2015年10月16日，欧盟委员会批准Basilea抗真菌药物CRESEMBA（艾沙康唑）硬胶囊和注射剂用于治疗侵袭性曲霉病和肺毛霉病，这也是继头孢托罗酯后欧盟批准Basilea公司的第二个药物。
New Drugs Online Report for isavuconazole
Information
Generic Name: isavuconazole  
Trade Name: Cresemba 
Entry Type: New molecular entity  
Development and Regulatory status
UK: Launched 
EU: Launched 
US: Launched 
UK launch Plans: Available only to registered users
Actual UK launch date: December 2015 
Comments
Dec 15: Launched in UK for treating invasive aspergillosis and mucormycosis [26]
15/12/2015 09:43:46 
Oct 15: Approved in EU for treating invasive aspergillosis and mucormycosis [24].
02/11/2015 10:43:42 
Aug 15: Astellas Launches CRESEMBA® (isavuconazonium sulfate) in the US for treatment of Invasive Aspergillosis and Invasive Mucormycosis [23].
11/08/2015 15:04:28 
Jul 15: EU positive opinion for Cresemba for use in adults for treatment of invasive aspergillosis, & mucormycosis in patients for whom amphotericin B is inappropriate [22].
24/07/2015 12:41:28 
Mar 15: Approved in the US [20].
09/03/2015 13:07:23 
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
Dec 15: Results of PIII SECURE trial (n=527), published in the Lancet online, found all-cause mortality from first dose to day 42 was 19% for isavuconazole (IC) and 20% voriconazole; difference −1.0%; 95% CI −7.8 to 5.7. Because upper bound of 95% CI did not exceed 10%, non-inferiority was shown. There were fewer adverse events with IC [25].
11/12/2015 09:29:12
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 evaluate 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
Evidence Based Evaluations
EPAR  http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002734/WC500196130.pdf 
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) NHSE 
High cost drug list? Yes
Tariff Not routinely commissioned by NHSE - IFR approval [21]
Implications Available only to registered users