Astellas’ Dificlir (fidaxomicin) could save NHS thousands of pounds

Fidaxomicin

873857-62-6 

3-(((6-Deoxy-4-O-(3,5-dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-O-methyl-β-D-mannopyranosyl)oxy)-methyl)-12(R)-[(6-deoxy-5-C-methyl-4-O-(2-methyl-1-oxopropyl)-β-D-lyxo-hexopyranosyl)oxy]-11(S)-ethyl-8(S)-hydroxy-18(S)-(1(R)-hydroxyethyl)-9,13,15-trimethyloxacyclooctadeca-3,5,9,13,15-pentaene-2-one

C₅₂H₇₄Cl₂O₁₈   Molecular Weight: 1058.03916 

US FDA:link         Launched – 2011   Clostridium difficile-associated diarrhea

OPT-80  
PAR-101

Using Astellas’ Dificlir (fidaxomicin) as a first-line treatment for clostridium difficile infection (CDI) is not only clinically effective but could also save the National Health Service thousands of pounds compared to the standard of care, according to data from a late-stage study

Read more at: http://www.pharmatimes.com/Article/14-05-14/Astellas_Dificlir_could_save_NHS_thousands_of_pounds.aspx#ixzz31qrtFXlT

Fidaxomicin (trade names Dificid, Dificlir, and previously OPT-80 and PAR-101) is the first in a new class of narrow spectrummacrocyclic antibiotic drugs.^[2] It is a fermentation product obtained from the actinomycete Dactylosporangium aurantiacum subspecies hamdenesis.^[3][4] Fidaxomicin is non-systemic, meaning it is minimally absorbed into the bloodstream, it is bactericidal, and it has demonstrated selective eradication of pathogenic Clostridium difficile with minimal disruption to the multiple species ofbacteria that make up the normal, healthy intestinal flora. The maintenance of normal physiological conditions in the colon can reduce the probability of Clostridium difficile infection recurrence.^[5] [6]

It is marketed by Cubist Pharmaceuticals after acquisition of its the originating company Optimer Pharmaceuticals. The target use is for treatment of Clostridium difficile infection. Fidaxomicin is available in a 200 mg tablet that is administered every 12 hours for a recommended duration of 10 days. Total duration of therapy should be determined by the patient’s clinical status. It is currently one of the most expensive antibiotics approved for use. A 20 tab pack costs upwards of £1350.^[7]

Fidaxomicin works by inhibiting the bacterial enzyme RNA polymerase, resulting in the death of Clostridium difficile.^[8] It is active against Gram positive bacteria especially clostridia. The minimal inhibitory concentration (MIC) range for C. difficile (ATCC 700057) is 0.03–0.25 μg/mL.^[3]

Approvals and indications

For the treatment of CDAD (Clostridium difficile-Associated diarrhea), the drug won an FDA advisory panel’s unanimous approval on April 5, 2011.^[14] and full FDA approval on May 27, 2011.^[15]

Fidaxomicin is an antibiotic approved and launched in 2011 in the U.S. for the treatment of Clostridium difficile-associated diarrhea (CDAD) in adults 18 years of age and older. In September 2011, the product received a positive opinion in the E.U. and final approval was assigned in December 2011. First E.U. launch took place in the U.K. in June 2012. Optimer Pharmaceuticals is conducting phase III clinical trials for the prevention of Clostridium difficile-associated diarrhea in patients undergoing hematopoietic stem cell transplant. Preclinical studies are ongoing for potential use in the prevention of methicillin-resistant Staphylococcus (MRS) infection. Early clinical studies had been under way for the prevention and treatment of vancomycin-resistant enterococcal (VRE) infection; however, no recent development has been reported for this indication.

The compound is a novel macrocyclic antibiotic that is produced by fermentation. Its narrow-spectrum activity is highly selective for C. difficile, thus preserving gut microbial ecology, an important consideration for the treatment of CDAD.

In May 2005, Par Pharmaceutical and Optimer entered into a joint development and collaboration agreement for fidaxomicin. However, rights to the compound were returned to Optimer in 2007. The compound was granted fast track status by the FDA in 2003. In 2010, orphan drug designation was assigned to fidaxomicin in the U.S. by Optimer Pharmaceuticals for the treatment of pediatric Clostridium difficile infection (CDI). In 2011, the compound was licensed by Optimer Pharmaceuticals to Astellas Pharma in Europe and certain countries in the Middle East, Africa, the Commonwealth of Independent States (CIS) and Japan for the treatment of CDAD. In 2011, fidaxomicin was licensed to Cubist by Optimer Pharmaceuticals for comarketing in the U.S. for the treatment of CDAD. In July 2012, the product was licensed by Optimer Pharmaceuticals to Specialised Therapeutics Australia in AU and NZ for the treatment of Clostridium difficile-associated infection. OBI Pharma holds exclusive commercial rights in Taiwan, where the compound was approved for the treatment of CDAD in September 2012, and in December 2012, the product was licensed to AstraZeneca in South America with commercialization rights also for the treatment of CDAD. 

Clinical trials

Good results were reported in 2009 from a North American phase III trial comparing it with oral vancomycin for the treatment ofClostridium difficile infection (CDI)^[9][10] The study met its primary endpoint of clinical cure, showing that fidaxomicin was non-inferior to oral vancomycin (92.1% vs. 89.8%). In addition, the study met its secondary endpoint of recurrence: 13.3% of the subjects had a recurrence with fidaxomicin vs. 24.0% with oral vancomycin. The study also met its exploratory endpoint of global cure (77.7% for fidaxomicin vs. 67.1% for vancomycin).^[11] Clinical cure was defined as patients requiring no further CDI therapy two days after completion of study medication. Global cure was defined as patients who were cured at the end of therapy and did not have a recurrence in the next 4 weeks.^[12]

Fidaxomicin was shown to be as good as the current standard-of-care, vancomycin, for treating CDI in a Phase III trial published in February 2011.^[13] The authors also reported significantly fewer recurrences of infection, a frequent problem with C. difficile, and similar drug side effects.

References

http://www.pharmatimes.com/Article/14-05-14/Astellas_Dificlir_could_save_NHS_thousands_of_pounds.aspx