美國核准減重藥物(台灣未引進): Lorcaserin/ Qsymia/ Contrave/針劑Saxenda

美國減肥新藥 台臨床試驗明年完成 發稿時間：2015/11/14 15:16（中央社記者龍珮寧台北14日電）美國近3年有4種減肥藥上市，醫師表示，國內針對其中1種正在進行臨床收案及試驗，藥物機轉是抑制食慾，而國外結果顯示，服藥追蹤1年後，5成可減重5%、2成減重10%。「2015年台灣醫學週—台灣聯合醫學會學術演講會」暨「台灣醫學會第108屆總會學術演講會」，今明2天在台北國際會議中心舉辦，台灣肥胖醫學會理事長黃國晉分享「肥胖藥物治療」。最近3年內，美國陸續核准4種可長期使用的減重藥物，包括2012年的Lorcaserin、Qsymia，及2014年核准的Contrave與針劑Saxenda。不過，這4種藥物還沒有引進台灣，自今年3月起，有其中一種在台大醫院、中國醫藥大學附設醫院及成大醫院進行臨床試驗，藥物的機轉是抑制食慾。黃國晉表示，目前國外臨床試驗追蹤1年後結果是，5成以上患者服藥後可減重5%以上，2成患者可減重10%以上。身體質量指數(BMI)24以上是過重、27以上則是肥胖。台灣肥胖醫學會參與今年在日本舉行的亞太醫學會，並共同簽署名古屋宣言「肥胖是一種疾病」，而肥胖會帶來許多慢性病，也會增加死亡風險。黃國晉說，衛生署調查顯示，BMI超過24以上的成年男性有50.8％、女性有36.9％。他指出，國內臨床試驗將招收200名肥胖且無糖尿病、B肝、C肝的患者，目已有100位，不過若服藥3個月以上，體重沒有減少5%以上就代表無效，應立刻停止用藥，試驗明年底完成。黃國晉指出，完成後會將結果及評估送衛福部相關單位審查，盼未來有其他的減肥藥物供需求民眾使用。但肥胖治療仍以調整生活型態像是改善飲食營養、增加體能活動為主，必要時才會提供藥物。

Contrave:  Bupropion/naltrexone is a combination drug treatment for obesity. It combines bupropion and naltrexone. Both drugs have individually shown some evidence of effectiveness in weight loss, and the combination is expected to have a synergistic effect. In September 2014, a sustained release formulation of the drug was approved for marketing in the United States under the brand name Contrave. The combination was subsequently approved in the European Union in the spring of 2015, where it will be sold under the name Mysimba. The FDA has put a boxed warning onto this medicine because it may affect mood and increase the likelihood of suicide. Although rare, signs of mood and behavioral changes should be reported to a doctor. Safety and effectiveness in children under the age of 18 has not been studied. Mechanism of action Individually, bupropion and naltrexone each target pathways in the central nervous system that influence food intake. Bupropion is a reuptake inhibitor and releasing agent of norepinephrine and a nicotinic acetylcholine receptor antagonist, and it activates proopiomelanocortin (POMC) neurons in the hypothalamus which give an effect downstream, resulting in loss of appetite and increased energy output. The POMC is regulated by endogenous opioids via opioid-mediated negative feedback. Naltrexone by contrast is a pure opioid antagonist, therefore further augmenting bupropion's activation of the POMC. Bupropion/naltrexone has an effect on the reward pathway that results in reduced food craving. In 2009, Monash University physiologist Michael Cowley was awarded one of Australia's top research honors, the Commonwealth Science Minister's Prize for Life Scientist of the Year, in recognition of his elucidation of these pathways, which led to the development of the combination medication. Orexigen submitted a New Drug Application (NDA) for this drug combination to the FDA On 31 March 2010. Having paid a fee under the Prescription Drug User Fee Act, Orexigen was given a deadline for the FDA to approve or reject the drug of 31 January 2011. On 7 December 2010, an FDA Advisory Committee voted 13-7 for the approval of Contrave, and voted 11-8 for the conduct of a post-marketing cardiovascular outcomes study. Subsequently, on 2 February 2011, the FDA rejected the drug and it was decided that an extremely large-scale study of the long-term cardiovascular effects of Contrave would be needed, before approval could be considered. It was ultimately approved in the United States in the fall of 2014. In December 2014, the EU's Committee for Medicinal Products for Human Use (CHMP) endorsed the combination for licensure as an obesity medication when used alongside diet and exercise. Approval was granted in late March 2015. In May 2015, Orexigen ended a safety study of its diet drug earlier than planned, because an independent panel of experts says the drug maker "inappropriately" compromised the trial by prematurely releasing interim data. The early data release reported a reduction in heart attacks that was no longer observed when a more complete view of the data was analyzed. Society and culture The sustained-release formulation, Contrave, is marketed by Takeda under license from the combination medication's developer, Orexigen Therapeutics. As of 2015, Orexigen received 20% of net sales from Takeda. At the time of its approval by FDA, Wells Fargo analyst Matthew Andrews estimated that Contrave's U.S. sales would reach approximately US$200 million in 2016, exceeding that of the dominant alternative obesity medications lorcaserin and phentermine/topiramate. Despite being initially impeded by technical issues, the growth in filled prescriptions in the first months after approval was very rapid — substantially exceeding the equivalent early uptake of either of the two alternative medications just cited. The first quarter of sales for Contrave (Q1 2015) showed net sales of US$11.5 million. Despite having been approved for use in Europe in March 2015, sales of Contrave have not begun as Orexigen has not yet found a marketing partner.

FDA approves weight-management drug Saxenda , FDA News Release, December 23, 2014 The U.S. Food and Drug Administration today approved Saxenda (liraglutide [rDNA origin] injection) as a treatment option for chronic weight management in addition to a reduced-calorie diet and physical activity. The drug is approved for use in adults with a body mass index (BMI) of 30 or greater (obesity) or adults with a BMI of 27 or greater (overweight) who have at least one weight-related condition such as hypertension, type 2 diabetes, or high cholesterol (dyslipidemia). BMI, which measures body fat based on an individual's weight and height, is used to define the obesity and overweight categories. According to the Centers for Disease Control and Prevention, more than one-third of adults in the United States are obese. Obesity is a public health concern and threatens the overall well-being of patients," said James Smith, M.D., M.S., acting deputy director of the Division of Metabolism and Endocrinology Products in FDA's Center for Drug Evaluation and Research. "Saxenda, used responsibly in combination with a healthy lifestyle that includes a reduced-calorie diet and exercise, provides an additional treatment option for chronic weight management for people who are obese or are overweight and have at least one weight-related comorbid condition. Saxenda is a glucagon-like peptide-1 (GLP-1) receptor agonist and should not be used in combination with any other drug belonging to this class, including Victoza, a treatment for type 2 diabetes. Saxenda and Victoza contain the same active ingredient (liraglutide) at different doses (3 mg and 1.8 mg, respectively). However, Saxenda is not indicated for the treatment of type 2 diabetes, as the safety and efficacy of Saxenda for the treatment of diabetes has not been established. The safety and effectiveness of Saxenda were evaluated in three clinical trials that included approximately 4,800 obese and overweight patients with and without significant weight-related conditions. All patients received counseling regarding lifestyle modifications that consisted of a reduced-calorie diet and regular physical activity. Results from a clinical trial that enrolled patients without diabetes showed that patients had an average weight loss of 4.5 percent from baseline compared to treatment with a placebo (inactive pill) at one year. In this trial, 62 percent of patients treated with Saxenda lost at least 5 percent of their body weight compared with 34 percent of patients treated with placebo. Results from another clinical trial that enrolled patients with type 2 diabetes showed that patients had an average weight loss of 3.7 percent from baseline compared to treatment with placebo at one year. In this trial, 49 percent of patients treated with Saxenda lost at least 5 percent of their body weight compared with 16 percent of patients treated with placebo. Patients using Saxenda should be evaluated after 16 weeks to determine if the treatment is working. If a patient has not lost at least 4 percent of baseline body weight, Saxenda should be discontinued, as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment. Saxenda has a boxed warning stating that tumors of the thyroid gland (thyroid C-cell tumors) have been observed in rodent studies with Saxenda but that it is unknown whether Saxenda causes thyroid C-cell tumors, including a type of thyroid cancer called medullary thyroid carcinoma (MTC), in humans. Saxenda should not be used in patients with a personal or family history of MTC or in patients with multiple endocrine neoplasia syndrome type 2 (a disease in which patients have tumors in more than one gland in their body, which predisposes them to MTC). Serious side effects reported in patients treated with Saxenda include pancreatitis, gallbladder disease, renal impairment, and suicidal thoughts. Saxenda can also raise heart rate and should be discontinued in patients who experience a sustained increase in resting heart rate. In clinical trials, the most common side effects observed in patients treated with Saxenda were nausea, diarrhea, constipation, vomiting, low blood sugar (hypoglycemia), and decreased appetite.

The FDA is requiring the following post-marketing studies for Saxenda:  clinical trials to evaluate dosing, safety, and efficacy in pediatric patients; a study to assess potential effects on growth, sexual maturation, and central nervous system development and function in immature rats; an MTC case registry of at least 15 years duration to identify any increase in MTC incidence related to Saxenda; and an evaluation of the potential risk of breast cancer with Saxenda in ongoing clinical trials. In addition, the cardiovascular safety of liraglutide is being investigated in an ongoing cardiovascular outcomes trial. The FDA approved Saxenda with a Risk Evaluation and Mitigation Strategy (REMS), which consists of a communication plan to inform health care professionals about the serious risks associated with Saxenda. Saxenda is manufactured by Novo Nordisk A/S, Bagsvaerd, Denmark and is distributed by Novo Nordisk, Inc. Plainsboro, New Jersey.

Lorcaserin, currently marketed under the trade name Belviq and previously Lorqess during development, is a weight-loss drug developed by Arena Pharmaceuticals. It has serotonergic properties and acts as an anorectic. Mechanism of action Lorcaserin is a selective 5-HT2C receptor agonist, and in vitro testing of the drug showed reasonable selectivity for 5-HT2C over other related targets. 5-HT2C receptors are located almost exclusively in the brain, and can be found in the choroid plexus, cortex, hippocampus, cerebellum, amygdala, thalamus, and hypothalamus. The activation of 5-HT2C receptors in the hypothalamus is supposed to activate proopiomelanocortin (POMC) production and consequently promote weight loss through satiety. This hypothesis is supported by clinical trials and other studies. While it is generally thought that 5-HT2C receptors help to regulate appetite as well as mood, and endocrine secretion, the exact mechanism of appetite regulation is not yet known. Lorcaserin has shown 100x selectivity for 5-HT2C versus the closely related 5-HT2B receptor, and 17x selectivity over the 5-HT2A receptor.

Qsymia is a combination of two FDA-approved drugs, phentermine and topiramate, in an extended-release formulation. Phentermine is indicated for short-term weight loss in overweight or obese adults who are exercising and eating a reduced calorie diet. Topiramate is indicated to treat certain types of seizures in people who have epilepsy and to prevent migraine headaches. Phentermine/topiramate ER was developed by Vivus, Inc., a California pharmaceutical company. Phentermine is a sympathomimetic amine which acts as an appetite suppressant and stimulant. Topiramate is an anticonvulsant that has weight loss side effects. The exact mechanism of action for both drugs is unknown.

藥物警訊：糖尿病藥物的胸腺腫瘤風險 – Liraglutide (VICTOZA) 發表於 2011/05/11 由 druginformation  近年來，向美國FDA申請許可的第二型糖尿病藥物有逐年增加的趨勢；2010年1月份，主張可與飲食、運動療程搭配的注射藥物 Liraglutide (VICTOZA) 經美國FDA許可上市。在我國，則有台灣諾和諾德藥品公司正在進行第三期的藥物試驗，以及另外4個尚未開始招募受試者的相關藥物試驗，分別由台灣諾和諾德公司與荷商葛蘭素史克藥廠提出申請。不過，縱使通過美國FDA上市許可，美國最大的非營利民間團體 Public Citizen 還是將 Liraglutide (VICTOZA) 列在「不要使用」（Do Not Use）的藥物清單中，主要的考量是：（1）liraglutide 將胸腺腫瘤風險提高3倍；（2）liraglutide 將胰臟炎風險提高4倍；（3）藥廠宣稱 liraglutide 能降低第二型糖尿病患者心臟病與中風之風險，但是沒有足夠的證據可證明。Liraglutide 屬於第二型糖尿病藥物領域中較新的一種分類 – 「incretin mimetics」（腸促胰泌素類似物），以美國FDA而言，liraglutide是這個分類中被許可的第二種藥物；另外一種藥物則是禮來公司製造的 exenatide（BYETTA）。與 liraglutide 相同的地方是，今年（2011）二月，一篇刊登在腸胃科期刊（Gastroenterology）的研究報告指出，與其他糖尿病藥物相較之下，使用 exenatide（BYETTA）的患者發生胰臟炎的機率高出了6倍。也因此，exenatide 同樣被 Public Citizen 列入了「不要使用」（Do Not Use）的藥物清單中。這些藥物都通過美國 FDA 的許可，然而，那是因為以新藥上市的法律規範來說，不以比舊有的藥物更有效、更安全為必要；以第二型糖尿病藥物而言，只要與安慰劑相較之下，能將血液中的糖化血紅素A1c（HbA1c）含量降低，就符合有效的標準，這也是 liraglutide 通過 FDA 許可的原因。以 liraglutide 的試驗資料為例，這個試驗針對250名患者，在52週的時間裡，以隨機、雙盲的方式，分別給予1.8毫克的 liraglutide、或者是8毫克的 glimepiride（AMARYL），結果發現，使用 liraglutide 平均可使患者的 HbA1c 降低0.6%，並且比使用 glimepiride 的患者降的更多。乍看之下，這樣的證據似乎證明了 liraglutide 比舊有的藥物更有效，但這對於臨床上糖尿病治療的意義為何，實在是耐人尋味。再者，根據 liraglutide 仿單中所敘述的，在另外一個維期26週的試驗裡，分別將 liraglutide 和glimepiride 都加上 metformin（甲福明），比較兩者的有效性與安全性。以有效性而言，兩組沒有顯著差異；但是，liraglutide 這組，顯然引起了更多的不良反應，例如噁心（15%：3.3%）、腹瀉（11%：3.7%）、與嘔吐（6.5%：0.4%）。雖然 liraglutide 還沒有在我國上市，從上述美國的經驗可以了解，這一樣又是另一個在糖尿病藥物領域中，具有高風險的藥物。其實，如同先前在「糖尿病治療：藥物不是優先選擇」一文中提過的，對於第二型糖尿病而言，透過「飲食」與「運動」是最安全也最有效的治療方式。若是已經認真改變生活方式、但病情仍未改善時，第二步才是採取胰島素注射控制，並搭配血糖控制藥物。Source: http://pharmnet.tw/