- New key preclinical results and a case study excerpted from our ongoing phase II clinical trial
- DNV3681 in vitro efficacy is superior to vancomycin and similar to the gold standard, fidaxomicin
- The prodrug DNV3837 is rapidly converted to DNV3681 in vivo and the active drug mostly concentrates in the GI tract
- The use of DNV3837 is a potential paradigm shift for CDI treatment
The new preclinical data presented show that DNV3681 is highly efficient against 333 clinical isolates of Clostridioides difficile, and its efficacy is superior to vancomycin and similar to the gold standard, fidaxomicin.
Preclinical and clinical data show that the prodrug DNV3837 is rapidly converted to DNV3681 in vivo and that the active drug mostly concentrates in the GI tract. This unusual pharmacokinetic profile could be explained by a strong efflux of the active drug by the intestinal efflux pumps from the blood to the GI lumen.
The patient case presented suffers from a severe Clostridioides difficile infection. His White Blood Cells count, an inflammatory marker, rapidly dropped after inclusion, remained in the upper limit during 8 days and was normal at the end of the treatment. The diarrhea episodes improved after 6 days of treatment and came back to normal 10 days after treatment after a transient constipation period. DNV3681 concentrations in feces were several order of magnitude higher than DNV3681 MIC901.
Georges Gaudriault, Chief Scientific Officer of
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ABOUT CLOSTRIDIOIDES DIFFICILE INFECTIONS (CDI)
More than 40% of hospitalized patients with Clostridioides difficile infection (CDI) have been classified as severe disease associated with higher morbidity and mortality2. The
To date, there is no proven therapeutic solution for CDI patients with severe vomiting, ileus and toxic megacolon. The oral route being compromised, the available treatments, which are mostly oral, have difficulty reaching the intestine because of the patient's pathological condition (reduced gastrointestinal motility, intubation, intestinal perforation, etc.), and the few antibiotics that could be administered intravenously do not cross the gastrointestinal barrier and therefore do not reach the infection site.
ABOUT THE DNV3837 ANTIBIOTIC CANDIDATE
DNV3837 – a prodrug6 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 first-line treatment targeting C. diff. It has demonstrated significant activity and superiority to reference treatments against isolates of C. diff., regardless of their virulence (including the hyper virulent BI/NAP1/027 strain).
DNV3837 is an intravenous antibiotic that, when converted to its active form DNV3681, crosses the gastrointestinal barrier and accumulates in the intestinal lumen, allowing it to precisely target the infection site. Several Phase I trials (on approximately a hundred 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 Clostridioides bacteria without affecting the gut microbiota.
FDA granted the DNV3837 drug with Qualified Infectious Disease Product (QIDP) designation and Fast Track status.
For more information on the DNV3837 Phase II clinical trial in Clostridioides difficile infections, visit ClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/NCT03988855
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1 MIC : Minimale Inhibitory Concentration. MIC90 is the lowest concentration inhibiting, in 18 to 24 hours, the multiplication of 90 % of clinical isolates.
3 MRSA: methicillin-resistant staphylococcus aureus
4 Guh AY, Mu Y, Winston LG et al. N Engl J Med 2020;382:1320–30
5 Balsells E, Shi T, Leese C, Lyell I, Burrows J, Wiuff C, Campbell H, Kyaw MH, and Nair H (2019) Global burden of Clostridium difficile infections: a systematic review and meta-analysis.
6 Prodrug: substance whose transformation in the body results in an active product
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- 20221005_DEINOVE_Poster_ESCMID-ASM_ENG_final
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