The rates of clinical cure after treatment with fidaxomicin were noninferior to those after treatment with vancomycin. Fidaxomicin was associated with a significantly lower rate of recurrence of C. difficile infection associated with non–North American Pulsed Field type 1 strains. (Funded by Optimer Pharmaceuticals; ClinicalTrials.gov number, NCT00314951.)
Concomitant antibiotic (CA) use compromised initial response to Clostridium difficile infection therapy and durability of that response. Fidaxomicin was significantly more effective than vancomycin in achieving clinical cure in the presence of CAs and preventing recurrence regardless of CA use.
The development of anticancer vaccines requires the identification of unique epitope markers, preferably expressed exclusively on the surface of cancer cells. This Account describes the path of development of a carbohydrate-based vaccine for metastatic breast cancer, including the selection and synthesis of Globo-H as the target, the development of the vaccine conjugate and adjuvant design, the study of the immune response and consideration of class switch, and the analysis of Globo-H distribution on the surface of various cancer cells, cancer stem cells, and normal cells. The first synthesis of Globo-H was accomplished through the use of glycal chemistry; this approach delivered sufficient material for evaluation in phase I human trials. The development of a programmable one-pot synthesis method rendered the synthesis more practical and enabled the midstage proof-of-concept phase II trial and late-stage phase III trial. Finally, enzymatic synthesis of Globo-H coupled with cofactor regeneration was used for the late-stage multicenter trials and manufacture of the product. Along this path of development, it was discovered that the vaccine induced antibodies to target not only Globo-H, but also SSEA3 and SSEA4. Moreover, these three glycolipids were found to be uniquely expressed not only on the cell surface of breast cancer but on 15 additional cancer types, suggesting the broad application of this vaccine in cancer treatment and perhaps cancer prevention. In addition, a new glycolipid adjuvant was designed to target the CD1d receptor on dendritic cells and B cells for presentation to and activation of T cells to modulate the immune response and induce a class switch from IgM to IgG, thereby overcoming the common problem of carbohydrate-based vaccines that often induce mainly IgM antibodies. As demonstrated in this vaccine development, the chemical approach to the synthesis and conjugation of carbohydrate-based immunogens provides the flexibility for access to various structures and linkers to identify optimal compositions for development. The enzymatic method was then introduced to enable the practical synthesis of the vaccine candidate for clinical development and commercialization. Overall, this Account illustrates the path of development of a cancer vaccine, from selection of a unique glycan marker on breast cancer cells and the cancer stem cells as target to the use of chemistry in combination with immunology and cancer biology to enable the design and development of the Globo-H vaccine to target three specific glycan markers exclusively expressed on the cell surface of a number of different types of cancer.
Current therapies for Clostridium difficile infection (CDI) are encumbered by treatment failures and recurrences. Due to its high in vitro activity against C. difficile but low activity against the typical intestinal flora, minimal absorption, and durable cure in the hamster model of C. difficile infection, OPT-80 was considered for clinical development as a therapy for CDI. This trial consisted of two phases. Four single oral doses of OPT-80 (100, 200, 300, and 450 mg) were administered in a crossover manner to 16 healthy volunteers in a doubleblind, placebo-controlled phase 1A study; a 1-to 2-week washout interval separated the treatments. In the double-blind phase 1B study, 24 healthy subjects were randomized to receive OPT-80 (150, 300, or 450 mg) or placebo for 10 days. In both studies, OPT-80's safety and tolerability were evaluated and the concentrations of OPT-80 and its primary metabolite (OP-1118) in plasma and feces were determined. OPT-80 levels in the urine were also analyzed for the phase 1A study. In both the single-dose and the multiple-dose studies, OPT-80 was well tolerated by all subjects in all dose groups. Maximal plasma concentrations were near or below the limit of quantification (5 ng/ml) across the dose range; urine concentrations were below the detection limit. The fecal total recovery of OPT-80 plus its major metabolite, OP-1118, approximated 100%. The tolerability, high fecal concentration, and low systemic exposure data from these studies support the further clinical development of OPT-80 as an oral therapy for CDI.Clostridium difficile-associated diarrhea (CDAD) is a significant problem in hospitals and long-term care facilities and in the community. Clostridium difficile is the most common cause of nosocomial diarrhea in developed countries (7,12,17). The organism accounts for approximately 20% of cases of antibiotic-associated diarrhea and the majority of cases of antibioticassociated colitis (2, 6, 10, 18). The rising incidence of CDAD has been attributed to the frequent prescription of broadspectrum antibiotics to hospitalized patients (4).OPT-80 is a naturally occurring 18-member macrocycle derived from fermentation (8, 16). The antimicrobial activity of OPT-80 versus anaerobic species including C. difficile has been examined (1, 3, 5, 9). OPT-80 displays a narrow antimicrobial spectrum with excellent activity against many clostridia including C. difficile and moderate activity against certain gram-positive cocci. It is inactive against gram-negative organisms and Candida spp. In an experiment in which 110 genetically distinct strains of C. difficile were tested, the MIC at which 90% of isolates tested were inhibited (MIC 90 ) was 0.125 g/ml, translating to 4-and 16-fold-better potencies than those of metronidazole and vancomycin, respectively, against this species: MIC 90 values of metronidazole and vancomycin for this panel of organisms were 0.5 and 2.0 g/ml, respectively (7a). Furthermore, OPT-80 is bactericidal, with a minimum bactericidal concentration against C. difficile...
Measurable and progressive deterioration in CDI treatment outcomes occurred with advancing age in those aged 40 and older, highlighting the need for prevention and treatment strategies. Fidaxomicin treatment was associated with a 60% lower risk of recurrence than vancomycin after adjusting for age, concomitant antibiotics, and C. difficile strain.
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