新型口服十一酸睾酮正在接受FDA审查

芝加哥——一种用于性腺功能减退男性的在研口服十一酸睾酮替代治疗药物，在2项Ⅲ期临床试验中显示出了与市售睾酮凝胶相当的疗效和安全性。这种在研药物在国际内分泌大会（ICE）和内分泌学会（ES）联合会议上引起了广泛关注。

这种十一酸睾酮口服制剂（商品名Rextoro）采用了专利性的自乳化技术，以达到比美国海外市场长期销售的十二酸睾酮口服制剂更稳定的吸收和更长的半衰期。

主要研究者、加州大学洛杉矶分校的Ronald S. Swerdloff教授指出，这种产品满足了市场需求，即能够方便、有效地治疗男性性腺功能减退，同时又能避免目前市售局部外用睾酮产品固有的意外污染女性和儿童的风险。“口服睾酮替代治疗将会是很多性腺功能减退男性的良好选择。”

依据这2项Ⅲ期临床试验，Clarus Therapeutics于今年上半年向美国食品药品管理局（FDA）提交了Rextoro上市申请。此外，该公司正在资助1项为期12个月的Ⅳ期开放安全性研究，其结果将在近期报告。

在2014年ICE/ENDO大会上报告的2项Ⅲ期研究中，有1项引出了Rextoro的安全性问题，而这项Ⅳ期研究正是旨在解决这一问题。这项引出安全性问题的多中心Ⅲ期研究纳入了325例患者，这些患者被随机分为Rextoro组和1% AndroGel组，结果显示Rextoro组患者的高密度脂蛋白（HDL）水平比基线时降低了22%，而AndroGel组患者降低12%。此外，Rextoro组有2例患者发生急性心肌梗死，而AndroGel组无患者发生。Rextoro组的红细胞压积水平升高3%，尽管平均值仍在正常范围内。

低密度脂蛋白（LDL）和总胆固醇、甘油三酯、C反应蛋白、脂蛋白相关磷脂酶A2和前列腺特异性抗原水平并无明显组间差异。

另一项关键Ⅲ期试验采用了调整后的Rextoro剂量滴定方案，在114天治疗期间HDL的下降幅度更轻微（9%）。这项试验为单组研究，对144例患者采用Rextoro治疗。

这种剂量调整方案为：初始口服Rextoro 200 mg 2次/日，继而在第30天和72早晨服药后3~5小时监测血清睾酮浓度。当检测值超出200~750 ng/dl范围时，可增加或减少50 mg。在采用这种方案时，75%患者的检测值维持在目标范围内，而在第1项Ⅲ期试验中，口服睾酮组和睾酮凝胶组分别有84%和79%的患者的检测值维持在目标范围内。在采用调整后方案治疗的情况下，仅有3%的患者发生短暂性血清睾酮峰值超出2500 ng/dl。

这2项Ⅲ期试验均由Clarus资助。Swerdloff医生是Clarus、Endo等制药公司的顾问。

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CHICAGO – A unique investigational oral testosterone replacement product for hypogonadal men showed efficacy and safety comparable to a commercially available testosterone gel in two phase III clinical trials, which drew considerable interest when presented at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.

This formulation of oral testosterone undecanoate, known as Rextoro, uses proprietary self-emulsifying technology to provide more consistent absorption and a longer half-life than oral testosterone undecanoate products long available outside the United States.

The new product fulfills an unmet need for an effective and convenient treatment for male hypogonadism that avoids the risk of unintended testosterone transference to women and children inherent in currently marketed topical testosterone products, said lead investigator Dr. Ronald S. Swerdloff, professor of medicine at the University of California, Los Angeles, and chief of the division of endocrinology at Harbor-UCLA Medical Center.

"An oral testosterone replacement therapy would be the preferred choice for many hypogonal men," he said.

Clarus Therapeutics filed for marketing approval for Rextoro with the Food and Drug Administration earlier this year on the strength of the two phase III studies. In addition, the company is sponsoring a supplemental phase IV, open-label, 12-month safety study to be reported later this summer.

The phase IV study is being conducted to resolve safety questions raised in one of the two phase III studies presented at ICE/ENDO 2014. In this 325-patient, open-label, 12-month multicenter trial in which patients were randomized to the investigational oral testosterone or to 1% AndroGel, the oral therapy group experienced a 22% reduction from baseline in HDL, compared with a 12% decrease with the testosterone gel. In addition, two patients in the oral testosterone group had an acute MI; none did in the topical therapy group. Hematocrit levels rose by 3% in oral testosterone–treated patients, although mean values remained within the normal range.

LDL and total cholesterol, triglyceride, C-reactive protein, lipoprotein-associated phospholipase A2, and prostate-specific antigen levels did not differ between the two treatment groups.

Moreover, in the second and pivotal phase III trial, which utilized a revised Rextoro dose-titration algorithm, the reduction in HDL over the course of 114 days of treatment was a more modest 9%. This second trial was a single-arm study involving 144 Rextoro-treated patients.

The revised dose-adjustment algorithm involved starting treatment at 200 mg of oral Rextoro twice daily, then measuring serum testosterone 3-5 hours after the morning dose on days 30 and 72. A value outside the range of 200-750 ng/dL triggered a 50-mg increase or decrease. When this algorithm was used, 75% of treated patients were maintained within the target eugonadal range, compared with 84% of the oral testosterone group and 79% of the testosterone gel–treated patients in the first phase III trial. Under the revised algorithm, only 3% of patients experienced a transient serum peak testosterone excursion greater than 2,500 ng/dL, Dr. Swedloff reported.

The phase III trials were funded by Clarus. Dr. Swerdloff is a consultant to Clarus and Endo Pharmaceuticals.