6月21日消息 - 环球医学据悉，FDA的一个咨询委员会以11-0、1票弃权的表决结果建议批准carfilzomib用于难治性多发性骨髓瘤。

肿瘤药物咨询委员会的成员判断认为，该药有希望带来的获益——对已经穷尽所有其他疗法的患者的进展性疾病进行控制——大于风险。

“对此，我们需要以真正穷尽治疗方案的患者为背景，”一位专家小组成员在投票之前说。

其他投赞成票的成员表示，他们对风险获益平衡感到很紧张，但被说服支持批准该药，因为多发性骨髓瘤需要新的治疗方法。

拟定的适应症将该药限定用于先前至少两种其他治疗（包括蛋白酶抑制剂和免疫调节剂）无效或复发者。

美国食品和药物管理局已授予carfilzomib加速审批资格，这意味着，该药将基于有限的数据获得批准，但制药商需要进行验证研究。

由Onyx制药公司制造的carfilzomib是一种第二代蛋白酶抑制剂，这使得该药的作用与目前已经获批的药物硼替佐米（万珂）相似。

另外， carfilzomib似乎并不会导致周围神经病变，这是一种限制硼替佐米治疗的主要副作用。

但FDA的工作人员在给咨询委员会的一份简报文件中表示，该药的其他各种毒性可能会大于其相对温和的疗效。

在该主要疗效研究纳入的266例患者中，24人在试验期间死亡，其中半数死于疾病进展之外的原因。

FDA的评价确定，9例死亡明确或潜在地与心脏毒性相关，其他2例死于肝衰竭，另外1例死于颅内出血。

此外，在各项II期试验接受carfilzomib的526例患者中，约有1/3的人由于不良事件停止治疗。

“FDA十分关注该药的各种严重毒性，包括与使用该药有关的死亡。这些毒性的发病机制尚不清楚。”FDA工作人员评价说。

FDA的评价人员指出，大部分安全性数据来自单组试验，这使得很难确定是否是该药导致了不良反应。

然而，该评价表明，心脏、肝脏和肺的不良反应“在该多发性骨髓瘤患者群中比预期的要高” ，因此必须归咎于carfilzomib。许多严重事件发生于给药24小时内，这表明这些事件是输液反应。

对于一种肿瘤药物，不寻常的是，FDA接受非对照研究将整体应答率（完全应答和部分应答的总和）作为主要疗效终点，而不是随机试验中基于生存的指标。

主要研究中的整体应答率为22.9％，几乎全部由完全应答组成。应答的中位持续期为7个月。

各项III期临床试验正在进行中，其中包括一项名为ASPIRE的对照研究，该研究在780例患者中评价carfilzomib，这些都是复发性骨髓瘤患者，但不一定是难治性。预计将在2014年得出研究结果。

Onyx公司的代表向该委员会恳请，在进行中的试验尚未完成之前，不要建议延迟该药的批准，理由是数千患者将不得不多等2~3年才能获得该药。

患者及其支持者呼吁专家小组投票支持批准该药。Robin Tuohy是国际骨髓瘤基金会的支持组织的主任，她的丈夫就患有该病，她说绝望的患者希望能有另外的治疗方案。

Michael Tuohy也在会上发言。“每个新的批准都能延长我们的生命，”他告诉委员会。“副作用吓不倒我。我能对付它们……要么就选择死亡。”

尽管并非必须，但FDA通常会遵循其咨询委员会的建议。（环球医学）

原文：

FDA Panel Gives Nod to Novel Myeloma Drug

An FDA advisory committee voted 11-0 with one abstention to recommend approval carfilzomib (Kyprolis) for patients with treatment-refractory multiple myeloma.

Members of the Oncologic Drugs Advisory Committee decided that the drug's promised benefits -- control of progressive disease in patients who have exhausted all other treatments -- outweighed the considerable risks.

"We need to put this in the context of patients who are really running out of options," said one panel member prior to the vote.

Other members who voted in favor said they were nervous about the risk-benefit balance, but were persuaded to support approval because of the need for new myeloma treatments.

The proposed indication would restrict the drug to patients relapsing or not responding after treatment with at least two other previous therapies, including a proteasome inhibitor and an immunomodulator.

The FDA has designated carfilzomib as eligible for accelerated approval, meaning that it would be approved on the basis of limited data but require the manufacturer to conduct confirmatory studies.

Carfilzomib, made by Onyx Pharmaceuticals, is a second-generation proteasome inhibitor, making it similar in action to the currently approved drug bortezomib (Velcade). Data from preclinical and human studies have indicated that the drug is active against bortezomib-resistant multiple myeloma cells.

It also appears that carfilzomib does not cause peripheral neuropathy, a major treatment-limiting side effect of bortezomib.

But in a briefing document prepared for the advisory committee, FDA staff had indicated that the drug's other toxicities may overwhelm its relatively modest efficacy.

Among 266 patients enrolled in the principal efficacy study, 24 died during the trial, half from causes other than disease progression.

The FDA review determined that nine of the deaths were clearly or potentially related to cardiac toxicity, with two others caused by liver failure and one by intracranial hemorrhage.

Moreover, about one-third of the 526 patients receiving carfilzomib in phase II trials discontinued because of adverse events.

"FDA is very concerned with the severe toxicities, including deaths that are associated with the use of this agent. The pathogenesis of these toxicities is not understood," the staff review concluded.

Much of the safety data came from single-arm studies, the FDA reviewers noted, making it difficult to determine whether an adverse effect resulted from the drug.

However, the incidence of cardiac, liver, and pulmonary effects was higher "than would be expected in this population of patients with multiple myeloma," and therefore must be attributed to carfilzomib, the review indicated. Many of the serious events occurred within 24 hours of administration, suggesting that they were infusion reactions.

Unusually for an oncology drug, the FDA agreed to accept the overall response rate (the sum of complete and partial responses) in an uncontrolled study as the primary efficacy endpoint, rather than survival-based measures in a randomized trial.

The overall response rate in the principal study was 22.9%, almost entirely consisting of partial responses. Median duration of response was about 7 months.

Phase III trials are underway, including a 780-patient-controlled study called ASPIRE that is evaluating carfilzomib in patients with relapsed but not necessarily refractory multiple myeloma. Results are slated to be available in 2014.

Representatives of Onyx pleaded with the committee not to recommend delaying approval until the ongoing trials are finished, citing the thousands of patients who would have to wait another two to three years before having access to the drug.

Patients and their advocates also called on the panel to vote for approval. Robin Tuohy, who serves as director of support groups for the International Myeloma Foundation and whose husband Michael has the disease, said patients were desperate for additional treatment options.

Michael Tuohy also spoke at the meeting. "Each new approval extends our lives," he told the committee. "Side effects don't scare me. I can deal with them. ... The alternative is death."

The FDA usually follows recommendations of its advisory committees but it is not required to do so.
 

相关链接：http://www.medpagetoday.com/HematologyOncology/Myeloma/33382 

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