首个也是唯一一个口服蛋白酶体抑制剂NINLARO(IXAZOMIB CITRATE)CAPSULE获美国FDA批准与两款其它药物合并用于治疗既往至少接受过一种治疗的多发性骨髓瘤患者。
2015年11月20日，美国食品和药物监管局(FDA)批准了Ixazomib（商品名Ninlaro， 美国Millennium制药公司生产）联合来那度胺（Lenalidomide）和地塞米松（Dexamethasone）用于治疗多发性骨髓瘤。这些患者已接受过至少一种先前治疗，而疾病仍然进一步发展。
Ixazomib是第一个被批准的口服蛋白酶体抑制剂
Ixazomib的批准是基于一个多中心参与的、随机的3期临床试验的有效结果。共有722例先前接受过1到3种治疗的多发性骨髓瘤患者参与该试验。试验患者被随机分配接受Ixazomib联合来那度胺和地塞米松或安慰剂联合来那度胺和地塞米松。Ixazomib联合来那度胺和地塞米松治疗的无进展生存期为20.6个月，安慰剂联合来那度胺和地塞米松治疗的无进展生存期则为14.7个月。
Ixazomib联合来那度胺和地塞米松治疗最常见的副作用（发生率>20%）包括腹泻、便秘、血小板减少、外周神经病、恶心、外周水肿、呕吐和背痛。
Ixazomib联合来那度胺和地塞米松治疗的推荐剂量和用法为：
Ixazomib 4毫克，口服，第1、8和15天，每28天为1个疗程；
来那度胺 25毫克，口服，第1到21天，每28天为1个疗程；
地塞米松40毫克，口服，第1、8、15和22天，每28天为1个疗程。
关于Ixazomib(商品名Ninlaro)的完整处方信息，请参阅：
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fcef9088-ebab-4bd8-933f-c35f9c8bd50b
批准日期：2015年11月20日  公司：武田制药美国公司
NINLARO（ixazomib）胶囊，口服使用
最初美国批准：2015年
描述
NINLARO（ixazomib）是一种抗肿瘤剂。 Ixazomib柠檬酸盐，前药，在生理条件其生物活性形式，ixazomib下快速水解。柠檬酸ixazomib的化学名称为1,3,2-二氧硼戊环-4,4-二乙酸，2 - [（1R）-1 - [[2 - [（2,5-二氯苯甲酰基）氨基]乙酰基]氨基] - 3-甲基丁基] -5-氧代 - 和结构式为：

柠檬酸ixazomib分子式为C20H23BCl2N2O9和其分子量为517.12。 Ixazomib柠檬酸具有一个手性中心，并为R立体异构体。 ixazomib柠檬酸在0.1N盐酸（pH值1.2）的在37℃下的溶解度为0.61毫克/毫升（报告为ixazomib）。溶解度增加的pH值升高。
NINLARO（ixazomib）用于口服的胶囊含有4,3或2.3毫克ixazomib相当于5.7，4.3或3.3毫克的柠檬酸ixazomib的。非活性成分包括微晶纤维素，硬脂酸镁，和滑石。胶囊壳含有明胶和二氧化钛。 4毫克胶囊壳含有红色和黄色的氧化铁，将3毫克胶囊壳含有黑色氧化铁和2.3毫克胶囊壳含有红色氧化铁。印刷油墨含有虫胶，丙二醇，氢氧化钾，和黑色氧化铁。
作用机理
Ixazomib是可逆蛋白酶抑制剂。Ixazomib优先结合并抑制20S蛋白酶体的测试5亚基的糜蛋白酶样活性。
Ixazomib诱导的体外多发性骨髓瘤细胞系的细胞凋亡。Ixazomib打击骨髓瘤细胞的体外细胞毒性表现出从谁曾多次既往治疗，包括硼替佐米，来那度胺，地塞米松后复发的患者。ixazomib和来那度胺的组合表明多发性骨髓瘤细胞系的协同细胞毒性作用。在体内，ixazomib证实在小鼠多发性骨髓瘤异种移植模型的抗肿瘤活性。
适应症和用法
NINLARO是来那度胺和地塞米松的多发性骨髓瘤患者谁收到至少一个前治疗的治疗组合表示的蛋白酶体抑制剂。
用法用量
推荐起始剂量为4mg上，8天1内服，和一个28天周期的15。
剂量应食品之前或之后至少两小时采取至少一小时。
剂型和规格
胶囊：4毫克，3毫克和2.3毫克
禁忌症
没有。
警告和注意事项
血小板减少症：治疗期间监测血小板计数至少每月一次，并调整剂量，根据需要。
胃肠毒性：调整给药为严重的腹泻，便秘，恶心，呕吐，根据需要。
周围神经病变：监测患者周围神经病变症状和调整剂量，根据需要。
外周性水肿：监测液体潴留。探讨根本原因，在适当的时候。调整给药，根据需要。
皮肤反应：监测患者皮疹和调整剂量，根据需要。
肝毒性：治疗期间监测肝酶。
胚胎 - 胎儿毒性：NINLARO可致胎儿危害。指教的潜在风险到胎儿生殖潜力的女性和使用有效的避孕。
不良反应
最常见的不良反应（≥20％）是腹泻，便秘，血小板减少症，周围神经病变，恶心，外周水肿，呕吐和背部疼痛。
药物相互作用
强CYP3A诱导剂：避免与NINLARO同时使用。
特殊人群中使用
肝损伤：减少患者NINLARO起始剂量为3毫克的中度或重度肝功能损害。
肾损害：减少NINLARO起始剂量为3毫克的患者有严重肾功能不全或终末期肾病需要透析。
哺乳期：终止哺乳。

Ninlaro(ixazomib MLN9708)
Ninlaro (Ixazomib): First Oral Proteasome Inhibitor Approved for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma
Multiple myeloma is a cancer of plasma cells in the bone marrow that often leads to bone destruction and bone marrow failure. According to the American Cancer Society, more than 26,800 new cases of multiple myeloma were diagnosed in 2015, and 11,240 deaths were attributed to the disease.
Representing approximately 1% of all cancers, multiple myeloma is the second most common hematologic malignancy after non-Hodgkin lymphoma.
The incidence of multiple myeloma is higher among men than in women. Individuals aged ≥65 years, those with a family history of the disease, and those with a history of monoclonal gammopathy of undetermined significance are at increased risk for multiple myeloma. Several common complications of multiple myeloma include bone pain, kidney dysfunction, bone loss, impaired immunity, and anemia.
Although the overall incidence of multiple myeloma continues to increase, the mortality rates associated with this malignancy have declined during the past  years.
Specifically, the advent of novel therapy options for multiple myeloma, as well as improvements in high-dose therapy and supportive care have contributed to extended survival for patients with multiple myeloma.
New anticancer drugs and novel combinations have emerged in part because of improved understanding of the bone marrow microenvironment and the biology of multiple myeloma. Immune modulators and proteasome inhibitors now represent the cornerstones of initial treatment for multiple myeloma based on their ability to enhance the overall response rates and survival.
Because novel agents have had a considerable impact on the US healthcare, understanding their relative cost-effectiveness is important for ensuring efficient use. Overall,  recent evaluations of the economics of new agents in multiple myeloma resulted in similar conclusions.Using claims data from more than 2600 patients with multiple myeloma, one study showed that the 1-year cost of bortezomib-based therapy was similar to the cost of older drug combinationswhereas the costs of thalidomide- and lenalidomide-based regimens were significantly higher than older combinations. In addition, patients taking thalidomide and lenalidomide had higher out-of-pocket costs because of Medicare Part D coverage gaps.
The second study modeled the cost-effectiveness of novel agents combined with melphalan and prednisone in patients with newly diagnosed multiple myeloma who were ineligible for a transplant.
 The researchers concluded that adding bortezomib to melphalan and prednisone was more cost-effective than adding thalidomide or lenalidomide to the same drug combination.
Despite strides in the treatment of patients with multiple myeloma, patients will experience disease relapse after initial treatment, and multiple lines of therapy are typically required. Considerations for patients with relapsed or refractory multiple myeloma include the duration of response to previous treatment and the risk for toxicity. There remains a marked need for additional therapeutic options for this patient population.
Ixazomib Approved for Relapsed or Refractory Multiple Myeloma
On November 20, 2015, the US Food and Drug Administration (FDA) approved ixazomib (Ninlaro; Takeda Oncology) capsules in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who received at least previous therapy.Ixazomib is the first oral proteasome inhibitor approved by the FDA for this patient population.
The safety and efficacy of ixazomib were demonstrated in the TOURMALINE-MM1 study, an international, phase , double-blind clinical trial.More than 720 patients with relapsed and/or refractory multiple myeloma were randomized to ixazomib plus lenalidomide and dexamethasone or to placebo plus lenalidomide and dexamethasone.After the first prespecified interim analysis, treatment with ixazomib plus lenalidomide and dexamethasone significantly extended progression-free survival (PFS) compared with placebo plus lenalidomide and dexamethasone.
Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products, said, “As we learn more about the underlying biology of multiple myeloma, we are encouraged to see the development of new ways to treat this disease. Today’s approvalprovides patients with a new oral treatment that slows disease progression when other therapy has failed.”
Mechanism of Action
Ixazomib is a reversible proteasome inhibitor that preferentially binds to the beta  subunit of the S proteasome and inhibits its chymotrypsin-like activity.Based on in vitro studies, ixazomib induces apoptosis of multiple myeloma cell lines.
It was also cytotoxic against myeloma cells from patients whose disease relapsed after previous therapies, including bortezomib, lenalidomide, and dexamethasone.
Dosing and Administration
The recommended starting doses of each component of the 28-day regimen are ixazomib 4 mg once weekly on days  and ; lenalidomide 25 mg once daily on days through ; and dexamethasone 40 mg once weekly on days 1, 8, 15, and 22.
The recommended starting dose of ixazomib in patients with moderate or severe hepatic impairment, severe renal impairment, or end-stage renal disease requiring dialysis is 3 mg.
Ixazomib should be taken on the same day of the week and at approximately the same hour of the day. Ixazomib should be taken at least hour before or at least hours after eating. The capsule should be swallowed with water and should not be crushed, chewed, or opened.
If a dose of ixazomib is delayed or missed, the dose should be taken only if the next scheduled dose is ≥72 hours away. The patient should not take a double dose of ixazomib to account for the missed dose. Overall, capsule strengths are available for ixazomib—4mg, 3mg, and 2.3mg.
Clinical Trials
TOURMALINE-MM1
TOURMALINE-MM1, a multinational, randomized, double-blind study, compared ixazomib plus lenalidomide and dexamethasone versus placebo plus lenalidomide and dexamethasone in patients with multiple myeloma whose disease progressed during or after  to  previous therapies.Overall, 722 patients were randomized in a ratio to the active triple-drug regimen or to placebo plus lenalidomide and dexamethasone until disease progression or until unacceptable toxicity.
The treatment cycles were repeated every 28 days in both study arms. Randomization was stratified according to the number of previous lines of therapy (1 vs 2 or 3), myeloma International Staging System (stage I or II vs stage III), and previous therapy status with a proteasome inhibitor (exposed vs not exposed).
The primary efficacy end point in TOURMALINE-MM1 was PFS according to the 2011 International Myeloma Working Group Consensus Uniform Response Criteria.The response assessments were conducted every weeks until disease progression.
Demographic and baseline characteristics were similar between the treatment arms. The patients’ median age was 66 years.
The majority (87%) of patients who received ixazomib plus lenalidomide and dexamethasone had stage I or II disease and 62% had received  previous therapy for multiple myeloma. Overall, 59% of the patients receiving ixazomib plus lenalidomide and dexamethasone had undergone stem-cell transplantation for multiple myeloma.
The PFS was significantly improved in the active combination arm compared with the placebo arm (Table).The median PFS was 20.6 months among patients receiving the ixazomib-based combination compared with 14.7 months in the placebo arm, a significant (P = .012) difference (hazard ratio, 0.74; 95% confidence interval).

The median time to response was months with ixazomib compared with 1.9 months with placebo. In the response evaluable population, the median duration of response was 20.5 months versus 15 months, respectively.
After a median follow-up of 23 months, a planned interim analysis of overall survival (OS) was conducted with 35% of the required number of deaths for the final OS analysis; an OS benefit was not demonstrated.
Adverse Events
Among patients receiving the ixazomib combination regimen in TOURMALINE-MM1, the most common adverse reactions (all grades) reported at a rate of ≥20% compared with the placebo arm included thrombocytopenia (78% vs 54%), neutropenia (67% vs 66%), diarrhea (42% vs 36%), constipation (34% vs 25%), peripheral neuropathies (a pooled term; 28% vs 21%), nausea (26% vs 21%), peripheral edema (25% vs 18%), vomiting (22% vs 11%), and back pain (21% vs 16%).
Serious adverse reactions reported in ≥2% of patients receiving the active regimen included thrombocytopenia (2%) and diarrhea (2%).For each of these adverse reactions, ≥1 of the 3 drugs was discontinued in ≤1% of patients receiving ixazomib plus lenalidomide and dexamethasone.
Various eye disorders were reported in 26% of patients receiving the ixazomib combination regimen compared with 16% of patients in the placebo arm.The most common eye disorders that were more common with ixazomib than with placebo included blurred vision (6% vs 3%, respectively), dry eye (5% vs 1%, respectively), and conjunctivitis (6% vs 1%, respectively). Grade 3 eye disorders were reported in 2% of patients receiving the ixazomib combination and in 1% of patients receiving the placebo combination.
Ixazomib does not have any contraindications.
Drug Interactions
Ixazomib should not be used concomitantly with strong cytochrome P3A inducers (ie, rifampin, phenytoin, carbamazepine, and St. John’s wort).
Warnings and Precautions
Thrombocytopenia
Platelet nadirs associated with ixazomib therapy typically occurred between days  and 21 of each 28-day cycle and recovered to baseline levels by the beginning of the next cycle.The discontinuation of ≥1 of the 3 drugs in the regimen because of thrombocytopenia occurred in <1% of patients who received the ixazomib combination and in 2% of patients who received the placebo combination.
Platelet counts should be evaluated at least monthly during treatment with ixazomib.
Gastrointestinal toxicities
Diarrhea, constipation, nausea, and vomiting occasionally required the use of antidiarrheal and antiemetic medications.
Peripheral neuropathy
The majority of peripheral neuropathy reactions were grade 1 or 2.12 Grade 3 peripheral neuropathy was reported in 2% of patients receiving both regimens. Patients taking ixazomib should be monitored for symptoms of neuropathy.
Peripheral edema
The majority of peripheral edema reactions observed with ixazomib were grade 1 or 2.12 Ixazomib dosing should be adjusted if grade 3 or 4 peripheral edema occurs.
Cutaneous reactions
Grade 3 rash—typically maculopapular and macular—was reported in 3% of patients receiving ixazomib and in 1% of patients receiving placebo.Supportive care and dose modification should be considered if grade ≥2 rash occurs with ixazomib.
Hepatotoxicity
Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic, and hepatotoxicity have each been reported in <1% of patients taking ixazomib. Patients receiving ixazomib should be tested for hepatic enzymes regularly, and the ixazomib dose should be adjusted if grade 3 or 4 events are observed.
Specific Populations
Pregnancy
Ixazomib can cause fetal harm when administered during pregnancy. Women should avoid becoming pregnant while taking ixazomib.Females of reproductive potential should be advised to use effective contraception during treatment with ixazomib and for 90 days after the final dose.
Lactation
It is not known whether ixazomib or its metabolites are present in human milk. Women taking ixazomib should discontinue nursing.
Men and women of reproductive potential
Effective contraceptives should be used while taking ixazomib and for 90 days after treatment with ixazomib.
Pediatric use
The safety and effectiveness of ixazomib have not been established in children.
Geriatric use
Of the patients with multiple myeloma in clinical studies of ixazomib, 55% were aged ≥65 years and 17% were aged ≥75 years.No differences in safety were observed between the younger and older cohorts.
Hepatic impairment
In patients with moderate or severe hepatic impairment, blood levels of ixazomib increased by 20% compared with patients with normal liver function.The starting dose of ixazomib should be reduced in this patient population.
Renal impairment
In patients with severe renal impairment or end-stage renal disease requiring dialysis, blood levels of ixazomib increased by 39% compared with normal renal function.12 The starting dose of ixazomib should be reduced in this patient population. Because ixazomib is not dialyzable, it can be administered without regard to dialysis timing.12
Conclusion
Ixazomib is the first oral proteasome inhibitor to demonstrate clinical benefit and an acceptable safety profile in patients with relapsed or refractory multiple myeloma. The TOURMALINE-MM1 study demonstrated that adding ixazomib to lenalidomide and dexamethasone significantly enhanced PFS compared with placebo plus lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma. The combination of ixazomib plus lenalidomide and dexamethasone represents the first all-oral triple therapy for patients with relapsed or refractory multiple myeloma.
In addition to the TOURMALINE-MM1 clinical trial, 4 global phase 3 trials are ongoing for ixazomib, including TOURMALINE-AL1, ixazomib plus dexamethasone in patients with relapsed or refractory amyloid light-chain amyloidosis; TOURMALINE-MM2, ixazomib plus lenalidomide and dexamethasone versus placebo plus lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma; TOURMALINE-MM3, ixazomib versus placebo as maintenance therapy in patients with newly diagnosed multiple myeloma after induction therapy and autologous stem-cell transplantation; and TOURMALINE-MM4, ixazomib versus placebo as maintenance therapy in patients with newly diagnosed multiple myeloma who have not undergone autologous stem-cell transplantation.

临床试验结果
此次获批是基于一项国际、随机、双盲临床试验的结果。该试验共纳入722例多发性骨髓瘤复发患者。受试者分别接受Ninlaro+来那度胺+地塞米松和安慰剂+来那度胺+地塞米松治疗。与服用安慰剂的患者相比，服用了Ninlaro的患者的无疾病恶化期更长，分别为14.7个月和20.6个月。
武田Ninlaro（ixazomib）-为FDA批准第三个治疗多发性骨髓瘤创新药物
2015年11月23日，由日本制药巨头武田（Takeda）开发的一款口服抗癌药Ninlaro（ixazomib）近日喜获FDA批准，联合Revlimid（lenalidomide，来那度胺）及地塞米松（dexamethasone），用于既往已接受过至少一种治疗方案的多发性骨髓瘤（MM）患者。此前FDA已授予ixazomib优先审查资格和孤儿药地位。
Ninlaro是一种蛋白酶体抑制剂，能够阻断多发性骨髓瘤细胞的酶，进而阻碍其生长及生存的能力。Ninlaro是FDA批准的首个口服蛋白酶体抑制剂。Ninlaro的获批，是基于一项随机双盲临床研究，该研究涉及722例复发性多发性骨髓瘤患者，数据显示，与安慰剂+来那度胺+地塞米松联合治疗组相比，Ninlaro+来那度胺+地塞米松联合治疗组无进展生存期（PFS：20.6个月 vs 14.7个月）显著延长。
Ninlaro也标志着FDA在本年度批准的第三个多发性骨髓瘤创新药物：
——诺华Farydak：今年2月，FDA批准诺华抗癌药Farydak（panobinostat）联合Velcade（bortezomib，硼替佐米）和地塞米松（dexamethasone）用于既往接受至少2种治疗方案（包括Velcade和一种免疫调节（IMiD）药物）治疗失败的多发性骨髓瘤（MM）患者。Farydak（panobinostat）是一种新型、广谱组蛋白脱乙酰酶（HDAC）抑制剂，具有一种新的作用机制，通过阻断组蛋白脱乙酰酶（HDAC）发挥作用，该药能够对癌细胞施以严重的应激直至其死亡，而健康细胞则不受影响。Faryda是FDA批准治疗多发性骨髓瘤（MM）的首个组蛋白脱乙酰酶（HDAC）抑制剂，该药的表观遗传学活性，可能有助于恢复多发性骨髓瘤细胞的功能。
—强生Darzalex：11月初，FDA加速批准强生单抗药物Darzalex（daratumumab），用于接受过至少三线治疗的多发性骨髓瘤（MM）患者。
Darzalex是FDA批准治疗多发性骨髓瘤（MM）的首个单克隆抗体药物。daratumumab是一种人源化抗CD38单克隆抗体，具有广谱杀伤活性，靶向结合多发性骨髓瘤细胞表面高度表达的跨膜胞外酶CD38分子，可通过多种机制诱导肿瘤细胞的快速死亡。
关于多发性骨髓瘤：
多发性骨髓瘤（multiple myeloma，MM）是一种浆细胞癌，见于骨髓。多发性骨髓瘤中，一组浆细胞（或骨髓瘤细胞）转化为癌细胞并增生，使浆细胞的数目高于正常水平。由于浆细胞在体内广泛游走，有可能累及体内多数骨骼，可能导致压缩性骨折、骨溶解性病灶和相关疼痛。多发性骨髓瘤可导致若干严重健康问题，累及骨骼、免疫系统、肾脏和个体的红细胞计数，部分较常见症状包括骨骼疼痛和疲乏，疲乏是贫血的症状。多发性骨髓瘤属罕见癌症，每年新发病例在美国约为20，000人、全球约为114，000人。