NGM-120

作者：汪梓昱 美工：何国红 罗真真 排版：马超 一、被忽视的代谢危机 恶病质是一种常见于大多数癌症患者的复杂消耗综合症，特征包括肌肉和脂肪丧失，伴随代谢重编程、炎症、食欲丧失及内分泌紊乱，在多种晚期实体瘤中均高度流行，其发生率因癌种与疾病阶段不同而可达50%–80%。该综合征显著削弱患者生活质量、降低抗肿瘤治疗耐受性并不利于总体预后。多项权威资料显示，约20%–30%的癌症相关死亡可直接归因于恶病质[1,2,3,4]。 癌症恶病质是由肿瘤及宿主炎症介质驱动的代谢综合征，核心表现为能量负平衡与进行性骨骼肌减少（图1）。其机制涉及促炎细胞因子等介导的肌肉与脂肪分解（图2）。临床诊断主要依据体重下降（如BMI＜20 kg/m²且体重下降＞2%，或6个月内体重下降＞5%）及肌肉量减少，并常结合BMI调整的分级系统进行精准评估[5]。 ▲ 图1. 癌症恶病质发病机制的三个层次（肿瘤源性因素、宿主反应和组织间相互作用）[5] 恶病质在多癌种中普遍存在，其进展受年龄、代谢状态、炎症衰老、性别、种族及社会经济因素等多维度影响，尤其老年患者更易出现肌肉流失和慢性炎症。持续监测体脂与肌肉质量对于早期识别高风险人群及指导治疗至关重要，而体成分评估在预测预后与支持治疗决策中也具有重要价值[5,6]。 ▲ 图2. 肿瘤来源和宿主产生的恶病质介质会在多个器官中引发消耗性病理过程[5] 二、全球治疗市场的崛起 癌症恶病质治疗正从非特异性支持转向靶向干预的新阶段，其市场快速产业化，成为一个前景广阔的市场。 据Grand View Research分析，全球该治疗市场规模预计从2025年约25–28亿美元增长至2033年约39亿美元，年复合增长率约4%–5%（图3）。市场扩张主要受全球癌症发病率上升、人口老龄化及治疗手段（包括小分子、抗体及联合方案）多样化驱动。 ▲ 图3. 全球癌症恶病质市场规模（亿美元）[7] 三、小分子药物：从改善食欲到重塑代谢 小分子药物在恶病质治疗中起到了先行者的作用。早期的一些药物，如Megestrol acetate（孕激素类）和Mirtazapine（抗抑郁药），通过改善食欲和情绪，缓解了部分恶病质患者的症状。然而，这些药物虽然能够在短期内改善患者的食欲和体重，但对于长时间维持肌肉质量和恢复功能性却作用有限。 Anamorelin（Adlumiz）作为一种口服的选择性ghrelin受体激动剂，通过模拟体内“饥饿信号”激素ghrelin的作用，刺激下丘脑食欲中枢，促进能量摄入，并刺激生长激素（GH）和类胰岛素样生长因子-1（IGF-1）的分泌，从而增强蛋白合成、促进瘦体重的增加。研究表明，Anamorelin能够显著改善癌症相关恶病质患者的瘦体重、体重和食欲。然而，尽管其在体重和食欲方面取得了显著效果，但对于肌力和功能性终点的改善效果仍然有限[8,9]。 此外，其他如Mifomelatide和Espindolol等小分子药物也在研发阶段，其中Mifomelatide通过调节下丘脑的能量平衡，改善体重和肌肉质量，而Espindolol则通过双重机制，既能抗分解，又能促进蛋白合成。这些新药物的研发，标志着小分子药物在恶病质治疗中不断向更为精准和高效的方向发展（表1）。 ▼ 表1 恶病质治疗中小分子与环肽类药物的代表性进展 （截至2025年12月）[10] 四、抗体药物：精准阻断炎症与代谢信号的新策略 01 靶向促炎细胞因子：抑制“炎症引擎” 慢性炎症被普遍认为是恶病质发生与进展的核心驱动力，促炎细胞因子持续激活可引发代谢紊乱、肌肉分解加速及食欲下降等一系列病理改变，因此，阻断驱动恶病质的关键炎症信号被视为最为直接且具有明确机制基础的治疗策略。 治疗策略主要是阻断IL-6介导的炎症信号通路。Clazakizumab是靶向IL-6的人源化单克隆抗体，通过阻断IL-6介导的炎症信号，期望减轻炎症驱动的肌肉消耗和症状负担。该药物曾在非小细胞肺癌相关恶病质/疲劳患者中开展Ⅱ期临床研究（NCT00866970），结果显示安全性良好并伴有一定症状和生物学改善信号，但整体疗效有限，未能推动该适应症的进一步开发。GFS202A作为IL-6/GDF-15双抗，试图同时抑制炎症信号与异常食欲/代谢调控通路，代表了在该机制方向上更为综合的探索思路。 02 靶向ActRII通路：解除肌肉生长抑制 Activin/肌生成抑制蛋白（Myostatin）-ActRII信号通路是骨骼肌生长与分化的关键负调节轴，在恶病质状态下异常激活，持续抑制肌肉合成并促进肌肉萎缩。针对该通路的治疗策略旨在阻断ActRIIA/IIB受体，从而解除对肌肉生长信号的抑制，恢复肌肉合成能力[12]。 治疗策略主要拮抗ActRIIA/IIB受体。Bimagrumab (BYM338) 是一种全人源单克隆抗体，可通过拮抗ActRII受体，使GDF-11等促肌肉生长信号正常传递。该药在癌症恶病质Ⅱ期临床试验中虽显著提升四肢骨骼肌指数，但未能达成改善体能状态（如6分钟步行试验）的主要终点，后续开发已基本中止。这表明仅增加肌肉质量可能不足以实现功能改善，提示未来或需联合治疗策略。Bimagrumab (BYM338) 是靶向ActRIIA/IIB受体的一款全人源单克隆抗体，最初开发用于肌肉萎缩性疾病。它通过阻断ActRII受体，使促肌肉生长信号（如GDF-11）得以正常作用。在癌症恶病质的II期临床试验中，虽然显著增加了四肢骨骼肌指数，但未能达到改善体能状态（6分钟步行试验）的主要终点，因此相关开发已基本停止。这提示单纯增加肌肉量可能不足以改善功能，或需联合治疗。 03 靶向食欲调节通路：解除中枢厌食与代谢失衡 GDF-15/GFRAL信号轴是介导癌症恶病质食欲抑制和能量代谢紊乱的核心通路（图4）。作为应激响应因子，GDF-15在肿瘤及微环境中高表达，其血浆水平与体重减轻、肌肉消耗及不良预后显著相关。该通路通过中枢作用导致能量负平衡，是连接肿瘤进展与全身消耗的关键枢纽，因而成为重要的治疗靶点[11]。 ▲ 图4. GDF-15 介导的癌症恶病质机制及其对肿瘤免疫的抑制作用[7] ▶ 治疗策略主要包括两类 1）中和GDF-15： 以Ponsegromab/Visugromab为代表。这类单克隆抗体通过清除循环中的GDF-15，减轻其对中枢食欲和代谢的抑制。早期临床数据显示，它们能持续降低血清GDF-15水平，并在体重、食欲等方面呈现改善趋势，为后续临床开发提供了依据[13,14]。 2）拮抗中枢受体GFRAL： 以NGM120/JMT203为代表。该策略直接阻断GDF-15在延髓区的信号传导，从而恢复食欲与代谢稳态。临床前及早期临床研究表明，GFRAL拮抗剂可改善体重、食欲及肌肉质量，部分研究还提示其具潜在抗肿瘤协同效应，有望成为“抗肿瘤-抗恶病质”联合治疗的组成部分。 ▲ 图5. 抗GDF-15/GFRAL 疗法在癌症中的作用机制[7] 总体来看，抗体药物正通过多靶点机制干预癌症恶病质，从炎症抑制到中枢代谢调控逐步取得突破。以Ponsegromab为代表的药物已在体重和食欲改善方面显示出积极信号。随着更多临床试验推进，这类药物或将成为癌症恶病质治疗的重要组成（图6，表2）。 ▲ 图6. 恶病质药物汇总 ▼ 表2 抗体药物在恶病质治疗中的研发态势概览 （截至2025年12月） 五、趋势与展望 癌症恶病质作为复杂的代谢紊乱性疾病，正从“不可逆的终末期消耗”转向“可干预的系统性失衡”这一新范式。随着机制研究不断深入，治疗理念正在形成更明确的方向：一是精准靶向关键炎症与代谢通路（如GDF-15、IL-6、Activin等），相关药物快速推进临床并有望显著提升疗效；二是多模态联合干预逐渐成为趋势，将小分子、抗体治疗与营养、运动等措施整合，实现更全面的改善；三是早期识别与分层治疗的重要性凸显，生物标志物正在推动精准管理的临床落地。 目前，以GDF-15抑制为代表的新药（如Ponsegromab）已进入关键III期阶段，有望成为未来联合治疗的核心基础，兼顾食欲调节与能量代谢改善。尽管仍面临机制复杂、患者异质性大等挑战，癌症恶病质正成为跨学科重点攻克领域，其临床价值与产业潜力均在持续提升。 Sanyou 10th Anniversary: Cachexia: Multidimensional Metabolic Dysfunction and Emerging Targeted Therapies 1. The Overlooked Metabolic Crisis Cancer cachexia is a common and complex wasting syndrome characterized by the loss of muscle and fat, driven by metabolic reprogramming, systemic inflammation, anorexia, and endocrine dysfunction. It is highly prevalent in advanced solid tumors, affecting 50%–80% of patients depending on cancer type and disease stage. Cachexia markedly impairs quality of life, reduces tolerance to anticancer therapies, and worsens overall prognosis. Notably, 20%–30% of cancer-related deaths are directly attributable to this condition.[1,2,3,4] Cancer cachexia is a tumor- and inflammation-driven metabolic syndrome characterized by negative energy balance and progressive skeletal muscle loss (Fig. 1). Its pathogenesis involves pro-inflammatory cytokine–mediated breakdown of muscle and adipose tissue (Fig. 2). Clinically, diagnosis is based mainly on unintentional weight loss (e.g., BMI < 20 kg/m² with > 2% loss, or > 5% loss within 6 months) accompanied by reduced muscle mass, often assessed using BMI-adjusted staging systems.[5] ▲ Figure 1. Three levels of the pathogenesis of cancer cachexia[5] Cachexia is common across many cancers and is influenced by factors such as age, metabolic status, inflammaging, sex, race, and socioeconomic conditions. Older patients are especially prone to muscle loss and chronic inflammation. Monitoring body fat and muscle mass is crucial for early risk identification, prognosis assessment, and treatment guidance.[5,6] ▲ Figure 2. Cachexia mediators derived from tumors and the host trigger catabolic pathological processes in multiple organs[5] 2. The Rise of the Global Therapeutic Market Cancer cachexia treatment is entering a new phase, shifting from non-specific supportive care toward targeted interventions, with rapid commercialization and strong market potential. According to Grand View Research, the global market is projected to grow from approximately USD 2.5–2.8 billion in 2025 to about USD 3.9 billion by 2033, at a compound annual growth rate of 4%–5% (Figure 3) [7]. This expansion is driven by rising global cancer incidence, population aging, and the diversification of therapeutic strategies, including small molecules, antibodies, and combination regimens. ▲ Figure 3. Global cancer cachexia market size (USD billions)[7] 3. Small-Molecule Drugs: From Appetite Stimulation to Metabolic Reprogramming Small-molecule drugs have played a pioneering role in the treatment of cachexia. Early agents such as Megestrol acetate (a progestin) and Mirtazapine (an antidepressant) alleviated symptoms in some patients by improving appetite and mood. However, while these drugs can increase appetite and body weight in the short term, their ability to sustain muscle mass and restore physical function is limited. Anamorelin (Adlumiz), an oral and selective ghrelin receptor agonist, represents a more targeted approach. By mimicking the ghrelin, it activates hypothalamic appetite centers, increases energy intake, and stimulates the release of growth hormone (GH) and insulin-like growth factor-1 (IGF-1), thereby enhancing protein synthesis and promoting gains in lean body mass. Clinical studies have shown that anamorelin significantly improves lean body mass, body weight, and appetite in patients with cancer-related cachexia. Nonetheless, despite these benefits, its effects on muscle strength and functional outcomes remain modest [8,9]. In addition, other small-molecule candidates such as mifomelatide and espindolol are under active development. Mifomelatide improves body weight and muscle mass by modulating hypothalamic energy balance, whereas espindolol acts through a dual mechanism that both reduces catabolism and promotes protein synthesis. Together, these advances highlight a shift toward more precise and efficient small-molecule therapies for cachexia (Table 1).[10] ▼ Table 1. Representative advances in small-molecule and Macrocyclic Peptide drugs for the treatment of cachexia (as of December 2025） 4. Antibody-Based Therapies: Novel Strategies for Precise Inhibition of Inflammatory and Metabolic Signaling 01 Targeting Pro-inflammatory Cytokines: Shutting Down the “Inflammatory Engine” Chronic inflammation is widely recognized as a central driver of cachexia onset and progression. Persistent activation of pro-inflammatory cytokines disrupts metabolism, accelerates muscle breakdown, and suppresses appetite. Accordingly, blocking key inflammatory signals represents one of the most direct and mechanism-based therapeutic strategies. Current approaches focus primarily on inhibiting IL-6-mediated signaling. Clazakizumab, a humanized monoclonal antibody targeting IL-6, aims to reduce inflammation-driven muscle wasting and symptom burden. In a phase II trial in patients with non-small cell lung cancer–related cachexia/fatigue (NCT00866970), clazakizumab showed good safety and modest symptomatic and biological signals, but overall efficacy was limited, halting further development in this indication.GFS202A, a dual antibody against IL-6 and GDF-15, seeks to simultaneously suppress inflammatory signaling and abnormal appetite/metabolic regulation, reflecting a more integrated strategy within this therapeutic pathway. 02 Targeting the ActRII Pathway: Unlocking Muscle Growth Inhibition The Activin/Myostatin-ActRII signaling pathway is a key negative regulator of skeletal muscle growth and differentiation. In cachexia, this pathway is abnormally activated, inhibiting muscle synthesis and promoting muscle atrophy. Therapies targeting this pathway aim to block ActRIIA/IIB receptors, thereby lifting the inhibition on muscle growth signals and restoring muscle synthesis capacity.[12] Current strategies focus on antagonizing ActRIIA/IIB receptors. Bimagrumab (BYM338) is a fully human monoclonal antibody that blocks the ActRII receptor, allowing muscle growth signals like GDF-11 to function normally. In a phase II trial for cancer cachexia, bimagrumab significantly increased skeletal muscle mass but failed to meet the primary endpoint of improving physical performance (e.g., 6-minute walk test). This suggests that merely increasing muscle mass may not be sufficient for functional improvement, indicating a potential need for combination therapies. 03 Targeting Appetite Regulation Pathways: Relieving Central Anorexia and Metabolic Imbalance The GDF-15/GFRAL axis is a key driver of appetite suppression and energy imbalance in cancer cachexia (Figure 4). GDF-15, highly expressed in tumors and their microenvironment, is strongly associated with weight loss, muscle wasting, and poor prognosis. By acting on the central nervous system to induce negative energy balance, this pathway links tumor progression to systemic wasting and represents a critical therapeutic target.[11] ▲ Figure 4. GDF-15–mediated mechanisms of cancer cachexia and its inhibitory effects on tumor immunity[7] ▶ Two Main Therapeutic Strategies： 1) Neutralizing GDF-15: Represented by Ponsegromab and Visugromab, these monoclonal antibodies reduce circulating GDF-15, alleviating its suppressive effects on appetite and metabolism. Early clinical data show that they consistently lower serum GDF-15 levels, with improvements in weight, appetite, and physical performance, supporting further clinical development[13,14] 2) Antagonizing Central Receptor GFRAL: Represented by NGM120 and JMT203, this strategy directly blocks GDF-15 signaling in the medullary region, restoring appetite and metabolic balance. Preclinical and early clinical studies indicate that GFRAL antagonists can improve weight, appetite, and muscle mass, with some studies suggesting potential anti-tumor synergy, making them promising candidates for combination "anti-tumor-anti-cachexia" therapy. ▲ Figure 5. Mechanisms of anti-GDF-15/GFRAL therapy in cancer[7] Overall, antibody drugs are intervening in cancer cachexia through multi-target mechanisms, making progress from inflammation suppression to central metabolic regulation. Drugs like Ponsegromab have shown promising signals in improving weight and appetite. As more clinical trials advance, these drugs may become a key component of cancer cachexia treatment (Figure 6, Table 2). ▲ Figure 6. Summary of antibody drug targets for cachexia ▼ Table 2. Overview of the development landscape of antibody therapeutics for the treatment of cachexia (as of December 2025) 5. Trends and Outlook Cancer cachexia is shifting from being viewed as an “irreversible end-stage wasting condition” to an “intervenable systemic imbalance”. With advancing mechanistic insights, treatment strategies are becoming clearer, including precise targeting of key inflammatory and metabolic pathways (e.g., GDF-15, IL-6, Activin), the growing use of multimodal combination approaches integrating drugs with nutrition and exercise, and the rising importance of early identification and biomarker-driven stratified management.At present, novel antibody drugs targeting GDF-15, such as Ponsegromab, have entered pivotal Phase III trials and are expected to form a core component of future combination therapies by improving both appetite regulation and energy metabolism. Despite challenges related to mechanistic complexity and patient heterogeneity, cancer cachexia is increasingly recognized as a key interdisciplinary focus with expanding clinical and industrial potential. ▶ Reference 1. Fearon K, Strasser F, Anker SD, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 2011;12(5):489-495. 2. National Cancer Institute. Treating Cancer Cachexia: Progress Looks Possible. National Institutes of Health; 2022. Accessed February 2025. https://www.cancer.gov/about-cancer/treatment/research/cachexia. 3. Gholamrezaei A, Broomfield A, McMillan DC, et al. Cancer cachexia: New insights and future directions. Cancers (Basel). 2023;15(23):5590. doi:10.3390/cancers15235590. 4. Baracos VE, Argilés JM, Prado CM, et al. Cancer-associated cachexia: Bridging clinical findings with mechanistic insights. Cancer Discov. 2025;15(8):1543-1558. doi:10.1158/2159-8290.CD-24-1234. 5. Berriel Diaz M, Rohm M, Herzig S. Cancer cachexia: multilevel metabolic dysfunction. Nat Metab. 2024;6(12):2222-2245. doi:10.1038/s42255-024-01167-9. 6. Rohm M, Kir S, Tisdale MJ, et al. Prevalence of and survival with cachexia among patients with cancer: A systematic review and meta-analysis. Adv Nutr. 2024;15(5):1132-1154. doi:10.1016/j.advnut.2024.06.005. 7. Grand View Research. Cancer Cachexia Treatment Market Size Report, 2025–2033. San Francisco, CA: Grand View Research; 2025. 8. Temel JS, Abernethy AP, Currow DC, et al. Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and 2): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15(7):783-792. 9. Takayama K, et al. Long-term efficacy and safety of anamorelin in cancer cachexia: pooled analysis of Japanese phase II/III studies. J Cachexia Sarcopenia Muscle. 2022;13:1923-1933. 10. Stewart Coats AJ, Ho GF, Prabhash K, et al. Espindolol for the treatment and prevention of cachexia in patients with stage III/IV non-small cell lung cancer or colorectal cancer: a randomized, double-blind, placebo-controlled, international multicentre phase II study (the ACT-ONE trial). J Cachexia Sarcopenia Muscle. 2016;7(3):355-365. doi:10.1002/jcsm.12126. 11. Sugiyama K, Starling N, Chau I. New Horizons with Growth Differentiation Factor 15 in Oncology: From Cancer Cachexia and Tumour Immunity to Novel Therapeutic Strategies. Curr Oncol. 2025;32(11):604. Published 2025 Oct 29. doi:10.3390/curroncol32110604. 12. Argilés JM, López-Soriano FJ, Busquets S. Therapeutic potential of myostatin and activin blockade in cachexia and sarcopenia. J Cachexia Sarcopenia Muscle. 2018;9(2):287-297. 13. Pfizer Inc. Pfizer Presents Positive Data from Phase 2 Study of Ponsegromab in Cancer Cachexia. Press Release; 2025. 14. CatalYm GmbH. Visugromab (GDF-15 antibody) Clinical Trial Information – NCT07112196. ClinicalTrials.gov; 2025. 15. GenFleet Therapeutics. Clinical Trial of Bispecific Antibody GFS202A (NCT06898255). 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