新药阿拉莫林

2014年ESMO年会上，澳大利亚阿德莱德费林德斯大学姑息治疗与营养支持部的DavidCurrow报告：阿拉莫林在两项临床试验中可帮助晚期肺癌、恶病质和厌食症患者显著增加去脂体重和体重，亦能提高食欲。（摘要号1483O_PR）
Currow指出，“这是我们有史以来第一次观察到癌症恶病质可从一种药物中持续获益。我们从来没有想过在不改变潜在癌症的情况下能够改写现状。”这些结果“将改变我们队晚期癌症疗法的看法，”他预言并补充道，这些结果有可能扩展应用于整个癌谱的患者中。
意大利贝加莫乔瓦尼二十三世医院癌症中心主任RobertoLabianca说：“这的确是一个重要进展，因为研究强调了亟需建立起针对晚期癌症患者的同步姑息性用药方案。”
癌症恶病质涉及多方面因素，典型表现为去脂体重下降。其他衰竭综合征还可能包括肌肉减少、疲乏、虚弱、食欲不振。随着患者的癌症不断进展，这些症状可能成为治疗的限制因素，他提到。
阿拉莫林口服药具有一种新的作用机制，是所谓的“饥饿激素”ghrelin的模拟物，可诱导生长激素释放。
这两项试验分别为Ⅱ期和Ⅲ期临床试验，即ROMANA1（n=484）和ROMANA2（n=495）。研究对象均为预期寿命超过4个月、之前6个月内体重下降5%或以上、或者体质指数低于20kg/m2、不适切除的晚期非小细胞癌患者（70%分期为IV期）。其中一项试验患者的平均体重为68kg，另外一项中为63kg。大多数患者（60%-80%）正在接受化疗或放疗，或正在同时接受放化疗。
患者随机分入阿拉莫林组（100mg每日一次）或安慰剂组。主要终点为采用双能X线吸收法测定的去脂体重，使用握力测试测定的肌肉强度，次要终点为体重和生活质量评估。
12周内，阿拉莫林组患者的去脂体重显著增加，安慰剂对照组患者体重则继续降低。增幅在6周后已经具有显著性。
ROMANA1研究中，阿拉莫林组的中位去脂体重增幅为1.10kg，安慰剂组则降低了0.44kg。ROMANA2中，增幅为0.75kg，安慰剂组降幅为0.96kg（P＜0.0001）。ROMANA1中，阿拉莫林组平均体重增幅为2.2kg，安慰剂组为0.14kg。ROMANA2中，平均体重增幅为0.95kg，安慰剂组平均降低了0.57kg（P＜0.0001）。
此外，患者还填写了厌食症/恶病质疗法功能评估调查问卷。其中一项试验的总分没有变化，另一项则呈现改善趋势，但调查表中主要针对厌食症/恶病质的分项评分显著改善，差异具有临床意义，ROMANA1试验中尤为明显。握力强度测试方面两组未见差异，结果均有所下降。但Temel认为，患者使用握力器时可能有问题。
瑞士圣加仑州医院的助理教授FlorianStrasser评论道，该药物对握力的影响不明显这一点尚需进一步解释。“握力测试仅针对上肢，下肢肢体没有受测，不足以反映生理功能和日常活动。研究人群相对年轻，身体状态较好，没有涉及多种对症治疗手段的相关信息，也就是说，没有可逆、继发的营养状况受影响的症状。因此还需要更多数据用于评价症状改善以及所担心的问题是否与口服ghrelin激动剂的已知机制相关。”据悉，患者现正处于一项扩展研究的随访阶段，计划在第12个月时予以最终评估。
这种药物“耐受性奇佳”，Temel表示。ROMANA1中最常见的药物相关不良事件为高血糖（5.3%）和恶心（3.8%），ROMANA2中为高血糖（4.2%）和糖尿病（2.1%）。高血糖和糖尿病可认为是药物作用机制的结果。
Temel解释道，阿拉莫林是ghrelin的模拟物，后者由胃分泌，是生长激素受体的配体。阿拉莫林与该受体结合，导致生长激素释放，引起代谢级联反应，影响多种不同因素，包括去脂体重，也包括血糖代谢。“因此我们推测血糖代谢和药物分解方面可能有些问题，而且我觉得令人高兴的是这些影响甚微，没有患者出现血糖水平升高的耐受问题。”部分患者的确出现了糖尿病，但发病率比较低，经处理可控。她还提到，很多其他的癌症治疗也可引起高血糖，例如类固醇类药物。
被问到该药是否对其他癌症也有效时，Temel说：“并没有发现非小细胞肺癌独有的阳性结果……要赌一把的话，我觉得这种药物对于其他类型的癌症也会有用。”
这些结果很有价值，ESMO姑息治疗工作组组长Strasser评论道，“阿拉莫林对这种迟早会遇到的、频繁的临床需求提供了一个应对办法。”这是从两项安慰剂对照双盲Ⅲ期试验中报告的首个抗恶病质药物。结果显示，其对癌症厌食症－恶病质症状（CACS）的不同方面具有持续作用。
“这些试验是否已经在实际的、世界范围的人群中显示出了确切的临床益处和有效性？可能还没有。”他表示。但数据很有价值，他强调，因为所报告的结果覆盖了多于1种的CACS相关表现，而这些症状相互之间具有联系。
Strasser指出，CACS主要包含4种相互影响的表现：肌肉减少、营养摄入减少、活动期癌症引起的代谢和炎性改变以及生理和心理功能减弱。患者及其家属对于每个方面的症状都会感到担忧，例如虚弱、食欲不振、早饱、味觉问题、疲乏以及进食相关情绪问题。
“目前的处理办法包括咨询营养医师、抵抗力训练、加强运动、心理疏导以及多种对症治疗手段。然而，这些干预措施的效果有限，综合征的相关表现还没有针对性的药物疗法，”Strasser说。这种综合征不但影响患者的预期寿命、影响家属，还对抗癌治疗的有效性、毒性以及总生存有影响。
Strasser指出，两项ROMANA试验都显示出阿拉莫林对肌肉的改善、对患者的症状和顾虑的改善，同时不良事件极少，也易于处理。“还需要更多数据考察肌肉质量增加是否伴有脂肪大量增多，如此才能证实患者食欲改善后机能储备也一并提振。这可能是一个新发现：激发食欲的药物可令肌肉质量和机能储备增加。”

如果服用的话，可也和别的药物联合用吗？得癌症的没有几个体质不虚弱的，看到百度上有非正版了，可是可信吗？

真有需要的话，还得大胆去弄！

有YL 了吗

有知道剂量的吗？

Helsinn Group, Switzerland, announced the results of Phase III Trials (ROMANA 1 and ROMANA 2) of Anamorelin/ONO-7643 in patients with Cancer Anorexia-Cachexia Syndrome (CACS) associated with Non-Small Cell Lung Cancer
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2014-11-24 10:58 上传

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二期临床结果：
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2014-11-24 13:12 上传

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Anamorelin Improves Appetite, Slows Weight Loss in Lung Cancer
http://www.onclive.com/conferenc ... Loss-in-Lung-Cancer
Patients with advanced lung cancer had improved appetite, less weight loss, and a significant increase in lean body mass when treated with a ghrelin agonist, two randomized trials showed. Patients in one phase III trial gained 2.4 pounds of lean body mass during 12 weeks of treatment with anamorelin, and those in the second trial had an average increase in lean body mass of 1.65 pounds. Placebo groups in both trials lost lean mass. Neither of the trials demonstrated improvement in the co-primary endpoint of hand-grip strength among patients randomized to anamorelin, investigators reported at the 2014 ESMO Congress meeting held in Madrid, Spain. “The benefits observed in these two studies are consistent and broad, addressing the critical issues of reduction in lean body mass, reduced body weight, diminished appetite, and patients’ symptoms and concerns related to cancer anorexia-cachexia,” said David Currow, BMed, MPH, a professor of palliative and supportive services at Flinders University in Adelaide, Australia. Anorexia and cachexia, or wasting syndrome, are common adverse effects of patients with advanced cancer. It is characterized by loss of muscle mass, decreased nutritional intake, metabolic and inflammatory alterations driven by active cancer disease, and decreased physical and psychosocial function. In particular, the condition affects a large proportion of patients with advanced lung cancer. Anamorelin mimics and stimulates the activity of ghrelin, a protein that induces the release of growth hormone. Ghrelin stimulates multiple pathways that regulate body weight, lean body mass, appetite, and metabolism, said Currow. The ghrelin receptor agonist was evaluated in two phase IIII randomized trials involving patients with unresectable stage III/IV non-small cell lung cancer. Eligibility criteria for the two trials included cachexia (associated with a ≥5% loss of body weight within the previous 6 months) or a body mass index <20 kg/m2. The ROMANA 1 trial involved 484 patients and the ROMANA 2 trial had a 495-patient study population. In both trials, patients were randomized to anamorelin 100 mg/d or placebo and followed for 12 weeks. Patients could continue chemotherapy during the trial, but not initiate systemic therapy, and they could receive maintenance chemotherapy. Both trials had co-primary endpoints of change in lean body mass from baseline to 12 weeks (as assessed by dual x-ray absorptiometry), and change in hand-grip strength in the nondominant hand. Secondary endpoints consisted of change in body weight and quality of life and overall survival. Collectively, the trials involved investigators in North America, Europe, Asia, Australia, New Zealand, and Australasia. The results showed the treatment groups in both trials were similar. Most patients in both arms were receiving some form of systemic or radiation therapy. In ROMANA 1, 14% of patients in the placebo arm and 11% in the anamorelin received no cancer therapy during the study. In ROMANA 2, 24.2% and 22.4% of placebo and anamorelin patients received no cancer therapy during the trial. When the trials ended, the data showed increased lean body mass in the anamorelin arms of both trials and loss of lean mass in the placebo groups. The differences in favor of the anamorelin easily achieved statistical significance (P <.0001 in both studies). Patients in ROMANA 1 had an average weight gain of about 5 pounds versus less than a half pound in the placebo arm (P <.0001). In ROMANA 2, weight gain averaged a little more than 2 pounds with anamorelin, whereas body weight declined by more than a pound in the placebo group (P <.0001) Quality-of-life assessment showed that patients treated with anamorelin had significant lessening anorexia-cachexia symptoms and concerns (P = .0004). Hand-grip strength did not improve with anamorelin in either trial. In ROMANA 1, hand-grip strength decreased to a lesser degree with anamorelin as compared with placebo, whereas hand-grip strength in ROMANA 2 declined slightly more in the anamorelin group than in the placebo group. Grade 2 or greater adverse events occurred in 10% to 15% of patients treated with anamorelin and 8% to 10% with placebo. Grade 3/4 adverse events occurred in 1% to 2.5% of patients in the anamorelin and placebo groups. The most frequent adverse events associated with anamorelin were hyperglycemia (4% to 5%) and diabetes (1% to 2%). Overall survival has yet to be analyzed. The ROMANA 1 and 2 trials were funded by Helsinn Therapeutics.

阿莫拉林比甲地孕酮更安全，更有效。甲地孕酮长期吃，副作用不小，而且会增加死亡率。

Support Care Cancer. 2013 Jan;21(1):129-37. doi: 10.1007/s00520-012-1500-1. Epub 2012 Jun 16.
Therapeutic potential of anamorelin, a novel, oral ghrelin mimetic, in patients with cancer-related cachexia: a multicenter, randomized, double-blind, crossover, pilot study.
Garcia JM1, Friend J, Allen S.
Author information
Abstract
PURPOSE:
Cachexia in cancer adversely affects patients' perception of symptoms, well-being, and response to therapy, and shortens survival. Anamorelin, an oral mimetic of ghrelin, has been shown to increase body weight and anabolic hormone levels in healthy volunteers and is being investigated to treat cancer cachexia.
METHODS:
This multicenter, double-blind, placebo-controlled, crossover study evaluated the effects of anamorelin in 16 patients with different cancers and cachexia. Patients were randomly assigned to anamorelin 50 mg/day or placebo for 3 days. A 3- to 7-day washout period followed and then treatments were switched. Assessments included body weight, appetite, food intake, growth hormone (GH) levels, patient-reported symptom assessments (e.g., the Anderson Symptom Assessment Scale [ASAS] and also an inclusion criterion), and safety.
RESULTS:
Anamorelin significantly increased body weight compared with placebo (0.77 kg vs. -0.33 kg). Food intake increased compared with placebo, but not significantly. GH significantly increased at all time points (0.5-4 h postdose). Insulin-like growth factor-1 (IGF-1) significantly increased by 54.09 ng/mL with anamorelin treatment compared with -3.56 ng/mL for placebo; significant changes in insulin-like growth factor-binding protein 3 (IGFBP-3) were 0.75 μg/mL vs. -0.19 μg/mL, respectively. Patient-reported symptoms, including appetite as measured by ASAS, significantly improved with anamorelin (8.1 vs. 1.0 for placebo). Adverse events (AEs) in four patients were possibly or probably related to anamorelin: hyperglycemia (two patients), nausea (one patient), and dizziness (one patient). Most AEs were mild; no patients withdrew due to AEs.
CONCLUSIONS:
Anamorelin showed significant metabolic, clinical, and patient-rated effects in cancer cachexia. Further studies are warranted.

可能逆转恶病质？ 期待