马西替坦获准用于治疗肺动脉高压

美国食品药品管理局(FDA)10月18日宣布，马西替坦(macitentan)已获准用于治疗肺动脉高压(PAH)。这是FDA批准的又一种内皮素受体拮抗剂。

FDA声明指出，在一项纳入742例PAH患者的研究中，马西替坦平均用药超过2年可有效减缓疾病进展，包括减缓运动能力下降、PAH症状恶化或需要其他PAH药物治疗。与治疗相关的常见副作用包括贫血、鼻咽炎、咽喉疼痛、支气管炎、头疼和尿路感染。

该药物将由美国爱可泰隆(Actelion)制药公司以商品名Opsumit上市。获批的适应证为用于PAH(WHO分级Ⅰ)治疗，以减缓疾病进展，包括延缓死亡、静脉或皮下注射前列环素类药物或PAH症状恶化(6分钟步行距离下降、PAH症状恶化以及需要其他PAH药物治疗)。批准剂量为10 mg/日，口服给药。

与其他内皮素受体拮抗剂一样，马西替坦的说明书中也包括了一项黑框警告内容，提示该药物具有致畸作用，禁止用于孕妇，女性患者只有通过旨在限制药物配给的REMS(风险评估与降低策略)程序才可获得该药物治疗。FDA指出，根据Opsumit REMS程序，该药物的配给将受到限制。处方医生必须登记参加REMS并获得处方授权，女性患者也必须加入REMS并遵守治疗前进行妊娠测试和采取避孕措施的要求，配给该药物的药房必须获得授权并只能向被核准的患者分发该药物。

爱可泰隆制药公司声称， SERAPHIN(内皮素受体拮抗剂改善PAH患者临床结局的研究)研究共计纳 入742例患者，比较了每日3 mg 、10 mg马西替坦与安慰剂的疗效。该研究允许患者接受磷酸二酯酶抑制剂-5抑制剂或前列环素类口服或吸入制剂治疗。

结果显示，3 mg和10 mg马西替坦组分别有38%和31%的患者达到主要终点(PAH事件或全因死亡复合终点)，而安慰剂组为46%。3 mg和10 mg马西替坦组风险比分别为0.7和0.55，具有统计学显著意义。

据该公司称，欧洲、加拿大、瑞士、澳大利亚、中国台湾、韩国和墨西哥等正在对马西替坦上市申请进行审评。

爱可泰隆制药公司还在销售另一个内皮素受体拮抗剂波生坦(Tracleer)，该药物于2001年获准用于PAH治疗。吉利德公司研发的同类药物安贝生坦(Letairis)于2007年获准上市。

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By: ELIZABETH MECHCATIE, Cardiology News Digital Network

Another endothelin receptor blocker, macitentan, has been approved for treating pulmonary arterial hypertension, the Food and Drug Administration announced on Oct. 18.

In a study of 742 patients with pulmonary arterial hypertension (PAH), macitentan over an average of 2 years was "effective in delaying disease progression, a finding that included a decline in exercise ability, worsening symptoms of PAH or need for additional PAH medication," according to the FDA statement issued on Oct. 18. Anemia, nasopharyngitis, sore throat, bronchitis, headache, and urinary tract infection were among the common side effects associated with treatment, the statement said.

It will be marketed as Opsumit by Actelion Pharmaceuticals US. The approved indication is for the treatment of PAH, WHO Group I, to delay disease progression, which includes death, initiation of intravenous or subcutaneous prostanoids, or clinical worsening of PAH (decreased 6-minute walk distance, worsened PAH symptoms and need for additional PAH treatment, according to Actelion). The approved dose is 10 mg daily; it is an oral medication.

Like the other endothelin receptor blockers, macitentan’s label includes a boxed warning that it is a teratogen and should not be used in pregnant women, and that women can receive the drug only through a REMS (Risk Evaluation and Mitigation Strategy) program that will restrict the drug’s distribution. Under the Opsumit REMS, distribution of the drug will be restricted and prescribers will have to enroll in the REMS and become certified to prescribe the drug. Female patients will also need to be enrolled and must comply with pregnancy testing and contraception requirements before starting treatment. Pharmacies that dispense the drug will need to be certified and will dispense the drug only to authorized patients, the FDA said.

The study of 742 patients was SERAPHIN (Study With an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome), which compared treatment with 3 mg or 10 mg of macitentan once a day, or placebo, and were allowed to be treated with phosphodiesterase-5 inhibitors or oral or inhaled prostanoids, according to Actelion.

The primary end point, a composite of a PAH event or death from any cause, was reached by 38% of patients receiving 3-mg macitentan and 31% of those receiving 10-mg macitentan, compared with 46% of patients receiving placebo. The hazard ratios of 0.7 for the 3-mg dose and 0.55 for the 10-mg dose were statistically significant.

Macitentan is under review in Europe, Canada, Switzerland, Australia, Taiwan, Korea and Mexico, according to Actelion.

Actelion also markets bosentan (Tracleer), another endothelin receptor antagonist, which was approved for treating PAH in 2001. Ambrisentan (Letairis; Gilead), also an endothelin receptor antagonist, was approved in 2007.