2015年7月3日，美国FDA今天批准了福泰制药的Orkambi，用于治疗12岁或以上的带有F508del基因变异的囊性纤维化患者。5月12日，美国FDA的一个专家小组以12票赞成，1票反对的悬殊投票支持Orkambi上市。Orkambi是第一个获得FDA批准用于治疗2个基因变异的囊性纤维化药物。
囊性纤维化（cystic fibrosis，CF）是一种因CF基因突变引起的严重遗传性疾病。囊性纤维化患者在美国大约有3万人，是在白种人中最常见的致命性遗传性疾病。囊性纤维化最常见的基因突变是F508del突变，其中从父母各遗传一个F508del突变的患者约占患者总数的一半。F508del变异的基因表达一种不正常的蛋白，引起人体上皮细胞氯离子通道的调节缺陷，导致呼吸道黏膜上皮的水和电解质跨膜转运障碍，致使黏液腺分泌物中的酸性糖蛋白含量明显升高，造成分泌物粘稠，从而影响患者的胃肠道和呼吸系统，包括慢性梗阻性肺部病变、胰腺外分泌功能异常、和汗液电解质异常升高等。
囊性纤维化不能治愈。目前的主要疗法还仅限于防止感染（比如使用抗生素），扩张支气管等改善症状的治疗方案。Orkambi是继Kalydeco之后美国FDA批准的第二个直接抵消遗传缺陷的囊性纤维化药物。Orkambi也是第一个获批用于治疗2个基因变异的CF药物。
Orkambi是Kalydeco（通用名：ivacaftor）和lumacaftor的复方组合，每片含有125毫克的ivacaftor和200毫克的lumacaftor。Kalydeco在2012年获得FDA批准上市，治疗一种极罕见的G551基因突变的囊性纤维化，而lumacaftor是新分子实体，之前没有获得FDA批准上市。在2个共有1108位CF患者参与的双盲、安慰剂对照的临床实验中，这些患者都是12岁或以上且伴有F508del突变。患者每日2次、每次服用2片的Orkambi，和安慰剂组相比肺功能获得改善。和药物相关的最常见不良事件包括呼吸急促、上呼吸道感染、恶心、腹泻、和皮疹。如果妇女使用Orkambi还可能增加月经异常。
Kalydeco虽然早在2012年就获得FDA批准上市，但适用人群只是一种极为罕见的G551基因突变的患者，仅占所有CF人数的4%。F508del突变是囊性纤维化最大的患者群体，12岁或以上的患者在美国就有8500左右。遗憾的是Orkambi的疗效还不够突出，虽然和安慰剂相比达到统计学显著，但仅仅平均提高患者3%左右的肺功能。而且Orkambi势必收费高昂（但预计低于单药Kalydeco的30万美元），为了这点疗效能否说服支付方慷慨解囊还要有待时间的考证。 
Pharmacological Class:
Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator.

Active Ingredient(s):
Lumacaftor, ivacaftor 200mg/125mg; tabs.

Company
Vertex Pharmaceuticals
Indication(s):
Treatment of cystic fibrosis (CF) in patients ≥12yrs who are homozygous for the F508del mutation in the CFTR gene. Limitations of use: efficacy and safety not established in patients with CF other than those homozygous for the F508del mutation.

Pharmacology:
Lumacaftor improves the conformational stability of F508del-CFTR, resulting in increased processing and trafficking of mature protein to the cell surface. Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell surface. In vitro studies have demonstrated that both lumacaftor and ivacaftor act directly on the CFTR protein in primary human bronchial epithelial cultures and other cell lines harboring the F508del-CFTR mutation to increase the quantity, stability, and function of F508del-CFTR at the cell surface, resulting in increased chloride ion transport.

Clinical Trials:
The efficacy of Orkambi in patients with CF who are homozygous for the F508del mutation in the CFTR gene was eva luated in two randomized, double-blind, placebo-controlled, 24-week clinical trials (Trials 1 and 2) in 1108 clinically stable patients with CF of whom 369 patients received Orkambi twice daily. Trial 1 eva luated 549 patients with CF who were ≥12 years (mean age 25.1 years) with ppFEV1 at screening between 40–90 [mean ppFEV1 60.7 at baseline (range: 31.1–94.0)]. Trial 2 eva luated 559 patients ≥12 years (mean age 25.0 years) with ppFEV1 at screening between 40–90 [mean ppFEV1 60.5 at baseline (range: 31.3–99.8)].

Patients in both trials were randomized 1:1:1 to receive either Orkambi (lumacaftor 400mg q12h/ivacaftor 250mg q12h; or lumacaftor 600mg once daily/ivacaftor 250mg q12h) or placebo. Patients took the study drug with fat-containing food for 24 weeks in addition to their prescribed CF therapies (eg, bronchodilators, inhaled antibiotics, dornase alfa, and hypertonic saline).

The primary efficacy endpoint in both trials was change in lung function as determined by absolute change from baseline in ppFEV1 at Week 24, assessed as the average of the treatment effects at Week 16 and at Week 24. In both trials, treatment with Orkambi resulted in a statistically significant improvement in ppFEV1. The treatment difference between Orkambi and placebo for the mean absolute change in ppFEV1 from baseline at Week 24 was 2.6 percentage points [95% CI (1.2, 4.0)] in Trial 1 (P=0.0003) and 3.0 percentage points [95% CI (1.6, 4.4)] in Trial 2 (P<0.0001).

For more clinical trial data, see full labeling.

Legal Classification:
Rx

Adults:
Take with fat-containing food (eg, eggs, avocados, nuts, butter, peanut butter, cheese pizza, whole-milk dairy products). 2 tabs every 12hrs. Currently taking strong CYP3A inhibitors (eg, itraconazole, ketoconazole, posaconazole, voriconazole, telithromycin, clarithromycin): initially 1 tab once daily for 1st week then continue with recommended daily dose. Hepatic impairment (moderate): 2 tabs in the AM and 1 tab in the PM; (severe): 1 tab in the AM and 1 tab in the PM, or less; use with caution.

Children:
Not established.

Warnings/Precautions:
If genotype is unknown, use an FDA cleared CF mutation test to detect the presence of the F508del mutation on both alleles of the CFTR gene. Advanced hepatic impairment. Assess ALT/AST and bilirubin levels prior to initiating therapy, every 3 months during the first year of treatment, and annually thereafter. If ALT/AST or bilirubin levels increased, monitor closely until resolved. Interrupt dosing if ALT/AST is >5XULN or if ALT/AST is >3XULN with bilirubin elevations >2XULN; after resolution, consider restarting. Monitor for respiratory events during treatment initiation. Perform baseline and follow-up eye exams. Severe renal impairment (CrCl ≤30mL/min) or ESRD. Pregnancy (Cat.B). Nursing mothers.

Interaction(s)
See Adults. Concomitant strong CYP3A inducers (eg, rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, St. John’s wort): not recommended. Concomitant sensitive CYP3A substrates or those with a narrow therapeutic index (eg, midazolam, triazolam, cyclosporine, everolimus, sirolimus, tacrolimus): not recommended. May affect CYP2B6, CYP2C8, CYP2C9, CYP2C19, P-gp substrates. Monitor digoxin. May antagonize montelukast, systemic corticosteroids (eg, prednisone, methylprednisolone), ibuprofen, citalopram, escitalopram, sertraline, omeprazole, esomeprazole, lansoprazole, ranitidine; dose adjustment may be needed. May antagonize clarithromycin, erythromycin, telithromycin; consider alternatives (eg, ciprofloxacin, azithromycin, levofloxacin). Concomitant itraconazole, ketoconazole, posaconazole, voriconazole: not recommended; if necessary, monitor closely or consider alternatives (eg, fluconazole). May antagonize repaglinide or affect sulfonylureas; dose adjustment may be needed. Concomitant warfarin; monitor INR. May reduce effectiveness of hormonal contraceptives and increase menstruation abnormality events; avoid.

Adverse Reaction(s)
Dyspnea, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, fatigue, abnormal respiration, increased blood creatinine phosphokinase, rash, flatulence, rhinorrhea, influenza.

How Supplied:
Tabs—112

LAST UPDATED:
9/11/2015