默沙东失眠新药suvorexant NDA遭FDA拒绝但低剂量版获批现曙光

默沙东（Merck & Co）7月1日宣布，已收到来自FDA有关实验性失眠新药suvorexant新药申请（NDA）的完整回应函（complete response letter，CRL）。

在CRL中，FDA拒绝批准默沙东新失眠药物suvorexant的新药申请（NDA），但为低剂量版本suvorexant的获批打开了大门。

默沙东称，在CRL中FDA表示，相关临床研究已证实了10mg至40mg剂量suvorexant在年老及非年老成人患者中的疗效；但对于大部分患者而言，应考虑10mg剂量作为起始剂量，而在该剂量suvorexant获批前，默沙东必须先准备好10mg剂量suvorexant。FDA还表示，对10mg剂量suvorexant耐受良好但无疗效的患者，应考虑使用15mg和20mg剂量suvorexant。

默沙东此前建议，老年患者起始剂量为15mg，若有必要时可增加至30mg，同时建议非老年人起始剂量为20mg，若有必要时可增加至40mg。在CRL中，FDA称，30mg和40mg剂量suvorexant的安全性数据不足以支持这2种剂量suvorexant的获批。

默沙东拒绝讨论suvorexant的获批时间表或潜在的推迟时长。

默沙东认为，没有必要对10mg剂量suvorexant开展进一步的临床研究，但会开展相应的生产研究（manufacturing studies）。

这类生产研究通常涉及标准生产开发及运作程序，来证明药物可以以一种稳定且可重复性的形式生产，同时也要求证明该药的保质期。

SI集团分析师Mark Schoenebaum此前预计，截止2018年suvorexant的年销售额将达到7亿美元。在一份研究报告中，Schoenebaum将FDA在CRL中的意见喻为，suvorexant的审批是“山重水复疑无路，柳暗花明又一村”，称FDA有可能批准15mg和20mg剂量suvorexant。Schoenebaum称，生产研究可能会使suvorexant的获批推迟一年，尤其是如果FDA要求低剂量suvorexant的长期稳定性测试时。

默沙东还表示，将与FDA讨论，对于正在服用中等剂量CYP3A4抑制剂的患者群体，是否需要开展更多的研究来支持5mg剂量suvorexant。

suvorexant属于名为食欲素受体拮抗剂的新一类失眠药物，若获批，将成为该类药物中首个上市的失眠药物。该药旨在通过阻断大脑中有助于保持清醒的的神经递质，来促进睡眠。

英文原文：FDA rejects Merck insomnia drug, seeks lower-dose

(Reuters) - U.S. health regulators have rejected Merck & Co's new insomnia drug application but opened the door to approving a lower-dose version of the medication, the company said on Monday.

Merck said it received a complete response letter from the U.S. Food and Drug Administration saying that the agency could consider a 10 milligram starting dose of suvorexant for most patients, but that the company would have to have that dosage ready before it could be approved.

The FDA in its letter said 15 mg and 20 mg doses would be appropriate in patients in whom the 10 mg dose is well-tolerated but not effective, Merck said.

ISI Group analyst Mark Schoenebaum said the manufacturing study could lead to about a one-year delay in approval, especially if the FDA asks for long-term stability testing of the lower dose version.

Merck declined to discuss the timeline or potential length of delay as a result of the FDA response.

Merck had proposed that elderly patients start by taking 15 milligrams of the drug and increase that to 30 if necessary, and had recommended that non-elderly adults start on 20 milligrams and increase to 40 milligrams if needed. In its letter, the FDA determined that doses of 30 mg and 40 mg were not safe for approval, Merck said on Monday.

Merck said it doesn't see the need for further clinical studies to move forward with a 10 mg dose, but would require manufacturing studies to move ahead.

Such manufacturing studies typically involve development of standard manufacturing and operational procedures to demonstrate that the pill can be manufactured in a stable and reproducible form. It could also require demonstrating that the medicine has a durable shelf life.

"We know how to do this. We do this all the time," Merck spokesman Steven Cragle said.

ISI's Schoenebaum, who forecast annual suvorexant sales of $700 million by 2018, in a research note estimated a modest impact to Merck from the delay, and found a silver lining in that "suvorexant at 15 mg and 20 mg doses appears to the FDA to be approvable."

He said a one-year delay lowers ISI's 2018 Merck EPS estimate by only 0.25 percent to 0.6 percent.

Merck also said it will discuss with the FDA whether additional studies will be required to support a 5 mg dose for certain patients.

Suvorexant belongs to a new class of insomnia medicines called orexin receptor antagonists and would be the first such medicine on the market if approved. It is designed to facilitate sleep by blocking neurotransmitters in the brain that help to keep a person awake.

Merck shares were up 13 cents at $46.58 in afternoon trading on the New York Stock Exchange.