ICLUSIG® (ponatinib)片为口服使用

美国初次批准：2012
 
适应证和用途
Iclusig是一种激酶抑制剂适用于为治疗对既往酪氨酸激酶抑制剂治疗耐药或不能耐受的有慢性相，加速相，或母细胞相慢性粒性白血病(CML)成年患者或对既往酪氨酸激酶抑制剂治疗耐药或不能耐受的Philadelphia染色体阳性急性淋巴母细胞白血病(Ph+ALL)(1)。这个适应证是根据反应率。没有用Iclusig的试验证明改善疾病相关症状或增加生存。

剂量和给药方法
● 45 mg有或无食物口服每天1次 (2)
● 对血液学和非-血液学毒性调整剂量或中断给药 (2.2，2.3)

剂型和规格
片：15 mg和45 mg (3)

禁忌证
无。

警告和注意事项
● 充血性心衰：监视患者充血性心衰的体征和症状和临床有指针时治疗 (5.3，6)。
● 高血压：监视高血压和临床有指针时治疗 (5.4，6)。
● 胰腺炎：每月监视血清酯酶； 中断或终止Iclusig (2.3，5.5，6)。
● 出血：对严重出血中断Iclusig (5.6，6).
● 液体潴留：监视患者for 液体潴留； 中断，reduce，or 终止Iclusig (5.7，6)。
● 心律失常：监视心律失常的症状 (5.8，6)。
● 骨髓抑制：血小板减少，中性粒细胞减少，和贫血可能需要中断或减低剂量。每两周监视全细胞计数共3个月和然后每月和当临床上指示。对ANC < 1000/mm3或血小板减少 < 50,000/ mm3中断Iclusig (2.2，5.9，6)。
● 肿瘤溶解综合征：开始用Iclusig治疗前确保水化和纠正高尿酸水平 (5.10).
● 伤口愈合受到损害和胃肠道穿孔：在接受大型手术患者中短暂中断治疗(5.11)。
● 胚胎-胎儿毒性：可能致胎儿危害。劝告妇女对胎儿的潜在风险(5.12，8.1)。

不良反应
最常见非-血液学不良反应(≥ 20%)是高血压，皮疹，腹痛，疲乏，头痛，干皮肤，便秘，关节痛，恶心，和发热。血液学不良反应包括血小板减少，贫血，中性粒细胞减少，淋巴细胞减少，和白细胞减少(6)。
为报告怀疑不良反应，联系ARIAD Pharmaceuticals，Inc. 电话(1-855-55-ARIAD)或FDA电话1-800-FDA-1088或www.fda.gov/medwatch

药物相互作用
强CYP3A抑制剂：如果共同给药不能避免减低 Iclusig剂量 (7.1)

特殊人群中使用
未曾在小于18岁患者中试验Iclusig的安全性和疗效。(8.4).

一般描述
Iclusig (ponatinib)是一种激酶抑制剂。盐酸ponatinib化学名is 3-(imidazo[1,2-b]pyridazin-3ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide hydrochloride. 分子式是C29H28ClF3N6O相当于分子量569.02 g/mol。其结构如下：

作用机制
Ponatinib是一种激酶抑制剂。Ponatinib在体外抑制ABL和T315I突变体ABL酪氨酸激酶的活性有IC50浓度分别为0.4和2.0 nM。Ponatinib抑制另外的激酶在体外的活性有IC50浓度0.1和20 nM间，包括VEGFR，PDGFR，FGFR，EPH受体和激酶的SRC家族，和KIT，RET，TIE2，和FLT3的成员。Ponatinib在体外抑制表达天然或突变体BCR-ABL，包括T315I细胞的生存能力。在小鼠中，用ponatinib治疗当与对照比较时减低表达天然或T315I突变体BCR-ABL肿瘤的大小。

临床研究
在一项单组，开放，国际，多中心试验在有CML和Ph+ALL其疾病被认为对既往酪氨酸激酶抑制剂(TKI)治疗耐药或不能耐受患者中评价Iclusig的安全性和疗效。所有患者被给予起始剂量45 mg的Iclusig每天1次。根据疾病相(慢性相CML[CP-CML]；CML加速相[AP-CML]；或母细胞相CML[BP-CML]/Ph+ALL)，对既往TKI治疗耐药或不能耐受(R/I)，和存在T315I 突变，患者被赋予6个队列之一。
而对既往TKI治疗CP-CML耐药性，被定义为未能实现或完全血液学反应(至3个月)，次要细胞遗传学反应 (至6个月)，或重大细胞遗传学反应(至12个月)。有CP-CML患者经受丧失反应或发生激酶结构区突变在缺乏完全细胞遗传学反应或进展至AP-CML或BP-CML在既往TKI治疗任何时间也考虑耐药。在AP-CML，BP-CML，和Ph+ALL耐药被定义为未能实现或重大血液学反应(在AP-CML至3个月，和BP-CML和Ph+ALL 至1个月)，丧失重大血液学反应(在任何时间)，或发生激酶结构区突变在缺乏完全重大血液学反应而既往用TKI治疗。
不能耐受被定义为既往TKI治疗由于毒性终止尽管CP-CML患者缺乏完全细胞遗传学反应优化处理或对有APCML，BP-CML，或Ph+ALL患者重大血液学反应。
在CP-CML主要疗效终点是重大细胞遗传学反应(MCyR)，其中包括完全和部分细胞遗传学反应(CCyR和PCyR)。在AP-CML，BP-CML，和Ph+ALL中主要疗效终点是重大血液学反应(MaHR)，被定义为或完全血液学反应(CHR)或无白血病(NEL)的证据。
试验纳入449例患者，其中444例对疗效分析为合格：267例患者有CP-CML(R/I队列：n=203，T315I：n=64)，83例患者有AP-CML，62例患者有BP-CML，和32例患者有Ph+ALL，5例患者对疗效分析不合格是由于缺乏T315I突变状态的确认，和这些患者未接受既往达沙替尼[dasatinib]或尼洛替尼。
在分析时，中位随访时间为10个月(对所有正在进行患者随访最短6个月)。

在表中描述基线人口统计指标特点。
在分析时，有CP-CML患者中Iclusig治疗的中位时间为281天，有AP-CML患者为286天，有BP-CML患者中为89天，和有Ph+ALL患者为81天。表9，和表10中总结疗效结果。
有CP-CML患者中实现MCyR，至MCyR中位时间为84天(范围：49至334天)。在分析时，尚未达到MCyR的中位时间。
 有AP-CML，BP-CML，和Ph+ALL患者中至MaHR中位时间分别为21天(范围：12至176天)，29天(范围12至113天)，和20天(范围：11至168天)。对AP-CML，BP-CML，和Ph+ALL 患者MaHR的中位时间分别为9.5个月(范围：1.1至17.7个月)，4.7个月(范围：1.8至14.1+个月)，和3.2个月(范围：1.8至8.8+个月)。

CORRECTING and REPLACING and ADDING MULTIMEDIA ARIAD Announces Accelerated Approval by FDA of Iclusig (Ponatinib) for Patients with CML and Ph+ ALL

Resistant or Intolerant to Prior Tyrosine Kinase Inhibitor Therapy
Please replace the release with the following corrected version due to revisions in the Important Safety Information section and the addition of an embedded link to the “Prescribing Information.” Also, a PDF document has been included as an additional multimedia asset.
The Iclusig™ bottle (Photo: Business Wire)
The corrected release reads:
ARIAD ANNOUNCES ACCELERATED APPROVAL BY FDA OF ICLUSIG (PONATINIB) FOR PATIENTS WITH CML AND PH+ ALL RESISTANT OR INTOLERANT TO PRIOR TYROSINE KINASE INHIBITOR THERAPY
~Approved for All Phases of CML
~Product Expected to be Available to Patients Within Approximately Two Weeks
~Conference Call Scheduled Today at 1:30 p.m. ET
ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) today announced that following a priority review, the U.S. Food and Drug Administration (FDA) has granted accelerated approval of Iclusig™ (ponatinib) for the treatment of adult patients with chronic, accelerated or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant or intolerant to prior TKI therapy.
“Today’s FDA approval of Iclusig is an important advance in the treatment of patients with CML and Ph+ ALL who are resistant or intolerant to prior TKI therapy,” stated Harvey J. Berger, M.D., chairman and chief executive officer of ARIAD. “Within less than five years, we were able to bring Iclusig from the start of clinical development to U.S. approval, achieving a major milestone in ARIAD’s history. We have now transformed ARIAD into a commercial oncology company addressing major unmet medical needs for cancer patients.”
Approximately 5,000 new cases of CML are diagnosed each year in the U.S. CML patients treated with TKIs can develop resistance or intolerance over time to these therapies. Iclusig is a targeted cancer medicine discovered and developed at ARIAD. It was designed by ARIAD scientists using ARIAD’s platform of computational chemistry and structure-based drug design to inhibit BCR-ABL, including drug-resistant mutants that arise during treatment. Iclusig is the only TKI that demonstrates activity against the T315I gatekeeper mutation of BCR-ABL, the most common mutation occurring in approximately ten percent of patients with drug resistance.
“The availability of Iclusig will improve the outcome of many patients with CML and Philadelphia-positive ALL who are resistant or intolerant to prior TKI therapy. It is an effective therapy that meets an unmet medical need and has to date overcome all known resistant mutations in preclinical studies,” said Jorge Cortes, M.D., professor and deputy chair, Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX. “Clinical responses to Iclusig have been observed in patients regardless of their mutation status or stage of disease. It is a valuable new treatment option for leukemia patients.”
“For patients with CML and Philadelphia-positive ALL who become resistant or intolerant to TKI treatments, the approval of Iclusig is very positive news,” said Rosalie Canosa, program division director at CancerCare. “The addition of Iclusig to the arsenal of anti-leukemia medicines is a significant development and one that offers hope for patients coping with CML and Philadelphia-positive ALL.”
The FDA approval of Iclusig was based on results from the pivotal Phase 2 PACE (Ponatinib Ph+ ALL and CML Evaluation) trial in patients with CML or Ph+ ALL who were resistant or intolerant to prior TKI therapy, or who had the T315I mutation of BCR-ABL. Iclusig had robust anti-leukemic activity, with 54 percent of chronic-phase CML patients, including 70 percent of patients with the T315I mutation, achieving a major cytogenetic response (MCyR) – the primary endpoint of the PACE trial for chronic-phase patients.
In patients with advanced disease, 52 percent of accelerated-phase CML patients, 31 percent of blast-phase CML patients and 41 percent of Ph+ ALL patients achieved a major hematologic response (MaHR) to Iclusig. MaHR was the primary endpoint in the trial for patients with advanced disease.
ARIAD PASS™ Patient Access and Support Services
Iclusig will be available to patients in the United States within approximately two weeks through a number of select specialty pharmacies. The Company has established the ARIAD PASS™ (Patient Access and Support Services) program, a comprehensive support system designed to help patients access, afford and adhere to treatment with Iclusig, including patients without insurance or who are underinsured. ARIAD PASS offers coverage support, including benefits verification and financial assistance through dedicated benefits coordinators. The program also includes ARIAD PASS Nurses who provide treatment support for patients taking Iclusig.
Healthcare professionals or patients can access information about ARIAD PASS by calling 1-855-447-PASS (855-447-7277) or visiting www.ARIADPASS.com.
Today’s Conference Call
ARIAD will hold a conference call and webcast today, December 14, at 1:30 p.m. ET to discuss the FDA approval of Iclusig, its availability, reimbursement and patient assistance program. The live webcast can be accessed by visiting the investor relations section of the Company’s website at http://investor.ariad.com. The call can be accessed by dialing 866-831-5605(domestic) or 617-213-8851 (international) five minutes prior to the start time and providing the pass code 51636171. A replay of the call will be available on the ARIAD website approximately two hours after completion of the call and will be archived for three weeks.
About Iclusig (ponatinib)
Iclusig is a kinase inhibitor. The primary target for Iclusig is BCR-ABL, an abnormal tyrosine kinase that is expressed in chronic myeloid leukemia (CML) and Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Iclusig was designed using ARIAD’s computational and structure-based drug design platform specifically to inhibit the activity of BCR-ABL. Iclusig targets not only native BCR-ABL but also its isoforms that carry mutations that confer resistance to treatment, including the T315I mutation, which is the most common mutation among resistant patients. Iclusig is the only TKI that is effective in CML and Ph+ ALL patients with this mutation.
Please see important safety information below, and the full prescribing information for Iclusig at www.ariad.com or www.iclusig.com.
Indication, Usage and Dosing
Iclusig is indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant or intolerant to prior TKI therapy.
This indication is based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig.

The recommended dose of Iclusig is a 45 mg tablet taken once-daily with or without food.
Important Safety Information
Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in Iclusig-treated patients. Serious arterial thrombosis occurred in 8% of Iclusig-treated patients. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events.
Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Iclusig for hepatotoxicity.
Warnings and Precautions
Twenty patients treated with Iclusig (4%) experienced serious congestive heart failure (CHF) or left ventricular dysfunction, with 4 fatalities. Monitor patients for signs or symptoms consistent with CHF and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious CHF.
Eight patients treated with Iclusig (2%) experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including hypertensive crisis. Treatment-emergent hypertension occurred in 67% of patients. Monitor and manage blood pressure elevations.
Clinical pancreatitis occurred in 6% of patients (5% Grade 3) treated with Iclusig. The incidence of treatment emergent lipase elevation was 41%. Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and evaluate patients for pancreatitis.
Serious bleeding events occurred in 5% of patients treated with Iclusig, including fatalities. The incidence was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Most events occurred in patients with grade 4 thrombocytopenia. Interrupt Iclusig for serious or severe hemorrhage.
Serious fluid retention events occurred in 3% of patients treated with Iclusig. One instance of brain edema was fatal. Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated.
Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 3 (1%) Iclusig-treated patients. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain).
Supraventricular tachyarrhythmias occurred in 5% of Iclusig-treated patients. Atrial fibrillation was the most common supraventricular tachyarrhythmia. Advise patients to report signs and symptoms of rapid heart rate (palpitations, dizziness).
Severe (Grade 3 or 4) myelosuppression occurred in 48% of patients treated with Iclusig. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended.
Two patients (<1%) treated with Iclusig developed serious tumor lysis syndrome. Hyperuricemia occurred in 7% of patients. Ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig.
Since Iclusig may compromise wound healing, interrupt Iclusig for at least 1 week prior to major surgery. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy.
Iclusig can cause fetal harm. Advise women to avoid pregnancy while taking Iclusig.
Adverse Reactions
The most common non-hematologic adverse reactions (≥20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia. Please see the full Prescribing Information for Iclusig, including the Boxed Warning.
About CML and Ph+ ALL
CML is characterized by an excessive and unregulated production of white blood cells by the bone marrow due to a genetic abnormality that produces the BCR-ABL protein. After a chronic phase of production of too many white blood cells, CML typically evolves to the more aggressive phases referred to as accelerated phase and blast crisis. Ph+ ALL is a subtype of acute lymphoblastic leukemia that carries the Ph+ chromosome that produces BCR-ABL. It has a more aggressive course than CML and is often treated with a combination of chemotherapy and tyrosine kinase inhibitors. The BCR-ABL protein is expressed in both of these diseases.
About ARIAD
ARIAD Pharmaceuticals, Inc. is a global oncology company focused on the discovery, development and commercialization of medicines to transform the lives of cancer patients. ARIAD’s first medicine, Iclusig™, is approved in the U.S. for the treatment of adult patients with chronic, accelerated or blast phase chronic myeloid leukemia that is resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy or Philadelphia chromosome-positive acute lymphoblastic leukemia that is resistant or intolerant to prior TKI therapy. Additional clinical trials of Iclusig in other cancers are ongoing. ARIAD is also studying AP26113, another molecularly targeted medicine, in certain forms of lung cancer. For additional information, visit http://www.ariad.com or follow ARIAD on Twitter (@ARIADPharm).
This press release contains “forward-looking statements” including, but not limited to, potential regulatory approvals, new indications or labeling for, or potential future sales of Iclusig. Forward-looking statements are based on management's expectations and are subject to certain factors, risks and uncertainties that may cause actual results, outcome of events, timing and performance to differ materially from those expressed or implied by such statements. These risks and uncertainties include, but are not limited to, preclinical data and early-stage clinical data that may not be replicated in later-stage clinical studies, the costs associated with our research, development, manufacturing and other activities, the conduct, timing and results of pre-clinical and clinical studies of our product candidates, the adequacy of our capital resources and the availability of additional funding, and other factors detailed in the Company's public filings with the U.S. Securities and Exchange Commission. The information contained in this press release is believed to be current as of the date of original issue. The Company does not intend to update any of the forward-looking statements after the date of this document to conform these statements to actual results or to changes in the Company's expectations, except as required by law.