日前，FDA的一个顾问委员会投票支持批准Basilea/安斯泰来的新型抗真菌药物Cresemba，分析师们预测这款药物会成为一款销售峰值逾5亿美元的产品。
该顾问小组推荐批准艾沙康唑(Isavuconazole；商品名Cresemba)静脉注射及口服剂型药物用于患有侵袭性曲霉菌病及侵袭性毛霉菌病的成年患者，这两种危及生命的真菌感染通常会在免疫功能不全的患者身上看到。
当前FDA批准的用于袭性曲霉菌病治疗的药物有两性霉素制剂、伊曲康唑、伏立康唑及默沙东的卡泊芬净。目前，仅两性霉素B被批准用于侵袭性毛霉菌病治疗。
临床试验发现，艾沙康唑在包括全因死亡率在内的安全性及有效性指标上与伏立康唑等同，伏立康唑是被推荐的用于侵袭性真菌感染的一线治疗药物。这款药物还显示对有肾脏问题的患者同样安全、有效，而伏立康唑用于这类人群时可能需要调整剂量。
艾沙康唑已经被FDA授予合格感染疾病产品(QIDP)资格，因为这款药物旨在治疗严重或危及生命的感染，而这种感染有可能对公共健康造成严重威胁。位于瑞士的Basilea与安斯泰来正在进行一项3期试验，以检测这款药物的第3种适应症-侵袭性念珠菌病，这项试验有望今年底产生结果。艾沙康唑用于这种类型的真菌感染也被FDA授予QIDP资格。
安斯泰来于2010年通过一项总值达5.5亿瑞士法郎的交易，从Basilea公司许可获得艾沙康唑的全球权利，该瑞士公司还有权获得两位数的销售提成。艾沙康唑还在欧洲被提交上市申请，其上市批准决定定于2015年底前做出。
人类抗真菌治疗的全球市场规模到2018年有望增长到大约139亿美元，出现一个3.2%的五年期年复合增长率(CAGR)，这主要由于抗生素及免疫抑制药物（包括癌症治疗药物）的使用增加而使得感染率上升，据市场研究公司BCC称。
New Drugs Online Report for isavuconazole
Information
Generic Name: isavuconazole
Trade Name: Cresemba
Entry Type: New molecular entity
Development and Regulatory status
UK: Pre-registration (Filed)
EU: Pre-registration (Filed)
US: Recommended for approval (Positive opinion)
UK launch Plans: Available only to registered users
Actual UK launch date:
Comments
Jan 15: US FDA Anti-Infective Drugs Advisory Committee vote 11-0 to recommend approval of once-daily IV & oral Cresemba (isavuconazole) for treatment of invasive aspergillosis. Astellas expects the FDA to make its final decision by March 8. Basilea holds full rights to Cresemba in markets outside the USA and Canada and it expects a European regulatory review to be completed by 4Q 2015 [19].
28/01/2015 09:06:54
Sept 14: US FDA has accepted for filing the New Drug Application (NDA) for isavuconazole for the treatment of invasive aspergillosis. In accordance with the FDA Prescription Drug User Fee Act (PDUFA), the FDA designated the date of March 8, 2015 for the completion of the review. [18]
08/09/2014 09:19:01
Jul 14: European Commission granted isavuconazole orphan drug designations for the treatment of invasive aspergillosis and mucormycosis (zygomycosis) [17].
21/07/2014 17:44:19
July 14: Marketing Authorization Application filed in EU for invasive aspergillosis. The MAA is supported by data from SECURE phase 3 study. [17]
18/07/2014 09:01:20
July 14: Filed in US for the treatment of invasive aspergillosis [16]
11/07/2014 08:25:09
May 14: Astellas reports that development only in the US is in accordance with the amended licence agreement [15].
16/06/2014 11:04:41
May 14: Development now only in the US (not EU) [15].
16/06/2014 11:03:26
Apr 14:Results from the SECURE and VITAL trials are expected to form the core of regulatory filings in the US and the EU in mid-2014 [13]
17/04/2014 13:25:09
Dec 13: The FDA has designated isavuconazole as a Qualified Infectious Disease Product (QIDP) for the treatment of invasive aspergillosis.Thisprovides priority review and a five-year extension of market exclusivity if approved in the US [11].
05/12/2013 09:03:26
Jul 13: The EMA has agreed to the Paediatric Investigation Plans (PIP) of isavuconazole for the treatment of invasive aspergillosis, mucormycosis and Candida infections in children [9].
18/07/2013 14:10:05
Jul 13: Data from the SECURE and VITAL studies are expected in 2H 2013 and could form the basis for filing in 1H 2014 [9].
18/07/2013 14:09:23
May 13: Granted orphan drug designationin the US for the treatment of invasive aspergillosis. [8]
30/05/2013 08:51:49
Mar 13: EU filing will be via the centralised procedure [7].
15/03/2013 16:45:45
Fast track in US [3].
24/02/2010 21:36:24
PIII study started Dec 06 [2].
31/01/2010 18:47:46
Trial or other data
May 14: Efficacy and safety data from the SECURE study presented at the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID). Treatment emergent adverse events for isavuconazole were statistically fewer relative to the study comparator voriconazole in the System Organ Classes of hepatobiliary (8.9% vs. 16.2%), skin (33.5% vs. 42.5%) and eye disorders (15.2% vs. 26.6%). In addition, isavuconazole (42.4%) showed statistically fewer study drug-related adverse events relative to voriconazole (59.8%). In both treatment groups, the most common treatment emergent adverse events for isavuconazole and voriconazole respectively were nausea (27.6% vs. 30.1%), vomiting (24.9% vs 28.2 %), pyrexia (fever) (22.2% vs 30.1%) and diarrhea (23.7% vs 23.2%) [14].
16/05/2014 11:03:35
Apr 14: In the PIII VITAL study (NCT00634049) in patients with aspergillosis and impaired renal function, investigator reported data showed that approximately 45 patients had zygomycosis (invasive mucormycosis, caused by mycormycetes) [see separate monograph], and 45 had pre-exisiting renal function impairment. As of September 2013, a review of diagnosis and outcomes is being conducted by an independent board [12].
17/04/2014 13:19:47
Sep 13: Astellas announces positive topline data from SECURE study, which achieved its primary objective in demonstrating non-inferiority versus voriconazole for the primary treatment of invasive fungal disease caused by Aspergillus species or certain other filamentous fungi. Isavuconazole was effective as determined by the primary endpoint of all-cause mortality through day 42 in the intent-to-treat population (n=516). The all-cause-mortality was 18.6% in the isavuconazole treatment group and 20.2% in the voriconazole group. The 95% confidence interval of the treatment difference between isavuconazole and voriconazole was within the pre-specified non-inferiority margin of 10%. Key secondary endpoint of overall success rate (composite of clinical, mycological, radiological responses) at the end-of-therapy in patients with proven/probable disease was similar between isavuconazole and voriconazole (35.0% and 36.4%, respectively). This outcome was based on a blinded assessment by the Independent Data Review Committee. Overall, drug- and non-drug-related adverse events were reported in 96.1% and 98.5% of patients in the isavuconazole and voriconazole treatment groups, respectively. The most frequent adverse events reported were nausea, vomiting, pyrexia (fever), diarrhea, and hypokalaemia (deficiency of potassium in the blood), which were reported at similar rates in both treatment groups. Study drug-related adverse events were reported in 42.4% and 59.8% of patients in the isavuconazole and voriconazole treatment groups, respectively [10].
02/10/2013 12:33:31
Jul 13: The PIII ACTIVE study´s primary efficacy endpoint of overall response is to be moved to the end of IV treatment period. The previous assessment at 2 weeks after IV and oral treatment will remain a secondary efficacy endpoint. The protocol change will facilitate the comparison with previous registration trials in invasive Candida infections. The study is expected to continue to recruit in 2014 [9].
18/07/2013 14:10:21
May 13: Topline data from two PIII studies are expected 2H 2013. The open-label VITAL study is investigating isavuconazole for the treatment of patients with invasive life-threatening fungal disease caused by emerging fungi and the treatment of aspergillosis patients with pre-existing renal impairment [8].
30/05/2013 08:58:38
Dec 12: Basilea and its partner Astellas Pharma report completion of recruitment in the PIII pivotal study, SECURE, which has enrolled 527 patients. SECURE is a global double-blind randomized study to eva luate the safety and efficacy of once-daily isavuconazole vs twice-daily voriconazole for up to 84 days of therapy in the primary treatment of invasive fungal disease caused by Aspergillus species or other filamentous fungi. The primary endpoint is non-inferiority in all-cause mortality through day 42. Results are due 2H 2013 [6].
17/12/2012 10:35:15
Sep 10: Initiation of study centres in the new PIII clinical programme is to be deferred to year-end or early 2011; this will allow the drug used in the trials to originate from the commercial-scale production line. Availability of PIII data continues to be anticipated by 2013 [5].
11/09/2010 18:59:05
Jun 10: Astellas has started a formal process to allow continuation of patient recruitment into the PIII studies. Study protocol amendments have been made to account for changes in clinical practice, the evolving regulatory environment and ongoing advancements in clinical diagnostics. There will be an increase in the number of patients recruited with probable and proven Aspergillus infections and more extensive use of the galactomannan diagnostic test. Treatment of first new patients is anticipated in Q3 2010 and patient recruitment completed in 2012. First trial results are expected in 2013. An Independent Data Safety Monitoring Board recently recommended continuation of the PIII clinical trial in invasive Aspergillus infections based on a futility analysis of the first 180 patients [4].
28/06/2010 17:21:14
Feb 10: Basilea has entered into a licence, co-development and co-promotion agreement with Astellas who will now take over PIII development of isavuconazole. Astellas is granted an exclusive right to commercialize isavuconazole but Basilea retains an option to co-promote the product in the US, Canada, Europe and China [3].
24/02/2010 21:35:08
NCT00634049: An open-label, uncontrolled PIII study of isavuconazole in the treatment of 100 patients with aspergillosis and renal impairment or of patients with invasive fungal disease caused by rare moulds, yeasts or dimorphic fungi. The study started in Apr 08. The drug administration schedule is 200mg isavuconazole three times a day iv or oral for 2 days, followed by daily administration of 200mg isavuconazole iv or oral [2].
31/01/2010 18:37:58
NCT00412893. A PIII study comparing the efficacy and safety of isavuconazole vs voriconazole in the primary treatment of 360 patients with invasive aspergillosis. The study started in Dec 06 and has a primary endpoint of non-inferiority in overall outcome (clinical, mycological and radiological response). In Jan 10, the Independent Data Safety Monitoring Board recommended continuation of the study based on a futility analysis of the primary efficacy endpoint in 180 patients. The company stated that the recruitment of new patients into the PIII clinical program is expected to resume in the first half of 2010 and topline data are anticipated to be available in 2011. [1,2]
31/01/2010 18:33:37
Isavuconazole shows high bioavailability and provides for a seamless IV-oral step-down option. The drug has predictable, linear pharmacokinetics with no relevant food effect, and the potential for fewer drug-drug interactions. It is highly water-soluble circumventing the need to add potentially kidney-damaging solubulizing agents to the IV formulation [1].
31/01/2010 18:25:50
References
Available only to registered users
Category
BNF Category: Antifungal drugs (05.02)
Pharmacology: Azole prodrug which binds & inhibits ergosterol synthesis by inhibiting CYP450-dependent 14-alpha sterol demethylase
Epidemiology: In 2011-12, there were 973 hospital admissions in England due to aspergillosis, accounting for 1,444 finished consultant episodes and 9,236 bed days (www.hesonline.nhs.uk).
Indication: Fungal infections
Additional Details: invasive aspergillosis
Method(s) of Administration
Intravenous
Oral
Company Information
Name: Basilea
US Name: Astellas
Further Information
Anticipated commissioning route (England) -
High cost drug list? Awaiting Update
Implications Available only to registered users |
