2017年5月17日，美国食品药品监督管理局（FDA）扩大了用于治疗囊性纤维化的Kalydeco（ivacaftor）的使用范围。 该批准将药物现在可以治疗的罕见基因突变的数量提高到已有的三倍，从10个突变提高到33个。FDA的决定部分基于实验室检测结果，并结合早期人体临床试验的证据。 该基于实验室数据的方法提供了一个增加更多的疾病罕见突变的途径。

FDA药物评估与研究中心主任医学博士肯德基•伍德科克（Janet Woodcock）指出：“许多罕见的囊性纤维化突变患者人数非常少，临床试验研究是不可行的。这个挑战促使我们使用基于精准医学的替代方法，这使得确定可能对Kalydeco响应的那些基因突变成为可能。”

囊性纤维化影响产生粘液、汗液和消化液的细胞。 由于大量的离子（氯化物）和水进出细胞，这些分泌的液体通常是薄而光滑的。 进展性疾病患者具有不能调节离子和水的运动的不良的囊性纤维化跨膜传导调节因子（CFTR）基因，导致分泌物变稠和变厚。 分泌物在肺、消化道和身体其它部位积聚，导致严重的呼吸和消化问题，以及其它并发症，如感染和糖尿病。

体外基于细胞的模型系统的结果已经显示可以合理地预测对Kalydeco的临床响应。 当在实验室检测中额外的突变对Kalydeco作出响应时，研究人员就能够对早期临床试验中证明的其它突变的临床效果进行外推。 这就促成增加该药物适用的基因突变。

Kalydeco，剂型为片剂或口服颗粒，与含有脂肪的食物一起服用，每天两次，有助于CFTR基因产生的蛋白质更好发挥作用，从而改善肺功能和囊性纤维化的其它方面，包括体重增加。 如果患者的基因型未知，则应使用FDA批准的囊性纤维化突变测试来检测CFTR突变的存在，然后使用突变试验指导推荐的双向测序进行验证。

囊性纤维化是一种罕见病，在美国有约30,000位患者。Kalydeco适用于2岁及以上的患者，这些患者，基于临床和/或体外（实验室）数据，对CFTR基因中的一个突变有响应。 扩大适应症将影响另外3％的囊性纤维化患者，约900名患者。 Kalydeco是以病人为中心的药物开发如何能够更好地理解疾病的一个范例。 例如，囊性纤维化基金会维护了一个28,000位患者的注册表，包含遗传数据，可用于研究。

Kalydeco的常见副作用包括头痛; 上呼吸道感染（普通感冒）包括喉咙痛、鼻窦充血或流鼻涕; 胃（腹部）疼痛; 腹泻; 皮疹; 恶心和头晕。 Kalydeco相关的风险包括升高的转氨酶（肝脏产生的各种酶）和小儿白内障。 与强CYP3A诱导剂（例如利福平、圣约翰草）的共同使用显着降低了Kalydeco的暴露，这可能降低有效性，因此不推荐。

Kalydeco由总部设在波士顿的Vertex Pharmaceuticals Inc.制造。

（以下为FDA的新闻稿原文）

FDA expands approved use of Kalydeco to treat additional mutations of cystic fibrosis

May 17, 2017

The U.S. Food and Drug Administration today expanded the approved use of Kalydeco (ivacaftor) for treating cystic fibrosis. The approval triples the number of rare gene mutations that the drug can now treat, expanding the indication from the treatment of 10 mutations, to 33. The agency based its decision, in part, on the results of laboratory testing, which it used in conjunction with evidence from earlier human clinical trials. The approach provides a pathway for adding additional, rare mutations of the disease, based on laboratory data.

“Many rare cystic fibrosis mutations have such small patient populations that clinical trial studies are not feasible,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “This challenge led us to using an alternative approach based on precision medicine, which made it possible to identify certain gene mutations that are likely to respond to Kalydeco.

Cystic fibrosis affects the cells that produce mucus, sweat and digestive juices. These secreted fluids are normally thin and slippery due to the movement of sufficient ions (chloride) and water in and out of the cells. People with the progressive disease have a defective cystic fibrosis transmembrane conductance regulator (CFTR) gene that can’t regulate the movement of ions and water, causing the secretions to become sticky and thick. The secretions build up in the lungs, digestive tract and other parts of the body leading to severe respiratory and digestive problems, as well as other complications such as infections and diabetes.

Results from an in vitro cell-based model system have been shown to reasonably predict clinical response to Kalydeco. When additional mutations responded to Kalydeco in the laboratory test, researchers were thus able to extrapolate clinical benefit demonstrated in earlier clinical trials of other mutations. This resulted in the addition of gene mutations for which the drug is now indicated.

Kalydeco, available as tablets or oral granules taken two times a day with fat-containing food, helps the protein made by the CFTR gene function better and as a result, improves lung function and other aspects of cystic fibrosis, including weight gain. If the patient’s genotype is unknown, an FDA-cleared cystic fibrosis mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use.

Cystic fibrosis is a rare disease that affects about 30,000 people in the United States.Kalydeco is indicated for patients aged 2 and older who have one mutation in the CFTR gene that is responsive to drug treatment based on clinical and/or in vitro (laboratory) data. The expanded indication will affect another 3 percent of the cystic fibrosis population, impacting approximately 900 patients. Kalydeco serves as an example of how successful patient-focused drug development can provide greater understanding about a disease. For example, the Cystic Fibrosis Foundation maintains a 28,000-patient registry, including genetic data, which it makes available for research.

Common side effects of Kalydeco include headache; upper respiratory tract infection (common cold) including sore throat, nasal or sinus congestion, or runny nose; stomach (abdominal) pain; diarrhea; rash; nausea; and dizziness. Kalydeco is associated with risks including elevated transaminases (various enzymes produced by the liver) and pediatric cataracts. Co-administration with strong CYP3A inducers (e.g., rifampin, St. John’s wort) substantially decreases exposure of Kalydeco, which may diminish effectiveness, and is therefore not recommended.

Kalydeco is manufactured for Boston-based Vertex Pharmaceuticals Inc.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

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