A primary immunodeficiency whose rarity means it can go undiagnosed or misdiagnosed in a patient for years now has its first drug. The FDA has approved a once-daily therapy that addresses the underlying genetic problem driving the inherited disorder, known as WHIM syndrome.

一种原发性免疫缺陷，其罕见性意味着多年来可能在患者中未被诊断或误诊，现在有了第一种药物。美国食品和药物管理局（FDA）批准了一种每日一次的疗法，用于解决导致遗传性疾病的潜在遗传问题，即突发奇想综合症。

The regulatory decision announced Monday for the X4 Pharmaceuticals drug covers WHIM patients age 12 and older. The daily capsule, known in development as mavorixafor, will be commercialized under the brand name Xolremdi (pronounced “zohl-REM-dee”).

周一宣布的针对X4制药的监管决定涵盖了12岁及以上的突发奇想患者。每日胶囊，在开发中称为mavorixafor，将以品牌Xolremdi（发音为“zohl-REM-dee”）商业化。

The name WHIM is an acronym for warts, hypogammaglobulinemia, infections, and myelokathexis, which are the four common clinical presentations of the disease. But the disease is not limited to those symptoms and it presents differently from one patient to another. There is no standard of care for WHIM, which is treated with various therapies that address its symptoms and frequent infections..

WHIM是疣、低丙种球蛋白血症、感染和骨髓增生异常的首字母缩写，这是该病的四种常见临床表现。但这种疾病不仅限于这些症状，而且患者之间的表现也有所不同。对于突发奇想症，没有标准的治疗方法，可以通过各种治疗方法来解决其症状和频繁感染。。

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With the Rise of AI, What IP Disputes in Healthcare Are Likely to Emerge?

随着人工智能的兴起，医疗保健领域可能会出现哪些知识产权纠纷？

Munck Wilson Mandala Partner Greg Howison shared his perspective on some of the legal ramifications around AI, IP, connected devices and the data they generate, in response to emailed questions.

Munck Wilson Mandala合伙人格雷格·豪森（GregHowison）在回答电子邮件中提出的问题时，分享了他对人工智能、IP、连接设备及其产生的数据产生的一些法律后果的看法。

“What’s exciting about this approval is for the first time, WHIM patients and their physicians have a treatment that targets the underlying cause of the disease,” Paula Ragan, CEO of Boston-based X4, said during a Monday conference call.

总部位于波士顿的X4公司首席执行官保拉·拉根（PaulaRagan）在周一的电话会议上表示：“这项批准令人兴奋的是，突发奇想患者及其医生首次针对疾病的根本原因进行了治疗。”。

There are more than 400 types of primary immunodeficiency, according to the Centers for Disease Control and Prevention. WHIM can confuse patients and clinicians, who either mistake the disease for one of those immunodeficiencies or chalk up the symptoms to children just getting a lot of infections—which many kids do, said Dr.

根据疾病控制和预防中心的数据，原发性免疫缺陷有400多种。突发奇想可能会混淆患者和临床医生，他们要么将疾病误认为是免疫缺陷之一，要么将症状归咎于儿童，就像许多儿童一样，只是感染了很多感染。

Teresa Tarrant, a professor of rheumatology and immunology at the Duke University School of Medicine and a principal investigator in the X4 drug’s pivotal study. WHIM is suspected when the severity and frequency of infections goes above and beyond what’s typical in most kids, she said in an interview..

特蕾莎·塔兰特是杜克大学医学院风湿病学和免疫学教授，也是X4药物关键研究的首席研究员。她在一次采访中说，当感染的严重程度和频率超过大多数孩子的典型程度时，就会怀疑是突发奇想。。

WHIM can be thought of as a traffic problem for immune cells. In some immunodeficiencies, the body doesn’t make enough immune cells or the immune cells it makes don’t function properly. In WHIM, functioning immune cells are produced by the bone marrow but they cannot get into circulation to fight pathogens.

突发奇想可以被认为是免疫细胞的交通问题。在某些免疫缺陷症中，身体没有产生足够的免疫细胞，或者它产生的免疫细胞功能不正常。在突发奇想中，功能正常的免疫细胞是由骨髓产生的，但它们不能进入循环以对抗病原体。

Myelokathexis, the “M” in WHIM, is the retention of immune cells in the bone marrow. WHIM stems from a rare mutation in the CXCR4 gene, which encodes a chemokine receptor, a protein involved in regulating the movement of immune cells in the body..

骨髓增生异常（Myelokathexis）是突发奇想中的“M”，是免疫细胞在骨髓中的滞留。突发奇想源于CXCR4基因的罕见突变，该基因编码趋化因子受体，一种参与调节体内免疫细胞运动的蛋白质。。

The first genetic mutation that leads to WHIM was identified in 2003. Scientific research, including work from X4, has since identified other mutations that lead to the disease. Defective CXCR4 protein keeps the signaling of the CXCR4 pathway in a hyperactive state, which in turn keeps immune cells trapped in the bone marrow, Tarrant said.

2003年发现了第一个导致突发奇想的基因突变。科学研究，包括X4的工作，已经确定了导致该疾病的其他突变。塔兰特说，有缺陷的CXCR4蛋白使CXCR4通路的信号传导处于过度活跃状态，从而使免疫细胞被困在骨髓中。

She likens this pathway to an on-off switch for getting cells out of the bone marrow. X4’s drug is a small molecule designed to selectively target and block the CXCR4 cell receptor..

她将这种途径比作从骨髓中提取细胞的开关。X4的药物是一种小分子，旨在选择性靶向和阻断CXCR4细胞受体。。

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A Personalized Approach to Medication Nonadherence

个性化的药物不依从性方法

At the Abarca Forward conference earlier this year, George Van Antwerp, managing director at Deloitte, discussed how social determinants of health and a personalized member experience can improve medication adherence and health outcomes.

在今年早些时候的Abarca Forward会议上，德勤董事总经理乔治·范安特卫普（GeorgevanAntwerp）讨论了健康的社会决定因素和个性化的会员体验如何改善药物依从性和健康结果。

“In WHIM, many patients have a problem with the off (switch), so the signaling is on all the time,” Tarrant said. “It’s hyperactive. This drug dampens down the hyperactive signaling.”

塔兰特说：“在突发奇想的情况下，许多患者都有关闭（开关）的问题，因此信号一直是打开的。”。“它是过度活跃的。这种药物抑制了过度活跃的信号传导。”

X4 evaluated mavorixafor in a placebo-controlled Phase 3 clinical trial that enrolled 31 patients with WHIM syndrome. The main goal of the 52-week study was to show a statistically significant increase in time, measured in hours, that neutrophil counts were above a specified threshold. Results showed that the trial met this goal as well as a key secondary endpoint measuring lymphocyte counts.

X4在一项安慰剂对照的3期临床试验中评估了mavorixafor，该试验招募了31名WHIM综合征患者。这项为期52周的研究的主要目标是显示中性粒细胞计数高于特定阈值的时间（以小时为单位）的统计学显着增加。结果表明，该试验达到了这一目标，并且是测量淋巴细胞计数的关键次要终点。

Additional results showed the X4 drug led to statistically significant reductions in annualized infection rates and clinically meaningful reductions in the severity and duration of infections. The drug was well tolerated by study participants..

其他结果显示，X4药物导致年度感染率的统计学显着降低，以及感染严重程度和持续时间的临床意义降低。研究参与者对该药物的耐受性良好。。

A rare disease is typically defined as one that affects 200,000 or fewer patients in the U.S. WHIM is ultra rare, affecting about 1,000 people in the U.S., according to X4’s market research. The median age of diagnosis is 5.5 years old. But some patients can go much longer before finding out what’s wrong.

在美国，罕见病通常被定义为影响20万或更少患者的疾病。根据X4的市场研究，突发奇想极为罕见，影响美国约1000人。诊断的中位年龄为5.5岁。但有些患者在发现问题之前可能会经历更长的时间。

Tarrant said her first clinical encounter with WHIM was someone whose disease went undiagnosed until the patient reached the late 30s. While some primary immunodeficiencies can be detected with newborn screening, WHIM is not one of them. These tests only pick up children with extremely low levels of immune cells, Tarrant explained.

塔兰特说，她第一次在临床上遇到心血来潮的人，直到病人30多岁才被确诊。虽然新生儿筛查可以检测到一些原发性免疫缺陷，但突发奇想并不是其中之一。塔兰特解释说，这些测试只检测免疫细胞水平极低的儿童。

The low levels in WHIM can be seen in bloodwork. But children typically don’t get a lot of blood draws, she said..

在血液检查中可以看到突发奇想的程度很低。但她说，儿童通常不会抽血。。

While WHIM can be diagnosed with a genetic test that confirms the CXCR4 mutation, Chief Commercial Officer Mark Baldry noted that the FDA decision does not require it. The label of Xolremdi covers patients who have a clinical diagnosis of WHIM. Xolremdi, available in 100 mg capsules, is dosed according to a patient’s weight.

虽然可以通过确认CXCR4突变的基因检测来诊断突发奇想，但首席商务官Mark Baldry指出，FDA的决定并不需要它。Xolremdi的标签涵盖了临床诊断为突发奇想的患者。Xolremdi有100毫克胶囊，根据患者体重服用。

Patients weighing 50 kg (about 110 pounds) or more are directed to take 400 mg once daily. For these patients, the drug’s annual wholesale price is $496,400. Those weighing less than 50 kg will take a 300 mg dose of Xolremdi once daily, which carries a $372,300 annual price. Based on clinical trial experience and company research, X4 estimates that 90% of WHIM patients will require the higher dose.

体重50公斤（约110磅）或以上的患者每天一次服用400毫克。对于这些患者，该药物的年批发价格为496400美元。体重不足50公斤的人每天服用300毫克Xolremdi，年价格为372300美元。根据临床试验经验和公司研究，X4估计90%的突发奇想患者需要更高剂量。

Baldry said Xolremdi is available now, though he added it could take six months to a year before payers start covering it..

Baldry说Xolremdi现在可以使用了，但他补充说，付款人开始支付可能需要六个月到一年的时间。。

Mavorixafor was licensed from Genzyme, a Sanofi subsidiary. With the molecule’s approval, X4 now owes a $7 million milestone payment, plus royalties from product sales, Chief Financial Officer Adam Mostafa said. The company is not providing any sales guidance for the drug at this time. The approval comes with a priority review voucher, which X4 may apply toward faster regulatory review of different rare disease drug in the future.

Mavorixafor获得了赛诺菲子公司Genzyme的许可。首席财务官亚当·莫斯塔法（AdamMostafa）表示，经molecule批准，X4现在欠下700万美元的里程碑付款，以及产品销售的版税。该公司目前不提供该药物的任何销售指导。该批准附有优先审查凭证，X4可能适用于未来对不同罕见病药物进行更快的监管审查。

But companies typically monetize these vouchers, selling them at prices topping $100 million. Mostafa said X4 plans to sell its voucher, and Sanofi-Genzyme is not owed any of the proceeds from that sale..

但公司通常将这些代金券货币化，以超过一亿美元的价格出售。莫斯塔法表示，X4计划出售其代金券，赛诺菲健赞不欠出售所得的任何款项。。

X4 is also evaluating mavorixafor as a treatment for chronic neutropenia. The company expects to begin a Phase 3 study in this indication by the end of June, according to an investor presentation. The pipeline includes two additional CXCR4-targeting drugs. X4P-003 is a next-generation drug that X4 says has enhanced properties and potential applications in other diseases associated with the CXCR4 receptor.

X4还评估了mavorixafor作为慢性中性粒细胞减少症的治疗方法。据投资者介绍，该公司预计将于6月底开始这一迹象的第三阶段研究。该管道包括另外两种CXCR4靶向药物。X4P-003是一种新一代药物，X4说它在与CXCR4受体相关的其他疾病中具有增强的特性和潜在的应用。

Meanwhile, X4P-002 offers the ability to cross the blood-brain barrier to reach that target. Both molecules are in preclinical development..

同时，X4P-002具有跨越血脑屏障达到该目标的能力。这两种分子都处于临床前开发阶段。。

Photo: ClarkandCompany, Getty Images

照片：克拉坎公司（ClarkandCompany），盖蒂影像（Getty Images）

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