Clostridium difficile-associated diarrhoea (“CDAD”) is established as a persistent and significant problem in the primary healthcare system. The clinical manifestations of fulminant CDAD signify a very severe condition with the possible development of pseudomembraneous colitis, toxic megacolon, bowel perforation, sepsis and death. However, the key clinical issue with CDAD is recurrent disease, with 30-50% of patients experiencing at least one recurrent period of CDAD following initial therapy. Each period of recurrent disease is associated with an increased risk of further recurrent periods, increased disease severity and increased mortality rates. Recurrent disease is frustratingly difficult to treat and results in a significant detrimental impact on patient welfare and disease progression and is associated with major economic and resource repercussions to the healthcare system.
The hyper-virulent C. difficile strain BI/NAP1/027 (which accounts for around 30% of EU cases and 50% of cases in North America) is associated with increased toxin production, compared with non-hypervirulent strains. These hypervirulent strains result in more severe forms of the disease, increased risk of life threatening complications, increased rates of recurrent disease and an increase in associated mortality rates. No drugs in current use or in development for CDAD have shown statistically significant reduction in recurrence rates of CDAD from these hypervirulent strains.
Clostridium difficile-associated diarrhoea (CDAD)
CDAD is a result of inflammation of the colon, and can range from asymptomatic colonisation to mild diarrhoeal illness, to more severe disease including pseudomembranous colitis, toxic megacolon, sepsis, and death.
Clostridium difficle has two forms; a vegetative form and spore form. The vegetative form releases toxins and causes disease, and is also the form susceptible to antibiotic treatment. The spore form is dormant and exists outside of the body or in the gut, under unfavourable conditions, and this form is resistant to antibiotics.
Clostridium difficile life cycle in CDAD
In the environment of normal gut microbiota, Clostridium difficile may be present in the form of dormant spores. Broad spectrum antibiotic treatment destroys microbiota, and Clostridium difficile is given the opportunity to start germination, forming vegetative cells, which overgrow, release toxins and cause CDAD. The bacteriostatic activity of the standard antibiotics currently in use, create an unfavourable environment that triggers sporulation of Clostridium difficile. Reconstituted microbiota suppress spore germination and prevent recurrence of CDAD, however delayed reconstitution of microbiota after cessation of therapy allows Clostridium difficile spores to germinate again and cause recurrence of CDAD. This means there is a window of opportunity for the eradication of Clostridium difficile, which is only when Clostridium difficile is still in the vegetative form, which is the first 10 hours from the start of therapy.
MGB-BP-3: A new paradigm in the Treatment of Clostridium difficile-associated diarrhoea (CDAD)
MGB-BP-3 has a very potent, fast bactericidal activity. It is the only drug with the potential to kill Clostridium difficile within the first 10 hours of contact. The new MGB-BP-3 treatment Paradigm should become 1st line treatment.
Differentiation of MGB-BP-3 in Clostridium difficile-Associated Diarrhoea
- Broad in vitro activity confirmed against Clostridium difficile
- Rapid killing effect seen for MGB-BP-3 against C. difficile strains, including hyper-virulent BI/NAP1/027; activity superior to vancomycin
- Superior activity to vancomycin confirmed in vivo
- MGB-BP-3 is superior to vancomycin in suppressing sporulation in all C. difficile strains tested
- MGB-BP-3 is active against vancomycin resistant enterococci (VRE)
Oral MGB-BP-3 completed a Phase I clinical trial in 2016, to assess safety and tolerability in healthy volunteers.This study was a single centre, double-blind, placebo-controlled, crossover study of single (SAD) and multiple (MAD) ascending doses of MGB-BP-3.
Currently, MGB Biopharma has initiated a Phase IIa clinical trial with MGB-BP-3, to assess the safety, tolerability, and efficacy in patients with Clostridium difficile-associated diarrhea (CDAD). This study is an exploratory, open-labelled study to assess incremental doses of MGB-BP-3.
Phase IIa Clinical Trials: Oral MGB-BP-3 is now entering a Phase IIa clinical proof of concept trial, conducted by Syneos Health. Ascending doses of oral MGB-BP-3 will be administered to patients with mild to moderate CDAD.
Our oral programme: MGB has successfully formulated, optimised and manufactured enterically coated, liquid-fill capsules of 250mg MGB-BP-3, and enterically coated tablets of 125mg MGB-BP-3, for use as an oral treatment of Clostridium difficile.