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抗生素新药Dificlir(fidaxomicin)在欧洲上市
2012年6月11日，安斯泰来（Astellas）欧洲子公司Astellas Pharma Europe在欧洲推出抗生素Dificlir（fidaxomicin）。
Dificlir，是一种口服、大环抗生素，用于治疗难辨梭状芽胞杆菌（Clostridium difficile infections，CDI），由Optimer制药公司开发。
安斯泰来拥有Dificlir在欧洲及其他一些位于中东、非洲及独联体的国家的开发及商业化权利。
在临床试验中，Dificlir达到了其与万古霉素非劣性的主要终点，同时也显着地减少了患者中CDI的复发。
New Drugs Online Report for fidaxomicin
Information
Generic Name: fidaxomicin
Trade Name: Dificlir (EU), Dificid (US)
Synonym: OPT 80; PAR 101
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: May 2012
Comments
May 12: Launched in the UK [27].
06/06/2012 14:37:08
Dec 11: Approved in EU for the treatment of adults with Clostridium difficile infections [24].
23/04/2012 16:48:54
Sep 11: EU positive opinion for treatment of C difficile infections in adults [22].
23/04/2012 16:48:42
Jul 11: Launched in US along with a Patient Assistance Programme to help eligible patients gain access to the drug [26].
23/04/2012 16:48:29
May 11: Approved in the US for treatment of Clostridium difficile-associated diarrhoea (CDAD). The approval was based on two studies which showed that fidaxomicin was associated with a similar rate of clinical response to vancomycin in pts with CDAD; in addition more pts treated with fidaxomicin had a sustained cure three weeks after the end of the treatment course [19].
01/06/2011 08:12:37
Apr 11: The FDA Anti-Infective Drugs Advisory Committee unanimously (13-0) recommended approval for the treatment of patients with Clostridium difficile infection (CDI) but was split on whether fidaxomicin prevents the recurrence of infections. The FDA will make a decision by May 30, 2011 [18].
06/04/2011 19:42:57
Jan 11: granted priority review in the US [16].
24/01/2011 21:29:41
Jan 11: Granted orphan drug status in US for paediatric C. difficile [15].
06/01/2011 09:21:02
Sep 10: Filed in the US for treatment of C Diff. The company has requested a priority review [13].
29/09/2010 18:32:45
Jul 10: Filed in EU via centralised procedure[11].
10/08/2010 17:49:09
Feb 10: US filing expected H2 2010 [9]
06/02/2010 16:45:14
Nov 09: the company expect to file in the US in 2010 [8].
15/11/2009 13:08:09
Fast track in US (5)
27/03/2009 20:50:02
Mar 09: Company to begin process of filing in EU in near future (4)
05/03/2009 12:12:55
US filing expected in 2009 (1).
13/01/2009 12:26:03
Trial or other data
Feb 12: Non-inferiority (NCT00468728) trial comparing the efficacy & safety of oral fidaxomicin with oral vancomycin in pts from the EU, Canada & the US published early online in Lancet Infectious Diseases. Eligible pts, aged 16 years or older with acute, toxin-positive C difficile infection were randomised to fidaxomicin (n=270; 200 mg every 12 h) or vancomycin (n=265; 125 mg every 6 h) for 10 days. Non-inferiority was prespecified with a margin of 10%. Modified intention-to-treat (mITT) and per-protocol populations were analysed. The primary endpoint was clinical cure, defined as resolution of diarrhoea (three or fewer unformed bowel movements per day for two consecutive days) and no further need for treatment. This was met in 198 (91.7%) of 216 pts in the per-protocol population given fidaxomicin vs. 213 (90.6%) of 235 given vancomycin, meeting the criterion for non-inferiority (one-sided 97.5% CI −4.3%). Non-inferiority was also demonstrated for the primary endpoint in the mITT population, with 221 (87.7%) of 252 pts given fidaxomicin & 223 (86.8%) of 257 given vancomycin cured (one-sided 97.5% CI −4.9%). Adverse effects were reported in be similar in both gps & consisted of GI symptoms (ie, nausea, vomiting, diarrhoea, & abdominal pain). A total of 20 (7.6%) of 264 pts given at least one dose of fidaxomicin & 17 (6.5%) of 260 given vancomycin died [25].
09/02/2012 13:04:00
Oct 11: A new retrospective analysis of data from two non-inferiority PIII studies presented at the Annual Meeting of the Infectious Diseases Society of America. Patients treated with fidaxomicin experienced a 37% reduction in persistent diarrhoea or death by day 12 of the study (95% CI: 2-60%; p=0.037 vs those on vancomycin; this was driven by 7 deaths among fidaxomicin -treated patients (1.2%) vs 17 (2.9%) in patients on vancomycin (p=0.06). The analysis demonstrated a 40% reduction in persistent diarrhoea, disease recurrence or death (all causes) vs vancomycin by day 40 of the study (95% CI: 26-51%; p<0.0001). Persistent diarrhoea or death in the first 12 days following start of treatment was most strongly predicted by previous anti-CDAD antibiotic use in the 24 hours prior to randomization (p=0.0001) and low baseline eosinophils (p=0.007) and/or albumin (p<0.0001). Patients with CDAD in the 3 months prior to entering the study had a 68% higher risk of recurrence or death during study days 13-40. Over 40 days, there was no evidence that the benefits of fidaxomicin over vancomycin varied according to disease severity, prior history of CDAD, previous anti-CDAD antibiotics, inpatient vs outpatient, patient age, baseline albumin or baseline creatinine levels [23].
25/10/2011 08:13:56
Aug 11: Results of a subgroup analysis of patients receiving concomitant systemic antibiotics in two PIII studies of fidaxomicin vs vancomycin for CDAD have been published in Clin Infect Dis. (2011) 53 (5): 440-447. 999 subjects with CDI were treated for 10 days with fidaxomicin or vancomycin, assessed for resolution of symptoms, and followed up for 4 weeks for evidence of recurrence. Concomitant antibiotics were prescribed for 275 patients (27.5% of total). In the absence of concomitant antibiotic use during the 10 days treatment phase, clinical cure rates for fidaxomicin and vancomycin were similar (92.3% vs. 92.8%; p= 0.80). However, when patients received one or more antibiotics concurrently, clinical cure rates were 90.0% vs. 79.4% (p = 0.04), respectively. The global cure rate was 80.8% and 69.1% (p < 0.001) when patients received no additional antibiotics at any time during the study period, and 72.7% vs 59.4% (p = 0.02) when they did. Recurrence rates were 16.9% vs 29.2% (p=0.048) when patients received other antibiotics [21].
17/08/2011 13:37:40
Jun 11: Optimer has priced Dificid at $2,800 for a 10-day course of treatment, almost twice the cost of branded vancomycin ($1,000 to $1,500 for a 10- to 14-day course of the lowest dose). Optimer claim that Dificid is cost-effective as it’s better at preventing recurrence [20].
15/06/2011 13:56:55
Feb 11: Optimer has signed an agreement with Astellas to develop and commercialize fidaxomicin in Europe and countries in the Middle East, Africa and the Commonwealth of Independent States [17].
07/02/2011 19:10:04
Feb 11: Results of an active comparative study reported in the N Engl J Med 2011 (364:422-31). The study enrolled 629 adult patients with acute symptoms of C. difficile infection and a positive result on a stool toxin test. Patients were randomised to fidaxomicin (200mg twice daily) or vancomycin (125mg four times daily) orally for 10 days. The primary endpoint was clinical cure (resolution of symptoms and no need for further therapy as of the second day after the end of the course of therapy). 548 (87.1%) patients were eva luated for the per-protocol analysis. Rates of clinical cure with fidaxomicin were noninferior to those with vancomycin in both the modified ITT analysis (88.2% vs 85.8%) and the PP analysis (92.1% vs 89.8%). Significantly fewer patients in the fidaxomicin group had a recurrence of infection: modified ITT analysis (15.4% vs. 25.3%, P=0.005), the PP analysis (13.3% vs. 24.0%, P=0.004). The lower rate of recurrence was seen in patients with non–North American Pulsed Field type 1 strains. The adverse-event profile was similar for the two therapies.
03/02/2011 09:21:25
Oct 10: Combined data from two PIII trials presented at the Annual Meeting of the Infectious Disease Society of America (IDSA). 1,164 adults with confirmed CDI were randomised to fidaxomicin or vancomycin for 10 dys. The primary endpoint was non-inferiority compared to vancomycin in clinical cure, defined as requiring no further CDI therapy 2 days after completion of study medication. If cured, patients were monitored for a subsequent 4-week period to eva luate recurrence, which was a secondary endpoint. Global cure, also a secondary endpoint, was defined as patients who were cured and did not have a recurrence during this subsequent 4-week period. Clinical cure rates were similar for both fidaxomicin and vancomycin (88% vs. 86%). Recurrence rates were 13% for the fidaxomicin arm vs. 24% for the vancomycin arm (p<0.001). Global cure rates were 75% for fidaxomicin vs. 63% for vancomycin (p<0.001). Fidaxomicin was well-tolerated in both studies [14].
01/11/2010 14:32:04
Sep 10: New data from the two PIII studies (n=1,164) presented at the 50th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy. A separate stratum was constructed of subjects who had experienced a prior CDI episode and recurred within three months of entering the study. These 178 pts were randomised to treatment of the recurrence with either fidaxomicin or vancomycin & 128 of these were subsequently eva luable for recurrence within the study (66 fidaxomicin & 62 vancomycin). Following treatment, 35.5% of the subjects who received vancomycin experienced another recurrence vs. 19.7% of those who received fidaxomicin (p=0.045) [12].
16/09/2010 11:01:42
Apr 10: Further results from the second PIII study were present at the ECCMID meeting. A subgroup analysis showed a clinically meaningful reduction in recurrence rates and higher global cure rates with fidaxomicin vs vancomycin in both BI/NAP1/027 and non-BI/NAP1/027 strains. Clinical cure rates were similar. Baseline demographic and disease characteristics of study participants were also presented. The BI/NAP1/027 strain was identified in 32% of subjects; 54% of participants were >65, 68% were in-patients, and 15% had a prior episode of CDI. An average of 7.5 bowel movements per day was observed among all subjects. The incidence of AEs was similar in the fidaxomicin and vancomycin arms [10].
13/04/2010 09:23:40
Feb 10: Company announced positive top-line results from the second PIII trial of fidaxomicin in C. difficile infection (Protocol 101.1.C.004). The study was conducted in approximately 100 clinical sites throughout North America and Europe. The trial met the primary endpoint of non-inferiority with 91.7% of patients treated with fidaxomicin (per protocol population) achieving clinical cure vs. 90.6% for vancomycin. Fidaxomicin also had significantly lower recurrence rates and higher global cure rates (defined as cure with no recurrence within four weeks of completing therapy) vs vancomycin; 12.8% and 25.3% of patients, respectively, experienced a recurrence (p = 0.002); 79.6% and 65.5% achieved a global cure (p < 0.001) [9].
06/02/2010 16:45:25
Nov 09: Enrollment of 536 adults in the second PIII is complete and top-line results expected Q1 2010. The double-blind study is comparing fidaxomicin (200mg twice daily) vs oral vancomycin (125mg four times a day) for 10 days in patients with CDI. The primary endpoint is cure; if cured, subjects will be followed for a four-week period to eva luate recurrence [8].
15/11/2009 13:07:40
May 09: Further results from the US PIII study presented. Clinical cure rates for fidaxomicin and vancomycin were similar in each of the following subgroups: patient status (in-patient/out-patient), age (under/over 65) and strain type (BI/NAP1/027) (7)
26/05/2009 11:49:18
Fidaxomicin is the first in a new class of antibiotics called macrocyclics, which inhibit the bacterial enzyme RNA polymerase, resulting in the death of C. difficile [6].
20/05/2009 09:22:46
Nov 08: In the US phase 3 study 629 patients with confirm CDI were randomly allocated to fidaxomicin 400 mg/day or vancomycin 500 mg/day for 10 days. The primary endpoint of clinical cure, defined as the patient requiring no further therapy for C. difficile infection two days after the completion of study medication, was similar (92.1% vs 89.8%, respectively). Fidaxomicin was associated with a significantly lower clinical + bacteriological relapse rate (13.3% vs 24.0%) (2,3).
13/01/2009 12:36:02
Two PIII trials, one in the US (which completed enrolment in July 2008) and the other in US and EU. Results of the first trial released in Nov 08, and the results of the second trial are expected in 2009 (1).
13/01/2009 12:25:30
Evidence Based eva luations
LNDG http://www.medicinesresources.nhs.uk/upload/documents/Evidence/Drug%20Specific%20Reviews/fidaxomcin.pdf
AWMSG http://www.wales.nhs.uk/sites3/Documents/371/Enc%202%20Appx%202%20fidaxomicin%20(Dificlir)%20ASAR%20M&W.pdf
NICE (MPC) http://www.nice.org.uk/mpc/evidencesummariesnewmedicines/ESNM1.jsp
SMC http://www.scottishmedicines.org/files/advice/fidaxomicin_Dificlir_FINAL_June_2012_for_website.pdf
EPAR http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002087/human_med_001511.jsp&mid=WC0b01ac058001d124&
murl=menus/medicines/medicines.jsp&jsenabled=true
NHSC http://www.nhsc-healthhorizons.org.uk/files/downloads/1337/1842.3b9a82fe6e2f0c798acdf774d344e696.pdf
References
Available only to registered users
Category
BNF Category: Antibacterial drugs (05.01)
Pharmacology: DNA-directed RNA polymerase inhibitor, narrow spectrum antibacterial agent
Epidemiology: C. difficile infection follows antibiotic therapy. In England in 2008-09, there were 36,095 reported cases (~70 per 100,000) but cases are declining. 80% occur in those >65 years old.
Indication: Clostridium difficile infection
Additional Details: treatment and prophylaxis
Method(s) of Administration
Oral
Company Information
Name: Astellas
US Name: Optimer
Further Information
Anticipated commissioning route (England) -
High cost drug list? Awaiting Update
Implications Available only to registered users |
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