FDA批准首个治疗罕见的骨髓纤维化药物Jakafi

11月18日，美国食品和药品管理局（FDA）于本月16日批准Jakafi（ruxolitinib）为首个专门用于治疗骨髓纤维化患者的药物。

骨髓纤维化是一种罕见骨髓疾病，其中骨髓被瘢痕组织替代，导致血细胞在肝脏和脾脏等器官中生成。这种疾病的特征是脾肿大、贫血、白细胞和血小板减少、及其他骨髓纤维化相关症状。其症状包括疲劳、腹部不适、肋下疼痛、饱腹感、肌肉和骨骼疼痛、瘙痒和盗汗。

Jakafi一天服用两次，是选择性贾纳斯（Janus）激酶（JAK）1／2酪氨酸蛋白激酶抑制剂。JAK 1和JAK 2参与调节血液和免疫功能，骨髓纤维化与JAK 1和JAK 2失调有关。

FDA药物评价与研究中心的血液与肿瘤产品办公室主任Richard Pazdur博士称，Jakafi代表了肿瘤学逐渐发展的趋势的一个例子，在详细科学地了解疾病的机制后，使药物针对特定的分子途径。使批准获得通过的临床试验主要关注骨髓纤维化患者常出现的问题，包括脾肿大和疼痛。

在对528名患者进行的两次临床试验中评价了Jakafi的安全性与疗效。这两次试验中的患者均对现有的骨髓纤维化治疗耐受或抵抗，或不适合接受异种基因骨髓移植手术（在此手术中患者接受基因相似但却不一定相同的捐献者的造血干细胞）。所有的患者都有脾肿大，都由于疾病所致症状而需要治疗。

所研究的患者接受了Jakafi或安慰剂（糖丸）治疗或最好的现有治疗（化疗剂羟基脲，或糖皮质激素）。与接受了安慰剂或最好现有疗法的患者相比，更多比例的接受Jakafi的患者其脾脏缩小35%以上。同样，与接受安慰剂的患者相比，更多比例的接受Jakafi的患者其骨髓纤维化相关症状（腹部不适、盗汗、发痒、骨骼和肌肉疼痛）减轻了50%以上。

在Jakafi治疗患者中出现的最严重的副作用包括血小板水平低（血小板减少症）、贫血、疲劳、腹泻、气短（呼吸困难）、头痛、头晕和恶心。

Jakafi经FDA的优先审查程序获得批准，这项为期六个月的加速审查针对的是可提供超越现有疗法的重大进步或可提供第一种疗法的药物。

根据处方药申报者付费法案（PDUFA），在此药物于今年12月3日的审查目标日期之前用其治疗已获批准，该药已被指定为孤儿药，该病在美国累及不超过20万人。

Jakafi由特拉华州威明顿市的因赛特制药公司（Incyte Corp.）制造。

Manufacturer:
Incyte Corporation

Pharmacological Class:
Kinase inhibitor.

Active Ingredient(s):
Ruxolitinib 5mg, 10mg, 15mg, 20mg, 25mg; tabs.

Indication(s):
Treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis.

Pharmacology:
Ruxolitinib inhibits Janus Associated Kinases (JAKs) JAK1 and JAK2, which mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function.

Clinical Trials:
The efficacy of Jakafi was evaluated in two clinical trials in patients with myelofibrosis. The starting dose was based on platelet count. Patients with a platelet count between 100–200X109/L were started on Jakafi 15mg twice daily, while patients with a platelet count >200X109/L were started on Jakafi 20mg twice daily. Doses were subsequently individualized based on tolerability and efficacy; maximum doses were 20mg twice daily if platelet counts were between 100 to ≤125X109/L, 10mg twice daily if platelet counts were between 75 to ≤100X109/L, and 5mg twice daily if platelet counts were between 50 to ≤75X109/L.

At primary endpoint, a significantly larger proportion of patients in the Jakafi group achieved a 35% or greater reduction in spleen volume from baseline in both studies (as compared to placebo in Study 1, and as compared to best available therapy in Study 2). A similar proportion of patients in the Jakafi group achieved a ≥50% reduction in palpable spleen length.

Legal Classification:
Rx

Adults:
Doses may be given by NG tube if unable to swallow tabs. Platelets >200X109/L: initially 20mg twice daily. Platelets 100–200X109/L: initially 15mg twice daily. May increase doses by 5mg twice daily to a max of 25mg twice daily; do not increase during the first 4wks of therapy and not more frequently than every 2wks. Discontinue treatment after 6mos if no reduction in spleen size or symptom improvement. Interrupt treatment if platelets <50X109/L. May restart or increase after recovery of platelets (see literature for max allowable restarting doses). Consider dose reductions if platelets decrease but remain >50X109/L (see literature). Concomitant strong CYP3A4 inhibitors: initially 10mg twice daily if platelets ≥100X109/L; if platelets <100X109/L: avoid. Moderate or severe renal impairment (CrCl 15–59mL/min) and platelets between 100–150X109/L: initially 10mg twice daily.

Children:
Not established.

Warnings/Precautions:
Monitor for thrombocytopenia, anemia, neutropenia; withhold or reduce dose if occur. Obtain CBC and platelets before initiating therapy, every 2–4 weeks until doses are stabilized, and then as clinically indicated. Risk of serious bacterial, mycobacterial, fungal, and viral infections; evaluate and treat if signs/symptoms occur. Confirm resolution of active infections before starting. Renal or hepatic impairment. Pregnancy (Cat. C). Nursing mothers: not recommended.

Interaction(s):
Potentiated by strong CYP3A4 inhibitors (eg, boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) and mild or moderate CYP3A4 inhibitors (eg, erythromycin). Antagonized by CYP3A4 inducers (eg, rifampin).

Adverse Reaction(s):
Thrombocytopenia, anemia, neutropenia, bruising, dizziness, headache, UTIs, weight gain, flatulence, herpes zoster.

How Supplied:
Tabs—60