STOCKHOLM (EGMN) – With a scant number of obesity drugs on the worldwide market, new additions are eagerly sought but face tough safety scrutiny.

In July, a U.S. Food and Drug Administration advisory panel voted against approval of a new obesity formulation, Qnexa, which combines the weight-loss warhorse phentermine plus the epilepsy drug topiramate because of safety concerns despite evidence of good efficacy. The same week the FDA panel made this recommendation, new findings on sibutramine, an effective agent many physicians rely on for treating obesity, came to light in a report on a 10,000-patient cardiovascular safety trial presented at the International Congress on Obesity. The findings showed sibutramine clearly boosted the risk for nonfatal myocardial infarction and stroke in patients with high cardiovascular risk.

That report helped heighten the attention paid to the safety of two other obesity formulations with trial results reported at the Congress: the glucagon-like peptide-1 (GLP-1) analog liraglutide, the focus of a 2-year, phase II trial with 564 patients on the active drug; and another combination of two well-seasoned drugs, naltrexone and bupropion, tested in a pair of 1-year, phase III trials with a total of more than 1,700 participants. A third new weight-management agent, the selective serotonin 2C receptor agonist lorcaserin, was tested on nearly 1,600 obese patients in 2-year, phase III study (N. Engl. J. Med. 2010;363:245-56).

“The combination formulations [phentermine plus topiramate, and naltrexone plus bupropion] are quite effective, but my concern is their safety,” Dr. Arne Astrup said in an interview during the Congress. “Based on our experience with rimonabant, withdrawn [in Europe in 2009] because of depression and suicide ideation, and with sibutramine, withdrawn [in Europe in January 2010] because of cardiometabolic risk, I think there will be a lot of focus on cardiovascular risk factors, blood pressure, and low-density lipoprotein cholesterol” when considering the safety of new agents. The two withdrawals by the European Medicines Agency meant that currently only one drug, orlistat, is approved for treating weight loss in Europe.

One-year results from the two phase III trials of naltrexone plus bupropion reported at the meeting showed that the combination led to a rise in LDL cholesterol over baseline that exceeded placebo, and a drop in baseline blood pressure that fell short of the BP decrease in the placebo groups of both studies.

The results “raise the question of how does this translate into reduced cardiometabolic risk? I think there will be a lot of focus on these risk factors,” said Dr. Astrup, professor and head of the department of human nutrition at the University of Copenhagen. The safety threshold for obesity drugs has to be set higher than the threshold for agents that treat more immediately life-threatening disorders, he said.

“We need to see blood pressure levels during the first month of treatment, before weight loss, and we need to see a meta-analysis of all phase III trials [for a specific drug or combination] to get a much better idea of the safety profile. Ideally, we should see 5,000-10,000 patients on the drug” to judge safety, Dr. Astrup said.

Significant adverse effects “are not really justified when treating obesity,” he added. “If you treat epilepsy or heart failure, you can use drugs with some adverse effects as long as the treatment does something good for the patient.” But when treating obesity, the overall cardiometabolic outcome must show benefit in addition to weight loss, “or you must reserve the drug only for obese patients who are at high risk for serious outcomes,” he said.

“We need long-term outcomes data. We’ve been in the situation before with molecules on the market [for treating obesity] that looked very promising but didn’t stand the test of time,” commented Dr. Tessa van der Merwe, a professor of endocrinology at the University of Pretoria (South Africa).

Although safety questions mean uncertain futures for the phentermine plus topiramate and the naltrexone plus bupropion combinations, better safety profiles may elevate the prospects for lorcaserin and liraglutide, Dr. Astrup said.

“The weight-loss efficacy of lorcaserin is slightly less than or equivalent to that of orlistat, and slightly less than that of sibutramine. ... However, safety and adverse event profiles seem to be better with lorcaserin than with orlistat or sibutramine. ... Phase III studies will be required to confirm these initial findings in larger populations of patients,” Dr. Astrup wrote in a editorial that accompanied the lorcaserin report (N. Engl. J. Med. 2010;363:288-90).

After reporting at the Congress on 2-year follow-up of 238 obese patients treated with liraglutide, which showed the drug’s safety and tolerability, Dr. Astrup also gave liraglutide a tentative thumbs-up.

“I think for the pharmaceutical management of obesity, we need tailor-made molecules where we know exactly how they’re working.” With liraglutide, which suppresses appetite, “we know how it works because it mimics a natural hormone we have a lot of knowledge about,” Dr. Astrup said. He also praised liraglutide’s route of delivery, a once-daily subcutaneous injection, as another safety plus for the drug rather than a logistical drawback.

“I think an injectable drug will help prevent abuse. It requires a certain commitment from the patient and the physician. The vast majority [of patients in the phase II study] thought it was an easy way to take the drug; it’s a kind of hormone replacement therapy for glucagon-like peptide-1.”

The 2-year results on liraglutide he reported involved patients who completed a 20-week, dose-ranging study that also randomized patients to placebo or to orlistat (Lancet 2009;374:1606-16). After completing 52 weeks on their initially assigned medication and dosage, all patients in the four liraglutide arms and the placebo group switched to a 3 mg/day dosage, while patients in the orlistat arm remained on that agent. In the 2-year, last observation carried forward analysis, average weight loss on liraglutide was 5.3 kg and average loss with orlistat was 2.3 kg. The most common adverse effect with liraglutide was nausea, which was transient and dose-related. Treatment with liraglutide also led to a substantial drop in systolic blood pressure and a greater change in lipid levels than seen with orlistat, which Dr. Astrup characterized as a “very positive cardiovascular disease profile,” along with “completely clean” outcomes for psychiatric adverse effects.

The good safety profile for liraglutide contrasted with questionable findings reported for the naltrexone plus bupropion combination, the focus of one phase III study with 584 patients treated with 32 mg of sustained-release naltrexone daily plus 360 mg of sustained-release bupropion daily, and a second phase III study with more than 1,100 participants randomized to either of two dosages of naltrexone, 16 mg or 32 mg daily, plus 360 mg/day bupropion. The combined drug regimen showed good efficacy, with 32 mg/day naltrexone plus bupropion producing a 9% average weight loss when used with behavior modification (in the single-dosage study) and an average 6% loss (in the two-dosage study), compared with average placebo-group losses of 5% (also with behavior modification) in the first study and 1% in the second.

But at 1 year in the single-dosage 32-mg naltrexone plus 360-mg bupropion study, systolic blood pressure fell an average of 4 mm Hg in the placebo group and an average of 1 mm Hg in the active-drug arm. Average diastolic pressure fell by 3 mm Hg in the placebo arm and 1 mm Hg in the active arm, reported Dr. Dennis Kim, senior vice president for medical affairs at Orexigen Therapeutics, the company developing a fixed-dose naltrexone and bupropion combination (Contrave). Blood pressure drops were greater with placebo, even though these patients lost less weight than those in the active-drug group. In the other trial of this combination, patients on 32 mg/day naltrexone and bupropion experienced a 2 mm Hg rise over baseline in acute systolic blood pressure during the first 8 weeks, followed by a fall after 12 weeks to an average systolic pressure 1 mm Hg below baseline, according to a poster at the Congress.

Dr. Astrup’s study was sponsored by Novo Nordisk, which is developing liraglutide. Dr. Astrup has received honoraria as a speaker for and adviser to Novo Nordisk and Neurosearch, as well as research grants from both companies; he has also received honoraria as an adviser to Merck and Co. Dr. van der Merwe had no disclosures.

Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

斯德哥尔摩(EGMN)——全球市场减肥药匮乏，亟待新型减肥药上市，但这类新药在上市前很难通过安全性审查这一关。

 

7月，美国食品药品管理局的一个咨询专家组鉴于安全隐患投票否决了一种新型减肥药Qnexa——减重药物苯丁胺与抗癫痫药托吡酯的复方控释片，尽管该药显示出了良好疗效。西布曲明是许多医生惯用的有效减肥治疗药，而就在同一周，FDA专家组提出：在国际肥胖会议上，一份涉及10,000例患者的心血管安全性试验的报告公布了有关西布曲明的最新研究结果。其结果显示，心血管高危患者服用西布曲明后非致死性心肌梗死和卒中的风险显著增加。

 

这项报告促使人们高度关注会上报告的其他两种减肥药的安全性和试验结果：胰高血糖素样肽-1 (GLP-1)类似物利拉鲁肽，即一项为期2年、有564例接受有效药物治疗的II期临床试验的试验药；另一种减肥药为两种极好的药物——纳曲酮与丁氨苯丙酮的复方制剂，相关试验为两项为期1年、受试者总数逾1,700名的III期临床试验。还有一种新型减肥药为选择性五羟色胺2C受体激动剂氯卡色林，其相关试验为一项历时2年、涉及近1,600例肥胖患者的III期临床研究(N. Engl. J. Med. 2010;363:245-56)。

 

“苯丁胺+托吡酯和纳曲酮+丁氨苯丙酮复方制剂相当有效，但我担心的是它们的安全性，” Arne Astrup博士在会议期间接受采访时说。“根据我们在利莫那班(rimonabant)方面的经验(此药在2010年1月因抑郁症和自杀意念而撤出欧洲市场)以及在西布曲明方面的经验(该药在2010年1月因心脏代谢风险而撤出欧洲市场)，我认为，在审度新药的安全性时应多多关注心血管危险因素、血压和低密度脂蛋白(LDL)胆固醇。”欧洲药品管理局(EMA)做出撤药的决定意味着目前欧洲只有奥利司他这惟一一种药物获准用于减肥治疗。

 

会上报告的两项纳曲酮+丁氨苯丙酮复方制剂III期临床试验的1年结果显示，与安慰剂对照相比，这种复方制剂导致LDL胆固醇升高并超出基线水平，同时试验组的基线血压降幅小于安慰剂对照组。

 

该结果“令人质疑这是如何转化为心脏代谢风险减少的？我认为人们大多关注的是这些危险因素。” 哥本哈根大学人类营养学系的教授兼系主任Astrup博士说。为减肥药设定的安全阈必须高于治疗更危重疾病的药物，他说。

 

Astrup博士说：“我们需要观察治疗第1个月内体重减轻前的血压水平，我们需要看到对所有III期试验的荟萃分析结果，以便于更好地了解药物安全谱。在判断药物的安全性方面，最好应观察5,000~10,000例服药的患者。”

 

他补充说：“治疗肥胖时出现严重不良反应是不应当的，如果你治疗癫痫或心力衰竭，你可以使用有某些不良反应的药物，只要治疗对患者有益。”但治疗肥胖时，总体心脏代谢结局必须显示患者有收益而非局限于体重减轻，“否则你只能将此药留着用于治疗严重结局发生风险很高的肥胖患者。”

 

南非Pretoria大学内分泌学教授 Tessa van der Merwe博士评论说：“我们需要长期的结局数据。在市场上用于治疗肥胖的药物看起来极有治疗前景，但经不住时间的考验，长时间以来我们一直面临着这种局面。”

 

Astrup博士说，尽管安全性问题意味着苯丁胺+托吡酯和纳曲酮+丁氨苯丙酮的复方制剂前途未卜，但较优的安全谱有可能会提高氯卡色林和利拉鲁肽的声望。

 

Astrup博士在氯卡色林报告的随刊编者按中写道：“氯卡色林的减重疗效略低于或等同于奥利司他，略优于西布曲明……然而，氯卡色林的安全性和不良事件谱看似优于奥利司他和西布曲明……这些初步结果还有待利用较大规模的受试群体做III期临床研究加以证实。”

 

在此次会议上，据报告，对238例接受利拉鲁肽治疗的肥胖患者随访2年的结果显示该药安全且耐受性良好，之后Astrup博士也对利拉鲁肽给予了暂时性认可。

 

“我认为对于肥胖的药物治疗而言，我们需要作用机制明确的特制分子。”利拉鲁肽可减少食欲，“我们之所以知道其作用机制，是因为它模拟的是一种我们非常熟悉的天然激素。” Astrup博士说。他也对利拉鲁肽的给药途径——每日1次皮下注射给予了赞扬，这也是增加该药安全性的一个方面而非其弊端。

 

“我认为，注射用药有助于防止滥用，这需要医患做出某种承诺。II期临床研究中的绝大多数患者认为这种用药方式很简单，类似于胰高血糖素样肽-1的激素替代治疗。”

 

他所报告的2年利拉鲁肽研究结果涉及已完成一项历时20周的剂量范围探讨研究的受试者，该研究亦将患者随机分入安慰剂对照组或奥利司他治疗组(Lancet 2009;374:1606-16)。在按照最初安排的药物和剂量完成52周的研究后，4个利拉鲁肽治疗组和安慰剂对照组的所有患者均换成3 mg/天的给药方案，而奥利司他治疗组的给药方案维持不变。在这项历时2年、末次观察提前的分析中，利拉鲁肽治疗组平均体重减轻5.3 kg，而奥利司他组平均减轻2.3 kg。应用利拉鲁肽最常见的不良反应为恶心，呈暂时性和剂量依赖性。利拉鲁肽治疗亦可导致收缩压大幅下降，血脂水平相对于奥利司他治疗组变化较大，Astrup博士将此描述为“对心血管疾病具有非常积极的意义，”以及精神病学不良反应结局“完全为空白”。

 

利拉鲁肽的良好安全谱与报道的纳曲酮+丁氨苯丙酮复方制剂的可疑结果形成对比。该复方制剂为一项包括584例患者的III期临床研究的试验药，这些受试者接受32 mg缓释纳曲酮每日1次与360 mg缓释丁氨苯丙酮每日1次联合治疗，而在另一项III期研究中，逾1,100名受试者被随机分配至2个纳曲酮剂量组(16 mg 或 32 mg，每日1次)之中的一组，同时联用360 mg/天的丁氨苯丙酮。联合用药方案显示了良好疗效，32 mg/天纳曲酮+丁氨苯丙酮联合治疗结合行为的改进使体重平均减轻9%(单剂研究中)和6%(双剂研究中)，而第一项研究中的安慰剂对照组平均减少5%(同时也结合行为的改进) ，第二项研究中的安慰剂对照组平均减少1%。

 

但在单剂32 mg纳曲酮联合360 mg丁氨苯丙酮研究进行到1年时，安慰剂对照组收缩压平均下降4 mm Hg，而活性药物治疗组平均下降1 mmHg。安慰剂对照组平均舒张压下降3 mmHg，活性药物治疗组下降1 mmHg，Orexigen Therapeutics 公司[研发固定剂量的纳曲酮与丁氨苯丙酮复方制剂(即Contrave)的公司]医学部资深副部长Dennis Kim博士报告说。安慰剂对照组血压降幅较大，即使这些患者体重减轻少于活性药物治疗组。据会上壁报论文中的报道，在有关这种复方制剂的另一项研究中，32 mg/天的纳曲酮+丁氨苯丙酮治疗组在前8周内收缩压升高超出基线2 mmHg，12周后又下降，较基线低1 mmHg。

 

Astrup博士的研究获得诺和诺德公司的资助，该公司正在研发利拉鲁肽。Astrup博士是诺和诺德公司和Neurosearch公司的讲师兼顾问并收到酬金，同时还获得这两个公司提供的研究基金；他本人还担任默克公司的顾问并收到酬金。van der Merwe博士无披露内容。

 

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