Karyopharm’s Xpovio nabs FDA nod despite checkered past

多发性骨髓瘤药物Xpovio定价每月2.2万美元,曾因安全性问题导致审批一波三折

2019-07-09 17:04:00 FiercePharma

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Karyopharm finally got its much-needed first commercial approval for a drug that has stirred up safety concerns—and suffered plenty of speed bumps—along the way. Now the company must cope with a limited FDA nod, and with a brand-new marketing chief to boot. The FDA waved through Karyopharm’s oral drug Xpovio (selinexor), used in tandem with dexamethasone, for multiple myeloma patients who’ve received at least four prior therapies and whose disease is resistant to several other forms of treatment. Karyopharm is launching the drug by Wednesday at a list price of $22,000 per month. But leading its fully-installed sales team of more than 70 staffers will not be Anand Varadan, who just resigned as chief commercial officer. Instead, Perry Monaco has been promoted to head up commercial operations as senior VP, the company disclosed in a securities filing. Xpovio's accelerated approval marks a temporary win for Karyopharm: The drug’s final approval will depend on results from a confirmatory trial. And the company has a lot of persuading to do. The FDA went against its advisory committee's advice in granting the green light ahead of that trial, despite safety concerns. The drug is first in a new class of selective inhibitor of nuclear export (SINE) drugs. Xpovio works by inhibiting the XPO1 protein, which causes tumor suppressor proteins to accumulate in the cell nucleus and eventually kill off the cell. In a phase 2b trial dubbed Storm, the Xpovio-dexamethasone combo elicited an overall response rate of 25.3% that lasted a median of 3.8 months in a prespecified subgroup of 83 patients. These patients had failed on existing multiple myeloma drugs, including Takeda’s Velcade, Amgen’s Kyprolis, Celgene’s Revlimid and Pomalyst, and Johnson & Johnson’s Darzalex. Jefferies analysts at that time called the data “an inflection point” for Xpovio, noting that the response rate was “superior to historical Darzalex" in patients who'd failed on four prior rounds of therapy. But cancer experts on an FDA advisory committee weren’t impressed. Raising safety red flags, the experts voted 8-5 against the drug’s approval. More than one-quarter of patients—27%—dropped out of the Storm trial because of adverse reactions, and 65.3% of patients had their Xpovio dosage interrupted. Surprisingly, the drug’s label didn’t include any black-box warning on safety. Instead, the FDA codified a long list of adverse events associated with the drug, and the label requires physicians to keep a close eye on each patient's blood count, basic serum chemistry and body weight, and adjust dosage accordingly. During a briefing with investors on the approval, CEO Christopher Primiano was quick to point out that the drug’s targeted patients are already heavily treated, with multiple existing conditions that render them vulnerable. “It will be key for Karyopharm to provide active support to work through the many potential toxicities associated with Xpovio,” RBC Capital analyst Brian Abrahams said in a Friday note to clients. “This will not only be to enable patients to stay on the drug, but also to ensure docs maintain positive perceptions ahead of the potential expansion into earlier-line combos, where toxicities are lower and the patient population less fragile.” To that end, Karyopharm will be teaching doctors what to expect when using Xpovio and how to manage adverse reactions—given the many possibilities—and on guidelines for reducing doses as needed, Monaco said on Wednesday’s call. About 6,000 U.S. multiple myeloma patients are treated in the fourth or later lines of therapy each year, Monaco said. “As we believe the value of Xpovio to the patient is independent of what dosing regimen is most appropriate,” the company is pricing all four different four-week dosing package options at the same $22,000, he said. The price is higher than what Abrahams’ team had previously expected, though the RBC analyst noted the approval is in a more restricted population and each eligible patient’s treatment duration will likely be shorter, at about three months. Assuming a 40% penetration, Abrahams estimates the approval will bring in about $130 million in peak sales. While the initial indication is small, Abrahams said Xpovio could find more opportunity in earlier-line multiple myeloma and in diffuse large B-cell lymphoma, “with the accelerated approval substantially increasing the likelihood this will be achievable.” Xpovio’s fate will be decided soon. Top-line data from the confirmatory phase 3 study called Boston, which combines Xpovio with Velcade and low-dose dexamethasone, will come out later this year or early next. In DLBCL, Karyopharm plans an FDA filing in the same time frame. If everything goes Xpovio’s way in its indication expansion, Abrahams predicts the drug could surpass $900 million in overall peak sales.
Karyopharm 最终获得了急需的首个商业批准,这是一种药物,在此过程中引发了安全担忧,并遭遇了大量的速度冲击。现在,该公司必须应付有限的 FDA 点头,并与一个全新的营销总监引导。 FDA 通过 Karyopharm 公司的口服药物 Xpovio (硒),与地塞米松联合使用,治疗多发性骨髓瘤患者,他们至少接受了四种先前的治疗,而且他们的疾病对其他几种形式的治疗具有抵抗力。 Karyopharm 将于周三以每月2.2万美元的价格上市。但领导其由70多名员工组成的全套销售团队的不是刚刚辞去首席商务官职务的 AnandVaradan 。 相反, PerryMonaco 被提升为高级副总裁,负责商业运营,该公司在一份证券备案文件中披露。 Xpovio 的加速批准标志着 Karyopharm 的暂时胜利:该药物的最终批准将取决于一项确认试验的结果。公司有很多说服人去做。尽管存在安全问题, FDA 还是反对其咨询委员会在试验前批准绿灯的建议。 该药物是第一类新型选择性核出口抑制剂( SINE )药物。Xpovio 通过抑制 XPO1蛋白发挥作用,而 XPO1蛋白会导致肿瘤抑制蛋白聚集在细胞核中,最终杀死细胞。 在一项名为 Storm 的2b 期试验中, Xpovio-地塞米松联合疗法的总有效率为25.3%,在83名患者的预先指定的亚组中,平均持续3.8个月。这些患者在现有的多发性骨髓瘤药物上失败了,包括武田(Takeda)的 Velcade 、安进(Amgen)的 Kyprolis 、新基(Celgene)的 Revlimed 和 Pomalyst 以及强生(Johnson & Johnson)的 Darzalex 。 杰富瑞当时的分析师称, Xpovio 的数据是“拐点”,并指出在之前四轮治疗失败的患者中,反应速度“优于历史上的 Darzalex ”。但是 FDA 咨询委员会的癌症专家并没有留下深刻印象。专家们举起安全红旗,以8票对5票反对药品的批准。 超过四分之一的患者(27%)因不良反应退出风暴试验,65.3%的患者的 Xpovio 剂量中断。 令人惊讶的是,该药物的标签没有包括任何关于安全的黑盒警告。相反, FDA 编纂了一长串与该药物相关的不良事件清单,该标签要求医生密切关注每个病人的血液计数、基本血清化学和体重,并相应调整剂量。 在向投资者通报批准情况时,该公司首席执行官克里斯托弗•普里米亚诺( Christopher Primiano )迅速指出,该药物的目标患者已经接受了大量治疗,现有的多种条件使他们变得脆弱。 RBC Capital 分析师布赖恩•阿布拉罕斯( Brian Abrahams )上周五在给客户的一份报告中表示:“核药学为研究与 Xpovio 有关的许多潜在毒性提供积极支持,将是关键。”“这不仅能让患者继续使用该药,还能确保医生在可能扩展到更早的药物组合之前保持积极的认知,在这些组合中,毒性较低,患者群体较不脆弱。” 摩纳哥在周三的电话中表示,为此目的, Karyopharm 将向医生传授在使用 Xpovio 时的期望,以及如何管理不良反应(考虑到许多可能性),以及减少剂量的指导方针。 莫纳科说,每年大约有6000名美国多发性骨髓瘤患者接受第四或以后的治疗。他表示:“我们认为, Xpovio 对患者的价值与最合适的剂量养生法方案无关。”该公司将所有四种不同的四周剂量治疗方案的定价都定在2.2万美元。 这一价格高于 Abrahams 团队此前的预期,不过加拿大皇家银行的分析师指出,批准治疗的人群更多,每个符合条件的患者的治疗时间可能更短,大约为3个月。 Abrahams 估计,如果市场渗透率达到40%,这一批准将带来约1.3亿美元的峰值销售额。虽然最初的迹象很小,但 Abrahams 说 Xpovio 可以在早期多发性骨髓瘤和弥漫性大 B 细胞淋巴瘤中找到更多的机会,“加速审批大大增加了这种可能性。” Xpovio 的命运将很快决定。来自名为波士顿的验证性第三阶段研究( Xpovio 与 Velcade 和低剂量地塞米松结合)的一线数据将于今年晚些时候或明年初公布。在 DLBCL 中, Karyopharm 计划在同一时间框架内提交 FDA 文件。 Abrahams 预测,如果一切顺利, Xpovio 的适应症扩张,该药的总销售额将超过9亿美元。

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