DNV3837

Antibiotic therapy for severe Clostridium difficile infections

Severe Clostridium difficile infections, a major health challenge

Severe Clostridium difficile infections (CDI) are gastrointestinal infections that are generally associated with a disturbance of the gut microbiota in compromised patients.

The incidence of CDI has doubled or quadrupled over the last 20 years in Europe and North America[1]. The US Centers for Disease Control and Prevention (CDC) recently identified CDIs as one of the leading causes of healthcare-associated infections before Staphylococcus aureus (MRSA[2]) infections.

In 2011, about half a million Americans were infected and more than 29 000 patients died within 30 days of diagnosis[3]. In 2021, experts predict 1.5 million cases of CDI for the United States and Europe combined.

The pathogen Clostridium difficile has been prioritized by WHO and the CDC.

To date, no effective antibiotic treatment is available for severe gastrointestinal infections because of the very consequences of the disease: oral treatments struggle to reach the intestine because of the pathological state of the patient (gastrointestinal tract motility, intubation, intestinal perforation, etc.), while intravenous (IV) antibiotics do not penetrate the gastrointestinal barrier and do not reach the site of infection.

DNV3837: An antibiotic in the clinical phase to fight severe Clostridium difficile infections

DEINOVE acquired in 2018 the German biotechnology company Morphochem and its compound DNV3837 (ex. MCB3837), which targets the treatment of severe CDI. This molecule, already administered in humans and whose safety and pharmacokinetic parameters have already been evaluated, is now ready to enter the clinical development phase II to be administered to patients to determine its effective dose.

✓ A first-in-class antibiotic effective against Clostridium difficile bacteria

DNV3837 – a prodrug of the DNV3681 molecule (also known as MCB3681) – is a narrow-spectrum, hybrid oxazolidinone-quinolone synthetic antibiotic targeting only Gram-positive bacteria. It is developed as a highly active 1st line treatment targeting Clostridium difficile.

It has demonstrated significant efficacy and superiority to reference treatments (fidaxomicin in particular) against isolates of C. difficile, regardless of their virulence (including the hyper virulent strain NAP1) or their resistance to other antibacterial drugs.

✓ Administered intravenously and able to cross the gastrointestinal barrier

In addition to its spectrum of activity, its interest lies mainly in the way the product is administered and distributed in the body, which makes it particularly interesting in the treatment of severe gastrointestinal infections.

DNV3837 is administered intravenously and is able to cross the gastrointestinal barrier, allowing it to precisely target the infection site. Several Phase I trials (on healthy volunteers) have shown a high concentration of the antibiotic in stools, a strong marker of its presence in the intestine. It has also demonstrated its ability to eliminate Clostridium difficile bacteria without destroying the gut microbiota, a definite advantage for patient prognosis. It has also shown an acceptable tolerance profile.

✓ Ready to enter Phase II

The next stage of development will be a Phase II clinical study involving a small number of patients. The United States Food and Drug Administration (FDA) has already agreed to the launch of this study. DEINOVE has chosen Medpace (NASDAQ: MEPD) to act as its CRO and to oversee the clinical trial scheduled to begin in 2019.

FDA granted the DNV3837 program the Qualified Infectious Disease Product[4] (QIDP) designation and Fast Track [5]status for accelerated product development.


Bibliography

Freeman, J et al. (2017) In Vitro activities of MCB3681 and Eight Comparators against Clostridium difficile Isolates with Known Ribotypes and Diverse Geographical Spread. Antimicrobial Agents and Chemotherapy 61:e02077-16. – Read online article

Voigt, B et al. (2016) Mode of Action of MCB3681 in Staphylococcus aureus – a Proteomic Study. Archives of Clinical Microbiology 7,6:31 – Read online article

Freeman, J et al. (2016) Comparative in-vitro activities of MCB3681 and 8 comparators against 200 Clostridium difficile isolates with known ribotypes and diverse geographical spread, ECCMID 2016. EV0267. – Read online article

Kapsner, T (2016) MCB3681 – the only intravenous treatment in clinical development for Clostridium difficile infections. ECCMID 2016. PIP08 – Read online article

Dalhoff, A et al. (2015) Analysis of effects of MCB3681, the antibacterially active substance of prodrug MCB3837, on human resident microflora as proof of principle. Clinical Microbiology and Infection 21:767.e1-767.e4. – Read online article

Kapsner, T (2015) MCB3681 – a novel narrow-spectrum Gram-positive antibacterial for intravenous treatment of Clostridium difficile. ECCMID 2015. PIP14 – Read online article

Rashid, M-U et al. (2014) Ecological impact of MCB3837 on the normal human microbiota. International Journal of Antimicrobial Agents 44:125–130. – Read online article

Rashid, M-U et al. (2014) In vitro activity of MCB3681 against Clostridium difficile strains. Anaerobe 28:216–219. – Read online article

Dalhoff, A et al. (2014) Mode of action of MCB3681 - analysis of MCB3681 proteome signature. ECCMID 2014. P1671 – Read online article 

Rashid, M-U et al. (2014) Ecological and pharmacodynamic effects of MCB3681 on skin, nasal, oropharyngeal and intestinal microbiota. ECCMID 2014. P1670. – Read online article

Rashid, M-U et al. (2014) In vitro activity of MCB3681 against Clostridium difficile strains. ECCMID 2014. P0802 – Read online article

Kresken, M. et al. (2006) In Vitro Activity of the Novel Antibacterial MCB3681 Against Selected Gram-Positive and -Negative Bacteria Compared to Established Antibiotics. 46th ICAAC. – See Poster F1-1967

Schubert S et al. (2006) Low Propensity for Development of Resistance to MCB3681, the Active Moiety of Oxaquin (MCB3837), in Gram-positive Bacteria with Vancomycin-, Linezolid-, Methicillin- and/or Ciprofloxacin Resistances. 46th ICAAC. – See Poster F1-1968

Gray C (2005) MCB3837, a novel antibiotic, is shown to be active in two mouse models - an important milestone in the process from test tube to patient. 45th ICAAC. – See Paper F513

Hubschwerlen C et al. (2003) Structure–activity relationship in the oxazolidinone–quinolone hybrid series: influence of the central spacer on the antibacterial activity and the mode of action. Bioorganic & Medicinal Chemistry Letters 13:4229–4233. – Read online article

Hubschwerlen C et al. (2003) Design, Synthesis and Biological Evaluation of Oxazolidinone–Quinolone Hybrids. Bioorganic & Medicinal Chemistry 11:2313–2319. – Read online article

 


[1] Aspects épidémiologiques et médico-économiques des infections à Clostridium difficile – A. Le Monnier, 14èmes journées nationales d’infectiologie 2013

[2] MRSA: meticillin-resistant Staphylococcus aureus

[3] Burden of Clostridium difficile Infection in the United States - Fernanda C. Lessa, The New England Journal of Medicine, 2015

[4] The QIDP designation is assigned to a drug that is a real innovation and gives the drug exclusive access to the market for an additional five-year period.

[5] The "Fast Track" status facilitates the development of the molecule through a faster and more flexible regulatory review of the application. This status is granted by the FDA to drugs under development that meet critical and unmet therapeutic needs.