Astellas Pharma EMEA

Use of Extended-Pulsed Regimen with DIFICLIR[TM] (fidaxomicin) is More Effective Than Standard vancomycin in Achieving Sustained Cure of Clostridium difficile Infection (CDI) and Preventing Recurrence[1]

Vienna (ots/PRNewswire) - CDI, a potentially fatal disease,[2] is three times as deadly as MRSA[3],[4] and is estimated to cost the EU EUR3 billion per annum[5]

New data presented today at the 27th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) 2017, demonstrate benefits of extended-pulsed fidaxomicin (EPFX), compared to standard vancomycin.[1] Data from the EXTEND study[1] show that EPFX provides a superior rate of sustained clinical cure at 30 days following treatment compared to standard vancomycin.[1] At 40 days, recurrence rates were also found to be almost 10 times lower in patients treated with EPFX compared with standard vancomycin.[1] EPFX is currently not an approved dosing regimen.[6]

"The results of the study show at 30 days after end of treatment (i.e. day 55 for extended fidaxomicin (EPFX) and day 40 for vancomycin), recurrence occurred in 4.0% and 16.8% of patients receiving EPFX and vancomycin, respectively", commented study author Professor Benoit Guery, Infectious Diseases Services, University Hospital of Lausanne. "The EXTEND study shows superiority of extended fidaxomicin over vancomycin[1] and importantly this result is obtained with the same number of tablets and therefore does not change the cost and clearly improves the cost-efficacy ratio." The extended-pulsed fidaxomicin regimen means that patients receive the same number of tablets as the standard licensed course of fidaxomicin (one tablet administered twice-daily for 10 days), but over a longer period of time.

A randomised, controlled, open-label study, the EXTEND trial is the first multicentre study of clinical outcomes for EPFX and was conducted in hospitals in 22 European countries.[1],[7] 356 patients aged 60 years or older with CDI were randomised (1:1) to receive fidaxomicin 200mg oral tablets, twice-daily on days 1 to 5, then once-daily on alternate days on days 6 to 25, or vancomycin 125mg oral capsules, four-times daily on days 1 to 10.[1] EPFX dosing was specifically designed to maintain efficacy in treating C. difficile bacteria, while maximising preservation of gut flora through alternate day dosing. This methodology allowed for an accurate assessment of the benefits of extended, rather than increased, use of fidaxomicin. The regimen was tested in an in vitro gut model at the University of Leeds prior to use in this study.[8]

At 30 days after end of treatment, sustained clinical cure was significantly higher for EPFX dosing compared with standard vancomycin (70.1% [95% confidence interval (CI) 63.3-76.8] versus 59.2% [CI 52.0-66.4], p=0.03).[1] CDI recurrence rates were significantly lower for EPFX than standard vancomycin: day 40, 1.7% versus 16.8%; day 55, 4.0% versus 17.9%; day 90, 6.2% versus 19.0%; all p<0.001.[1] Both treatment regimens presented similar safety profiles.[1]

Dr. Andreas Karas, Senior Medical Director, Astellas Pharma EMEA, commented, "Recurrence of disease is one of the largest ongoing unmet needs of CDI treatment and the EXTEND study was designed to specifically get this as low as possible by minimising the impact on the gut flora by using a pulsed dosing regimen. Getting recurrence to levels as low as shown in this trial is a positive outcome for patients but also for health systems that bear the economic burden".

Economic analyses of the EXTEND study data indicate that EPFX is a cost-effective treatment strategy compared with standard vancomycin.[9] This finding was driven by the reduction in hospitalisation costs, resulting from the reduced recurrence rates associated with EPFX.[9]

Fidaxomicin is indicated in adults for the treatment of CDI. The recommended dose is one 200mg tablet administered twice-daily for 10 days. Extended-pulsed regimen with fidaxomicin is not currently approved.[6]

About Clostridium difficile infection

Clostridium difficile infection (CDI) is a recurring and preventable bacterial infection of the colon that causes severe and potentially deadly diarrhoea.[2],[10],[11] C. difficile bacteria are naturally present in the gut of up to 3% of healthy adults, usually without any problems. This is because the colonising C. difficile bacteria are 'kept under control' by the 'good bacteria'.[11] An alteration in the balance of the gut microflora, often caused by broad-spectrum antibiotics, can reduce the number of 'good' bacteria, allowing C. difficile to multiply and cause inflammation, severe diarrhoea and potentially life-threatening complications.[10],[11] CDI is one of the top ten hospital-acquired infections (HAIs) in European hospitals[12] and is estimated to be three times as deadly as MRSA.[3],[4] People in hospital with CDI are up to three times more likely to die in hospital (or within a month of infection) than those without CDI.[13],[14] Recurrence has been identified by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) as the most important problem in the treatment of CDI,[15] and occurs in up to 25% of patients within 30 days of initial treatment with broad-spectrum antibiotics.[16],[17],[18]

About DIFICLIR[TM] (fidaxomicin)

DIFICLIR[TM] is a macrocyclic antibiotic indicated for the treatment of Clostridium difficile infection in adults;[6],[19] it is targeted to kill the C. difficile bacteria[20] while sparing the 'good' bacteria in the gut that are important to protect against recurrent disease.[21],[22],[23] The safety profile of DIFICLIR[TM] is based on data from 564 patients with CDI treated with fidaxomicin in Phase III studies.[24] The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines recommend DIFICLIR[TM] as a first line therapy option in CDI patients at risk of recurrence and in patients with severe and non-severe CDI.[25]

About the EXTEND study

A phase IIIb/IV trial, EXTEND is the first multicentre study of clinical outcomes for extended-pulsed fidaxomicin. EXTEND is a randomised, controlled, open-label study conducted in hospitals in 22 European countries. The primary objective of the study was to evaluate whether EPFX was superior to standard vancomycin therapy for sustained clinical cure of CDI 30 days after end of treatment.[1]

The study was initiated and sponsored by Astellas Pharma EMEA.

About Astellas Pharma EMEA

Astellas Pharma EMEA operates in 40 countries across Europe, the Middle East and Africa, and is the EMEA regional business of Tokyo-based Astellas Pharma Inc. Astellas is a pharmaceutical company dedicated to improving the health of people around the world through the provision of innovative and reliable pharmaceuticals. The organisation's focus is to deliver outstanding R&D and marketing to continue growing in the world pharmaceutical market. Astellas presence in Europe also includes an R&D site and three manufacturing plants. The company employs over 4,500 people across the EMEA region. In 2013 Astellas was awarded SCRIP Pharmaceutical Company of the Year in recognition of its commercial success and pipeline development.

References

1. Guery B, et al. Randomised, controlled, open-label study comparing the efficacy of extended-pulsed fidaxomicin (EPFX) with vancomycin therapy for sustained clinical cure of Clostridium difficile infection in an older population: the EXTEND study. Abstract presented at ECCMID 2017.

2. Ananthakrishnan AN. Clostridium difficile infection: epidemiology, risk factors and management. Nat Rev Gastroenterol Hepatol. 2011;8:17-26.

3. Bauer MP, et al. Clostridium difficile infection in Europe: a hospital-based survey. Lancet. 2011;377:63-73.

4. European Centre for Disease Prevention and Control/European Medicines Agency (ECDC/EMEA). Joint technical report The bacterial challenge: time to react. Stockholm: ECDC / EMEA; 2009. Available from: http://ecdc.europa.eu/en/publications/Publications/0909_TER_The_Bacterial_Challenge_Time_to_React.pdf (last accessed April 2017).

5. Kuijper EJ, et al. ESCMID study group for Clostridium difficile. Emergence of Clostridium difficile associated disease in North America and Europe. Clin Microbiol Infect. 2006;12:2-18.

6. DIFICLIR Summary of Product Characteristics (SmPC) for European Union, 2016.

7. Guery B, et al. Randomised, controlled, open-label study comparing the efficacy of extended-pulsed fidaxomicin (EPFX) with vancomycin therapy for sustained clinical cure of Clostridium difficile infection in an older population: the EXTEND study. NCT02254967 study information. Available from: https://clinicaltrials.gov/ct2/show/NCT02254967 (last accessed April 2017).

8. Chilton CH, et al. Successful treatment of simulated Clostridium difficile infection in a human gut model by fidaxomicin first line and after vancomycin or metronidazole failure. J Antimicrob Chemother. 2014;69(2):451-62.

9. Watt M, et al. Cost-effectiveness of extended-pulsed fidaxomicin (EPFX) versus standard vancomycin (SV) in older patients with Clostridium difficile infection in England. Abstract presented at ECCMID 2017.

10. McMaster-Baxter NL, Musher DM. Clostridium difficile: recent epidemiologic findings and advances in therapy. Pharmacotherapy. 2007;27:1029-39.1.

11. Sunenshine R, McDonald L. Clostridium difficile-associated disease: new challenges from an established pathogen. Cleve Clin J Med. 2006;73:187-97.

12. European Centre for Disease Prevention and Control (ECDC). Point prevalence survey of healthcare-associated infections and antimicrobial use in European acute care hospitals 2011-2012. Stockholm, 2013. Available from: http://ecdc.europa.eu/en/publications/Publications/healthcare-associated-infections-antimicrobial-use-PPS.pdf (last accessed April 2017).

13. Oake N, et al. The effect of hospital-acquired Clostridium difficile infection on in-hospital mortality. Arch Intern Med. 2010;170:1804-10.

14. Hensgens MP, et al. All-Cause and disease-specific mortality in hospitalized patients with Clostridium difficile infection: a Multicenter Cohort Study. Clin Infect Dis. 2013;56:1108-16.

15. Bauer MP, et al. European Society of Clinical Microbiology and Infectious Disease (ESCMID): treatment guidance document for Clostridium difficile-infection (CDI). Clin Microbiol Infect. 2009;15:1067-79.

16. Johnson S, et al. Vancomycin, Metronidazole, or Tolevamer for Clostridium difficile Infection: Results From Two Multinational, Randomized, Controlled Trials. Clin Infect Dis. 2014;59(3):345-54.

17. Lowy I, et al. Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med. 2010;362;3:197-205.

18. Louie TJ, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364:422-31.

19. Mullane KM, Gorbach S. Fidaxomicin: first-in-class macrocyclic antibiotic. Expert Rev. Anti Infect. Ther. 2011;9(7):767-777.

20. Babakhani F, et al. Killing kinetics of fidaxomicin and its major metabolite, OP 1118, against Clostridium difficile. J Med Microbiol. 2011;60:1213-7.

21. Finegold SM, et al. In vitro activities of OPT-80 and comparator drugs against intestinal bacteria. Antimicrobial agents and chemotherapy. 2004;48:4898-902.

22. Tannock GW, et al. A new macrocyclic antibiotic, fidaxomicin (OPT-80), causes less alteration to the bowel microbiota of Clostridium difficile-infected patients than does vancomycin. Microbiology. 2010;156:3354.

23. Louie TJ, et al. OPT-80 eliminates Clostridium difficile and is sparing of bacteroides species during treatment of C. difficile infection. AAC. 2009;53:261-263.

24. Weiss K, Allgren RL, Sellers S. Safety analysis of fidaxomicin in comparison with oral vancomycin for Clostridium difficile infections. Clin Infect Dis. 2012;55(S2):S110-15.

25. Debast SB, et al. European Society of Clinical Microbiology and Infectious Diseases (ESCMID): update of the treatment guidance document for Clostridium difficile infection (CDI). Clin Microbiol Infect. 2014:20(s2):1-26.

April 2017

AI/17/0001/CB

Contact:

Josie Fisher
Ruder Finn
jfisher@ruderfinn.co.uk
Tel: +44(0) 20-7438-3068

Astellas Pharma EMEA Press Office
Tel: +44(0)7919-302-926



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