靶向于CGRP的偏头痛预防药物的II期研究取得成功

两项II期研究显示，与安慰剂相比，两种靶向于血管舒张肽的试验性偏头痛预防药物（ALD403和LY2951742）可显著减少每个月的偏头痛天数。两种药物总体上使每个月平均偏头痛天数减少4天以上，并且其中1种药物使30%患者的偏头痛得以根除。

ALD403研究由加州大学旧金山分校的Peter Goadsby博士及其同事进行，入组163例每个月发生5~14次偏头痛的患者，其中81例随机接受1,000 mg ALD403单次输注，其余患者接受安慰剂。随访时间为24周。主要终点为5~8周时偏头痛天数相对基线时的平均变化。

结果显示，活性治疗组患者的改善显著优于安慰剂组，两组的偏头痛天数分别平均减少5.6天（66%）和4.6天（52%）。活性治疗组12周时偏头痛天数减少至少50%的患者比例为60%（安慰剂组30%），偏头痛天数减少至少75%的患者比例为32%（安慰剂组9%），偏头痛天数减少100%的患者比例为16%（安慰剂组0%）。这些差异均具有统计学显著性。两组在不良事件类型或发生率、生命体征和实验室安全性数据方面没有差异。

由梅奥医学中心的David W. Dodick博士及其同事进行的LY2951742研究也同样取得成功。该研究入组217例每个月发生4~14次偏头痛的患者。患者随机接受安慰剂或LY2951742 150 mg每两周1次皮下注射治疗12周。主要终点为每个月偏头痛天数的平均变化。次要终点为头痛天数变化、偏头痛发作和反应者比例。

结果显示，活性治疗组偏头痛天数的降幅显著大于安慰剂组（–4.2 vs. –3天；63% vs. 42%降幅）。LY2951742对所有次要终点的疗效均显著优于安慰剂，包括头痛天数（–4.9 vs. –3.7）、偏头痛发作（–3 vs. –2.3）和总体反应率（70% vs. 45%）。探索性分析显示，活性治疗组33%的患者为完全反应者，偏头痛天数减少100%，而安慰剂组的完全反应者比例为17%。LY2951742组发生率高于安慰剂组的不良事件包括注射部位疼痛、上呼吸道感染和腹痛。

这两种药物均为抑制降钙素基因相关肽（CGRP）的单克隆抗体。CGRP由活化的三叉感觉神经释放，其可扩张颅内和颅外血管并调节血管的伤害性感受，在偏头痛发作的产生中发挥重要作用。ALD403和LY2951742通过靶向于CGRP来起到预防偏头痛的作用。Dodick博士表示，两种药物将进入III期研究，如果最终被证实安全有效，则将为患者提供非常有效的治疗选择，并且只需间歇性皮下注射或输注治疗即可，不必像目前一样需每天使用口服药物1~3次。此外，由于这两种药物均作用于CGRP这一特定靶点，因此较少引起副作用，这与现有药物相比是一大进步。现有偏头痛预防药物的副作用（体重增加、镇静、注意力改变、疲劳等）发生率较高，加上缺乏疗效，在很大程度上导致患者不依从于治疗。近期发现，约有86%的患者在1年内停用其口服偏头痛预防药物，甚至是在每隔1天发生头痛的慢性偏头痛患者中也是如此。

有一些证据显示，CGRP在慢性偏头痛、药物过度使用性头痛和丛集性头痛等目前非常难以治疗的其他严重头痛障碍中也发挥重要作用。因此，靶向于CGRP的这两种药物也可能有助于缓解这些类型的头痛。

ALD403研究获Alder Biopharmaceuticals公司支持。LY2951742研究获Arteaus Therapeutics和Eli Lily公司支持。Goadsby博士和Dodick博士与多家药企存在利益关系。

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Two investigational migraine prevention drugs that target a vasodilating peptide significantly decreased the number of migraine days per month, compared with placebo, during a pair of phase II studies.

Both drugs reduced mean migraine headache days per month by more than 4 days overall, and one even eliminated migraine in up to 30% of patients.

The antibodies could be game changers for migraine patients, Dr. Peter Goadsby said in an interview.Each is a monoclonal antibody that inhibits calcitonin gene–related peptide (CGRP). Activated trigeminal sensory nerves release the peptide, which dilates intra- and extracranial blood vessels and modulates vascular nociception.

"Here are the first mechanism-based preventive treatments for migraine," said Dr. Goadsby of the University of California, San Francisco. "They are easy to use, biweekly or even monthly injections, which are effective and well tolerated. For neurologists it means the first major addition to the preventive armamentarium for a generation or more, and for patients, a tangible advance that they can look forward to enjoying soon."

During the annual meeting of the American Academy of Neurology, Dr. Goadsby will present the findings on ALD403, developed by Alder Biopharmaceuticals. His colleague Dr. David W. Dodick of the Mayo Clinic, Rochester, Minn., will present findings on LY2951742, which is being developed by Arteaus Therapeutics in conjunction with Eli Lily. Both presentations are scheduled for May 1.

The trial of ALD403 comprised 163 patients who experienced 5-14 migraine headache days per month; 81 were randomized to receive a single infusion of 1,000 mg ALD403 and the rest received placebo. Patients were followed for 24 weeks. The primary outcome was the mean change in migraine days between weeks 5-8 and baseline.

Patients in the active treatment group fared significantly better than those in the placebo group, with a mean reduction in migraine headache days of –5.6, compared to –4.6 for the placebo group (66% vs. 52% decrease).

Most patients taking the study drug had at least a 50% reduction in migraine headache days at 12 weeks (60% vs. 30%); the proportions of those with at least a 75% reduction were 32% vs. 9%. A 100% reduction occurred in 16% of the active group and in none of the placebo group. These differences were all statistically significant.

There were no differences in the type or frequency of adverse events, vital signs, or laboratory safety data between the two treatment groups.

The LY2951742 study was similarly successful. It comprised 217 patients who experienced 4-14 migraine headache days per month, said Dr. Dodick. They were randomized to placebo or to biweekly subcutaneous injections of LY2951742 150 mg for 12 weeks. The primary end point was the mean change in number of migraine days per month. Secondary end points were the change in headache days, migraine attacks, and responder rate.

LY2951742 was significantly better than placebo in all secondary end points including headache days (–4.9 vs. –3.7), migraine attacks (–3 vs. –2.3), and overall response rate (70% vs. 45%).Patients in the active treatment group experienced a significantly greater reduction in migraine days than those taking placebo (–4.2 vs. –3 days; 63% vs. 42% decrease).

In an exploratory analysis, 33% of those in the active treatment group were complete responders, with a 100% reduction in migraine headache days, compared with 17% of the placebo group,

Adverse events seen more frequently with LY2951742 than placebo included injection site pain, upper respiratory tract infections, and abdominal pain.

Both drugs will advance to phase III studies, Dr. Dodick said in an interview. "If they are ultimately confirmed to be effective and safe, this will represent a new era in mechanism-based migraine prevention – in other words, treatment directed at a molecule now known to be very important in generating a migraine attack. This would provide a highly effective treatment option that is delivered intermittently by subcutaneous injection or infusion rather than requiring patients to consume oral medications 1-3 times daily."

And, he said, because the antibodies act on the very specific target of CGRP, they exhibit a very favorable side effect profile.

"This would be a major advantage over currently available medications, which have a high rate of side effects [weight gain, sedation, altered concentration, fatigue, etc]. The lack of efficacy and the side effect profile of currently available preventive migraine medications account in large part for the lack of adherence to these medications. We recently showed that even in patients with chronic migraine who experience headaches every other day, about 86% have discontinued their oral migraine preventive drug within 1 year."

Drugs that hit CGRP may even help other headache types, Dr. Dodick added.

"There is some evidence that CGRP is also important in other serious headache disorders such as chronic migraine, medication overuse headache, and cluster headache – disorders that are currently very difficult to manage."

The ALD403 study was supported by Alder Biopharmaceuticals. The LY2951742 study was supported by Arteaus Therapeutics in conjunction with Eli Lily. Both Dr. Goadsby and Dr. Dodick have financial relationships with numerous pharmaceutical companies, including receiving research monies, and participating as officers or speakers.