Reevemark Jacqueline Zuhse/Jill Steinman [email protected] 212-433-4600 SOURCE EIT Pharma 21% more press release views with Request a Demo

临床3期临床结果上市批准申请上市

2026-10-18

·小药说药知识文库

基于肿瘤标志物的靶向治疗

引言根据美国国家癌症研究所的定义，生物标志物是指在血液、其他体液或组织中发现的生物分子，是正常或异常过程、或某种疾病或状况的体征。肿瘤标志物存在于肿瘤组织或血液、尿液、粪便、唾液等体液中，由肿瘤产生或机体对肿瘤产生反应而形成。肿瘤标志物由六种不同类型的标志物组成：早期检测、诊断、预后、预测、治疗靶点和替代终点。其中，治疗靶点标志物可识别新疗法治疗的分子靶点，是现代靶向治疗的核心基础。近年来，基于遗传和分子特征优化患者的精准医疗护理可以最大限度地发挥精准医学的获益。与传统化疗药物相比，靶向癌症治疗包括小分子靶向药物、单克隆抗体、抗体药物偶联物，以及特异性靶向癌细胞中蛋白质或基因的生物药物，具有高效力和低毒性。在过去30年中该领域取得了显著进展，靶向治疗已成为癌症治疗的主流策略。 RAS信号通路靶向治疗 RAS靶向治疗的历史与挑战自从在大鼠肉瘤病毒中发现RAS以来，靶向RAS因其在肿瘤发生和发展中的重要作用而备受关注。然而RAS靶向治疗的开发极具挑战性，RAS蛋白表面非常光滑，缺乏药物结合口袋使靶向RAS变得困难；细胞内高GTP浓度、补偿通路的激活以及RAS抑制剂给药后RAS-RAF-ERK通路基因的耐药突变导致RAS抑制剂效果不佳。由于RAS抑制剂发现连续失败，RAS曾被认为是不可成药的靶点。 2013年Shokat及其同事发现了KRAS G12C中包含突变半胱氨酸残基的结合口袋，开启了RAS靶向治疗的新篇章，推动了第一个小分子KRAS G12C抑制剂sotorasib的快速发展。目前针对KRAS G12C突变的抑制剂已被批准用于临床。 KRAS G12C突变抑制剂 2021年，美国FDA批准sotorasib（AMG510）用于治疗KRAS G12C突变非小细胞肺癌患者，这是第一个获批的KRAS G12C特异性共价抑制剂，不可逆地结合KRAS G12C的GDP结合非活性构象从而阻断其活性。临床试验表明sotorasib在KRAS G12C突变的晚期实体瘤患者中发挥抗癌活性，包括非小细胞肺癌、结直肠癌、胰腺癌、子宫内膜癌、阑尾癌和黑色素瘤。首个靶向KRAS G12C抑制剂的随机III期试验显示，sotorasib显著增加KRAS G12C突变非小细胞肺癌患者的无进展生存期。然而sotorasib单药治疗的客观缓解率仍远不能令人满意，一项II期临床试验显示sotorasib单药治疗晚期KRAS G12C突变结直肠癌患者的客观缓解率仅为9.7%，表明其联合治疗策略需要进一步评估。 2022年12月，adagrasib（MRTX849）获得FDA首次批准用于治疗KRAS G12C突变的晚期或转移性非小细胞肺癌患者。Adagrasib具有长半衰期（约24小时）、广泛的组织分布和剂量依赖性药代动力学等良好的药代动力学特征。值得注意的是，adagrasib可穿透脑脊液并导致KRAS G12C突变非小细胞肺癌脑转移患者的病灶消退。临床试验表明adagrasib单药治疗耐受性良好，46例患者的疾病控制率达87%，adagrasib联合cetuximab在KRAS G12C突变结直肠癌患者中显示出临床活性。 sotorasib和adagrasib的批准为开发更有效的RAS G12C抑制剂打开了大门。其他KRAS G12C突变抑制剂如JNJ-74699157（ARS-3248）、divarasib（GDC-6036）、garsorasib（D-1553）、JDQ443和RMC-6291正在进行不同阶段的临床试验。尽管KRAS G12C抑制剂的开发正在广泛进行，但它们仅对少数KRAS G12C突变患者有效，且中位无进展生存期相当短，不到1年。 KRAS G12C抑制剂的耐药机制癌症细胞携带KRAS突变可分为两类：KRAS依赖性和KRAS非依赖性，后者可能对KRAS抑制剂不太敏感。获得性耐药的机制大致可分为三类：KRAS改变（包括KRAS Y96、R68和H95残基的突变，KRAS G12D/V/R、G13D和Q61H突变同样导致对KRAS G12C抑制剂的耐药性）；改变的垂直信号级联（上游信号通路影响KRAS-GTP结合亲和力，下游信号通路如MEK-ERK和EGFR的改变均可诱导药物耐药）；肿瘤微环境的变化如免疫逃逸通路产生对KRAS G12C抑制的耐药性。因此KRAS G12C抑制剂与其他药物联合被认为是提高其抗肿瘤效果的有效方法。非KRAS G12C突变抑制剂 KRAS G12C突变仅代表突变的一小部分，其他突变包括G12D、G12V、G12S和G12R。MRTX1133是选择性非共价KRAS G12D抑制剂，对KRAS G12D具有高亲和力，并在体内有效抑制PDAC异种移植小鼠模型的肿瘤生长。RMC-9805是选择性、口服生物可利用的共价KRAS G12D抑制剂，可有效阻断体内外KRAS G12D突变癌细胞的生长。此外，RMC-6236是抑制所有RAS突变亚型的pan-RAS抑制剂，目前正在进行晚期KRAS突变实体瘤的I期临床试验。然而由于这些突变蛋白缺乏活性残基和内在水解活性，开发针对上述KRAS突变的高效抑制剂仍是一个巨大挑战。其他RAS靶向策略现有KRAS G12C抑制剂治疗窗口狭窄，仅对少数KRAS突变癌症患者有效。许多研究致力于发现替代策略来靶向RAS。Pan-RAS抑制剂通过直接靶向多种RAS突变癌症拓宽了治疗窗口，pan-RAS抑制剂RAS-IN-3144可阻断KRAS G13D突变MDA-MB-231细胞来源的小鼠异种移植肿瘤的生长。Rigosertib是RAS类似物，通过与RAF的RAS结合域相互作用抑制RAS介导的胰腺癌生长。此外，寡核苷酸可通过促进mRNA降解或干扰翻译来抑制蛋白质合成，AZD4785是靶向KRAS mRNA的高亲和力反义寡核苷酸，通过消耗细胞KRAS mRNA和蛋白质来抑制下游信号通路。近年来，蛋白水解靶向嵌合体技术可直接降解靶蛋白，已被用于特异性降解癌细胞中的KRAS。此外，成纤维细胞来源的负载G12D siRNA的外泌体可有效抑制PDAC肿瘤生长。基质细胞来源的KRAS外泌体目前正在进行I期临床试验评估胰腺癌患者的疗效。靶向RAS上游：RAS质膜定位只有RAS蛋白的质膜定位才能刺激下游效应子和信号通路。如果阻断翻译后修饰和膜定位，RAS蛋白将处于非活性状态，提示抑制RAS膜定位是有效的治疗策略。法尼基转移酶在RAS定位中起关键作用，法尼基转移酶抑制剂可通过抑制法尼基转移酶阻止RAS在质膜上的定位，从而导致下游信号传导的阻断。Tipifarnib是一种口服生物可利用的非肽拟态喹诺酮类FTI，2019年12月被FDA授予快速通道指定，用于治疗含HRAS突变且在含铂化疗后进展的头颈部鳞状细胞癌患者。Tipifarnib在HRAS突变复发性/转移性头颈部鳞状细胞癌的II期临床研究中的客观缓解率为55%，常见不良反应为贫血和淋巴细胞减少。Lonafarnib最初由Merck & Co发现作为研究性肿瘤药物，也是口服活性FTI，可阻断RAS在质膜上的定位。Salirasib是法尼基半胱氨酸模拟物，通过干扰RAS与质膜的结合来阻断所有RAS亚型的功能。然而一项II期临床研究显示salirasib在KRAS突变肺癌中的治疗活性较差，其后续临床试验的开发已终止。磷酸二酯酶-δ是参与调节法尼基化RAS膜定位和信号传导的异戊二烯结合蛋白。PDEδ抑制剂可影响RAS的膜定位和信号传导，代表了一种有前景的RAS靶向治疗策略。 PI3K-AKT-mTOR通路靶向治疗 PI3K抑制剂 PI3K在调节多种细胞过程中起核心作用，包括细胞增殖、生长、存活、分化和代谢。PI3K在多种癌症中被异常激活，其通路激活可驱动肿瘤发生、进展和耐药。 PI3K抑制剂可分为泛PI3K抑制剂、PI3Kα特异性抑制剂、PI3Kβ特异性抑制剂、PI3Kδ抑制剂和PI3Kγ抑制剂等不同类型。Alpelisib（BYL719）是选择性的PI3Kα抑制剂，已被FDA批准与fulvestrant联合用于治疗HR+、HER2−、PIK3CA突变的晚期乳腺癌。PI3Kδ抑制剂大多已被FDA批准用于临床治疗：Idelalisib于2014年被FDA批准用于治疗复发CLL患者；Duvelisib于2018年被FDA批准用于治疗复发或难治性CLL和小淋巴细胞淋巴瘤。目前还没有PI3Kγ抑制剂可用于临床治疗，IPI-549作为强效高选择性PI3Kγ抑制剂正在HNSCC和TNBC的临床II期试验中。此外，双靶向PI3K和mTOR抑制剂也在癌症治疗中发挥潜在作用，Ompalisib（GSK2126458）已完成实体瘤的I期临床试验。尽管PI3K抑制剂的副作用可能导致严重和致命的免疫相关不良反应，PI3K抑制剂在临床治疗中具有巨大潜力，探索PI3K抑制剂与其他靶向治疗的联合可能是降低毒性和改善临床活性的有效策略。 AKT抑制剂 AKT属于丝氨酸/苏氨酸激酶家族，包含三种结构高度相似的亚型AKT1、AKT2和AKT3，使得开发其亚型特异性抑制剂具有挑战性。具有AKT1突变和AKT2和AKT3扩增的肿瘤对AKT抑制剂高度敏感，而许多PIK3CA突变癌细胞对AKT的依赖性较低。目前多种选择性ATP竞争性pan-AKT抑制剂已被开发，包括capivasertib、ipatasertib（GDC0068）和GSK2141795，它们可抑制所有三种AKT亚型。2023年11月16日，FDA批准capivasertib与fulvestrant联合用于治疗携带一个或多个PIK3CA/AKT1/PTEN改变的HR+、HER2−局部晚期或转移性乳腺癌成人患者。AKT变构抑制剂如MK-2206具有更好的AKT特异性。然而AKT抑制剂的选择性差和毒性等问题仍是亟待解决的挑战，PROTAC和AKT药物联合策略可能改变AKT药物开发的格局。 mTOR抑制剂 mTOR通路参与多种肿瘤细胞过程，过度激活的mTOR信号传导在多种癌症中观察到，抑制mTOR已被FDA和EMA批准为抑制PI3K-AKT-mTOR信号传导的有效策略。目前针对mTOR的药物开发是热门方向，mTOR抑制剂可分为三代：抗生素变构抑制剂（第一代）、ATP竞争性抑制剂（第二代）和新型mTOR抑制剂（第三代）。雷帕霉素及其类似物（称为rapalogs）是第一代mTOR变构抑制剂。依维莫司（RAD001）已被批准用于治疗肾细胞癌和HR+和HER2−乳腺癌。2007年5月30日temsirolimus（CCI-779）被批准用于治疗晚期肾细胞癌。第二代小分子mTOR抑制剂选择性靶向mTOR的活性激酶位点，作为ATP竞争性抑制剂发挥作用。大量ATP竞争性mTOR抑制剂正在进行临床试验，包括MLN01289（INK128）、AZD2014、OSI-027和AZD8055等。第三代mTOR抑制剂RapaLinks是重要的研究突破，通过连接子将雷帕霉素与ATP竞争性mTOR抑制剂连接以提高药物疗效。 RAF-MEK-ERK通路靶向治疗 RAF-MEK-ERK通路调节细胞内生长信号，在超过30%的人类癌症中被激活。BRAF是人类癌症中常见的突变蛋白激酶，特别是在黑色素瘤中频发BRAF V600点突变，被认为是癌症治疗的理想靶点。第一代选择性RAF抑制剂如vemurafenib和dabrafenib已在BRAF V600E或BRAF V600K突变患者中证实具有治疗效果，尽管其疗效被快速上升的耐药性所削弱。为提高第一代RAF抑制剂的效率和克服耐药性，已开发第二代新型RAF抑制剂如pan-RAF抑制剂和RAF二聚体断裂剂。目前进展最快的pan-RAF抑制剂是DAY101，正在II期研究中评估其对携带BRAF改变的复发性或进展性低级别胶质瘤或晚期实体瘤患者的安全性和有效性。PLX8349是口服可用的第二代BRAF抑制剂，有效抑制突变BRAF细胞而不激活MAPK通路，从而克服第一代RAF抑制剂的耐药性。 MEK和ERK抑制剂是RAS-RAF信号通路的典型效应子。大多数MEK抑制剂是变构抑制剂而非阻断ERK磷酸化的ATP竞争性抑制剂。MEK抑制剂或ERK抑制剂与RAF抑制剂联合可有效阻断BRAF突变或KRAS突变癌细胞中RAF抑制剂或ERK抑制剂诱导的反馈激活通路。靶向HGF/c-MET通路 c-MET是肝细胞生长因子的高亲和力受体，其异常激活与肿瘤进展和不良预后相关。c-MET基因扩增、突变、转录失调、降解缺陷和异常HGF产生导致HGF/c-MET的异常表达和肿瘤进展。已开发多种针对HGF/c-MET通路的治疗策略，包括小分子c-MET抑制剂、抗c-MET抗体、抗HGF抗体、HGF抗体模拟工程蛋白和HGF竞争性类似物。Amivantamab已被批准用于治疗携带EGFR外显子20插入突变且对铂类化疗耐药的转移性非小细胞肺癌患者。SAIT301是三星开发的促进c-MET降解的人源化单克隆抗体，通过降解c-MET下调EGR-1抑制鼻咽癌细胞侵袭和迁移。ABT-700是人源化二价单克隆抗体，抑制c-MET二聚化和激活。ARGX-111是非岩藻糖基化IgG1抗体，竞争性结合c-MET、抑制c-MET活性并下调c-MET在细胞表面的表达。抗HGF抗体方面，Rilotumumab（AMG-102）是结合HGFβ链结构域的抗HGF单克隆抗体，特异性阻断c-MET的激活。Ficlatuzumab（AV-299）是人源化抗HGF抗体，已在晚期胰腺癌和头颈部鳞状细胞癌患者中作为单药或与化疗药物联合进行临床试验。YYB-101是人源化HGF抗体，通过结合HGFα链抑制c-MET激活，在难治性晚期实体瘤患者中显示出良好的安全性和有效性。竞争性HGF类似物NK4包含HGFα链N端发夹结构域和4个kringle结构域，通过竞争HGF与MET的结合来抑制c-MET磷酸化和激活，有效抑制许多肿瘤细胞的新血管形成、生长、侵袭和转移。 HGF/c-MET通路在癌症中起关键作用，是癌症治疗的有吸引力的治疗靶点。尽管小分子c-MET抑制剂和抗体类药物已显示出有意义的临床疗效，但耐药性和副作用的挑战仍需解决。基于生物标志物发现对患者进行适当分层可能有助于识别能够从抗HGF/c-MET治疗中获益的患者亚群。靶向DNA损伤反应通路 PARP抑制剂 PARP抑制剂选择性地靶向缺乏HR DNA修复因子BRCA1或BRCA2或HR受损的肿瘤。目前已有六种PARP抑制剂获批用于癌症患者的临床治疗，包括olaparib、rucaparib、niraparib、talazoparib、fuzuloparib和pamiparib。 Olaparib是第一个引入临床实践的PARP抑制剂，2014年获批用于治疗携带BRCA1/2突变的转移性卵巢癌患者。2016年rucaparib获批用于治疗携带有害BRCA1/2突变的晚期卵巢癌患者。2019年niraparib获批用于治疗HR缺陷的晚期卵巢癌患者。2022年3月olaparib被FDA批准用于携带遗传性BRCA1/2突变和HER2高危早期乳腺癌患者的辅助治疗。FDA已批准olaparib和talazoparib用于治疗携带有害胚系BRCA1/2突变的晚期或转移性HER2阴性乳腺癌患者。Olaparib也用于携带胚系BRCA1/2突变的转移性胰腺癌患者的维持治疗。Rucaparib已应用于携带胚系或体细胞BRCA1/2突变的转移性去势抵抗性前列腺癌患者的二线治疗。PARP抑制剂已被批准作为卵巢癌患者的一线全身治疗。然而PARP抑制剂的获得性耐药仍是一个紧迫的问题，通常由三种机制导致：药物靶点相关效应包括药物外排泵的上调或PARP或功能相关蛋白的突变；BRCA1/2功能恢复导致HR恢复；或DNA末端保护和/或复制叉稳定性丧失。 ATM抑制剂 ATM是协调DSB修复的顶端DDR激酶。AZD0156是有效的选择性口服活性ATM抑制剂，已完成晚期实体瘤安全性和初步疗效的I期临床试验。AZD1390是高效的、高选择性的口服生物可利用的ATM抑制剂，可有效增敏DDR突变的乳腺癌脑转移对放射治疗的反应。M4076是ATP竞争性ATM抑制剂，IC50值<1 nM，通过阻断DSB修复抑制肿瘤细胞生长并增强肿瘤细胞对放射治疗的敏感性。鉴于ATM在DSB信号传导和修复中的重要作用，ATM抑制联合治疗目前是各种临床试验中有吸引力的癌症治疗策略。ATM抑制剂增强拓扑异构酶抑制剂和PARP抑制剂等DNA损伤药物的抗癌活性。 ATR抑制剂 ATR激酶通过调节DNA复制起始和复制叉过程来维持准确的DNA复制，支持ATR是癌症治疗的重要靶点。Ceralasertib（AZD6738）是选择性有效的ATR抑制剂，具有良好溶解度、生物利用度和药代动力学特性。Berzosertib（VX-970）是高效的、选择性的静脉注射ATR抑制剂，IC50为19 nM。BAY1895344是新型有效的选择性ATR抑制剂，在癌症中表现出强单药疗效以及与DNA损伤疗法联合的协同活性。ATR抑制剂与PARP抑制剂联合用于治疗携带BRCA1/2突变的肿瘤。基于ATR抑制剂的联合治疗可能是癌症治疗的有前景策略。 CHK1抑制剂 CHK1是ATR的下游效应子，由DDR激活，其抑制剂有效抑制具有高复制应激水平的癌细胞的增殖。一些CHK1抑制剂已在临床试验中评估或正在评估中，特别是与吉西他滨、顺铂和喜树碱等DNA损伤药物联合使用。然而CHK1抑制剂在临床研究中的结果并不理想，LY2603618联合培美曲塞治疗晚期NSCLC患者的II期评估显示无显著临床活性且增加血栓栓塞事件风险。尽管CHK1抑制剂在临床前研究中是有益的，但其临床获益仍有待证实，p53突变状态可能是影响细胞对CHK1抑制剂敏感性的关键因素，需要识别影响CHK1抑制剂疗效的生物标志物。靶向肿瘤微环境靶向炎症通路炎症被认为是肿瘤起始、进展、侵袭、转移和治疗耐药的关键特征之一。调节肿瘤炎症通路的药物主要包括非特异性药物如非甾体抗炎药、他汀类药物和皮质类固醇，以及靶向药物如中和抗体、小分子抑制剂和重组细胞因子。 NSAIDs主要通过抑制COX活性和前列腺素合成发挥抗癌效率，已被发现可降低癌症死亡率，并在结直肠癌、乳腺癌、前列腺癌和头颈癌患者中显示出良好的治疗和预防效果。阿司匹林作为最广泛使用和典型的抗炎药物之一，已被用作广谱癌症预防药物。 IL-6在癌症进展中发挥关键作用，IL-6抗体可能发挥治疗功效并使癌症患者受益。Tocilizumab是靶向人IL-6受体的重组人源化单克隆抗体，特异性结合可溶性和膜结合IL-6受体并抑制信号转导。Siltuximab是靶向人IL-6受体的单克隆抗体，2014年4月22日被FDA批准用于治疗多中心Castleman病患者。 JAK/STAT信号通路在癌症中的重要作用提示靶向该通路作为潜在的抗癌策略。抑制JAK/STAT信号通路已被证明可下调细胞增殖和存活、减少干细胞特性和炎症反应、抑制侵袭和转移、改善恶性肿瘤中的免疫抑制。Ruxolitinib是Incyte公司开发的首创、强效、ATP竞争性小分子JAK1/2抑制剂（JAK1 IC50=3.3 nM，JAK2 IC50=2.8 nM）。Pacritinib是JAK2和FLT-3的强效抑制剂（IC50分别为23和22 nM），2022年2月被FDA加速批准用于治疗中危或高危原发或继发性骨髓纤维化成人患者。靶向衰老细胞衰老细胞通过激活SASP向邻近活癌细胞以及肿瘤微环境中的其他细胞传递信号分子。SASP涉及释放大量生物活性蛋白趋化因子、细胞因子和蛋白酶，在肿瘤发生中发挥双刃剑效应。一方面SASP通过维持衰老程序、永久阻断正常细胞的肿瘤转化以及招募免疫细胞清除体内受损或表达致癌基因的细胞来发挥肿瘤抑制作用，另一方面一些SASP因子具有促肿瘤作用。靶向衰老细胞的策略包括senolytics和senomorphics两大类。Senolytics选择性地消除衰老细胞，而senomorphics调节SASP的排泄，可能保留衰老细胞的SASP依赖性促肿瘤效应并发挥协同抗肿瘤作用。IL-6单克隆抗体siltuximab、多信号抑制剂二甲双胍和JAK抑制剂ruxolitinib可减少SASP，从而减少SASP诱导的促肿瘤和损伤效应。雷帕霉素作为mTOR抑制剂，已被发现通过抑制mTOR减少SASP，并限制衰老旁观成纤维细胞对前列腺癌的生长促进作用。肿瘤标志物靶向治疗的挑战与展望耐药性挑战靶向治疗的耐药性仍是临床实践中的严重挑战。以KRAS抑制剂为例，获得性耐药机制包括KRAS改变、改变的垂直信号级联以及肿瘤微环境的变化。HGF/c-MET抑制剂的获得性耐药与c-MET扩增和过表达、c-MET突变、平行信号通路的激活以及HGF分泌的诱导相关。PARP抑制剂的获得性耐药通常由药物靶点相关效应、BRCA1/2功能恢复以及DNA末端保护和/或复制叉稳定性丧失导致。因此如何克服获得性耐药以及提高靶向抑制剂的安全性需要迫切解决。生物标志物驱动的患者分层基于生物标志物发现对患者进行适当分层可能有助于识别能够从特定靶向治疗中获益的患者亚群。识别预测性生物标志物以从所有癌症患者中区分出最可能对抗癌治疗产生反应的患者，可提高治疗效率、降低治疗成本并避免不良事件。例如在PD-1/PD-L1抑制剂治疗前通过反映肿瘤免疫微环境和肿瘤细胞内在特征的生物标志物组合进行患者选择，可增强抗PD-1/抗PD-L1治疗的临床效果。精确的患者分层是实现靶向治疗最大临床获益的关键。结语基于肿瘤标志物的靶向治疗已成为癌症治疗的主流策略，在过去30年中取得了显著进展。从KRAS G12C抑制剂sotorasib和adagrasib的获批，到PI3K-AKT-mTOR通路抑制剂、RAF-MEK-ERK通路抑制剂、HGF/c-MET通路抑制剂和DDR通路抑制剂的开发，靶向治疗正在深刻地改变癌症治疗的格局。然而耐药性、毒性和患者选择等挑战仍然存在，需要更深入地阐明靶向治疗耐药的机制以实现癌症患者的精准治疗。肿瘤标志物的发现和应用为靶向治疗提供了坚实的科学基础，推动着精准医学不断向前发展。参考资料：Tumor biomarkers for diagnosis, prognosis and targeted therapy. Signal Transduct Target Ther. 2024 May 20;9(1):132

100 项与洛那法尼相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D04768	洛那法尼	A16AX20 A16AX	DB06448

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
核纤层蛋白病	欧盟	-	2022-07-18
核纤层蛋白病	冰岛	-	2022-07-18
核纤层蛋白病	列支敦士登	-	2022-07-18
核纤层蛋白病	挪威	-	2022-07-18
早衰	美国	Sentynl Therapeutics, Inc.	2020-11-20

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
慢性丁型肝炎	临床3期	以色列	Eiger BioPharmaceuticals, Inc.	2021-05-15
慢性丁型肝炎	临床3期	新西兰	Eiger BioPharmaceuticals, Inc.	2021-05-15
慢性丁型肝炎	临床3期	土耳其	Eiger BioPharmaceuticals, Inc.	2021-05-15
丁型肝炎	临床3期	美国	Eiger BioPharmaceuticals, Inc.	2018-12-01
丁型肝炎	临床3期	比利时	Eiger BioPharmaceuticals, Inc.	2018-12-01
丁型肝炎	临床3期	保加利亚	Eiger BioPharmaceuticals, Inc.	2018-12-01
丁型肝炎	临床3期	加拿大	Eiger BioPharmaceuticals, Inc.	2018-12-01
丁型肝炎	临床3期	法国	Eiger BioPharmaceuticals, Inc.	2018-12-01
丁型肝炎	临床3期	德国	Eiger BioPharmaceuticals, Inc.	2018-12-01
丁型肝炎	临床3期	希腊	Eiger BioPharmaceuticals, Inc.	2018-12-01

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临床结果

适应症

分期

评价

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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


NCT03719313 (D-LIVR, AASLD2024)	临床3期	丁型肝炎	88	Pegylated-interferon-α-2a (pegIFN) + Ritonavir-boosted lonafarnib (LNF)	艱鑰願顧鑰衊窪構範鏇(膚選積蓋鹹選鑰鹹鑰積) = 淵窪夢構繭範顧積壓鏇觸鏇鏇鹽糧構選壓齋廠 (願獵鑰憲窪壓膚鹽糧網 ) 更多	积极	2024-11-15
NCT02527707 (LOWR-4, CTgov)	临床2期	慢性丁型肝炎	15	lonafarnib+Ritonavir	蓋鹽觸積醖淵蓋憲簾憲(壓積醖鑰網積齋築製遞) = 蓋鑰憲網憲範範製憲蓋醖齋網選廠壓願衊積艱 (製憲鏇製鹽鬱衊醖壓窪, 1.4) 更多	-	2023-06-22
NCT00425607 \| NCT00916747 (Pubmed \| Genet Med)	N/A	核纤层蛋白病 \| 早衰	-	Lonafarnib	範醖鹽艱淵繭鑰醖齋顧(鬱網廠網繭範廠觸齋觸) = 顧積襯遞鬱夢廠繭餘網製廠鹽遞齋觸憲鹽壓範 (鏇簾窪壓鏇齋繭範鏇餘 )	积极	2022-12-12
NCT02430181 (LOWR-1, CTgov)	临床2期	慢性丁型肝炎	21	lonafarnib+Ritonavir	鏇網鑰夢淵積蓋壓廠壓(鹽觸餘艱範廠範膚鬱艱) = 衊繭獵膚憲簾糧廠壓顧簾餘壓憲餘齋製憲選選 (鹽願膚鹽襯糧鹹衊蓋遞, 鏇餘範夢選齋願顧膚選 ~ 遞壓願願壓齋遞醖簾憲) 更多	-	2022-11-29
NCT03600714 (CTgov)	临床2期	慢性丁型肝炎	26	Lonafarnib+Peg-interferon lambda+ritonavir	壓窪鹽鏇蓋遞鑰膚鹹鏇 = 襯遞夢積網遞網網構膚壓鏇繭醖顧壓築鹹醖遞 (齋膚製觸壓鏇廠遞膚築, 網艱淵壓觸鹹窪願糧廠 ~ 鬱選憲鬱鏇鹽艱憲顧餘) 更多	-	2021-12-01
LIFT HDV Study (EASL2020)	临床2期	丁型肝炎 HDV RNA \| HBV DNA	26	Peginterferon Lambda	觸願淵醖簾願膚鬱壓築(蓋簾蓋艱膚窪築廠鏇繭) = 憲餘廠製齋艱壓淵醖糧鬱簾衊獵鑰餘獵醖齋糧 (衊範獵鑰憲積膚願艱選, 2.9–3.8)	-	2020-08-27
LIFT HDV Study (EASL2020)	临床2期	丁型肝炎 HDV RNA \| HBV DNA	26	Lonafarnib	觸願淵醖簾願膚鬱壓築(蓋簾蓋艱膚窪築廠鏇繭) = 艱網壓窪積壓顧夢齋簾鬱簾衊獵鑰餘獵醖齋糧 (衊範獵鑰憲積膚願艱選, 2.9–4.5)	-	2020-08-27
Pubmed 人工标引	N/A	早衰	258	Lonafarnib	繭簾積壓鹽繭襯鏇遞窪(餘憲願觸選餘夢膚簾願) = Treatment was associated with a lower mortality rate (hazard ratio, 0.12; 95% CI, 0.01-0.93; P = .04). In the combined cohort, there were 4 deaths (6.3%) among 63 patients in the treated group and 17 deaths (27.0%) among 63 patients in the matched untreated group (hazard ratio, 0.23; 95% CI, 0.06-0.90; P = .04). 觸積膚鬱餘網蓋選衊窪 (憲糧艱蓋壓遞夢蓋餘築 )	积极	2018-04-24
Pubmed 人工标引	N/A	早衰	258	control		积极	2018-04-24
NCT00879034 (CTgov)	临床2期	核纤层蛋白病 \| 早衰	5	Lonafarnib+Pravastatin+Zoledronic Acid	衊顧遞鹽獵築廠襯積膚 = 鏇憲襯廠製膚築製製築膚夢鑰齋構鹽醖鬱觸醖 (鬱簾醖夢獵衊願廠觸糧, 鑰範襯網遞構遞衊繭淵 ~ 淵壓遞鹹襯鹹齋積鏇鬱) 更多	-	2017-07-31
NCT00425607 (CTgov)	临床2期	核纤层蛋白病 \| 早衰	29	Lonafarnib	鹽鑰衊觸繭醖鹹廠膚獵 = 壓餘鏇獵積簾鏇製繭構餘獵膚糧餘餘廠醖齋夢 (範鹹襯齋獵簾膚鬱遞構, 憲襯糧選衊憲餘壓簾遞 ~ 鹹積網積鏇繭糧選膚膚) 更多	-	2017-05-24