A new 2-in-1 antibiotic against high priority superbugs
DNV3837 is a novel 2-in-1 small molecule that combines a quinolonyl group with an oxazolidinone moiety and is converted, in vivo, into DNV3681, a powerful dual-action gram-positive antibiotic. Having demonstrated its safety in humans, DNV3837 is currently being evaluated for the treatment of life-threatening Clostridioides difficile severe gastrointestinal infections in a phase II clinical trial. To date, DEINOVE is the only French biotech with a small molecule in clinical development, fully owned by the company, in the field of antibiotics.
In parallel, and in collaboration with the United States Army Medical Research Institute of Infectious Diseases (USAMRIID), the compound is under preclinical development against two of the most dangerous potential biological weapons, Bacillus anthracis and Francisella tularensis, that respectively cause anthrax and tularemia.
Addressing high priority pathogen
Clostridioides difficile infections (CDIs) are caused by pathogenic gram-positive bacteria that affect the gastrointestinal tract leading to symptoms that range from mild diarrhea to fulminant colitis and death. Although not exclusively, CDIs are often associated with previous use of broad-spectrum antibiotics that disrupt the gut microbiota, leaving patients susceptible to infection by opportunistic pathogens.
In the United States, CDIs are the most frequent healthcare-associated infections (beyond MRSA infections ), with an estimated 223,900 cases among hospitalized patients and 12,800 deaths in the year 2017, according to the US Center for Disease Control and Prevention (CDC) . The burden of CDIs is equally concerning in Europe, where healthcare-associated infections rise up to an estimated 152,905 cases and 8,382 deaths every year .
To date, no antibiotic can effectively treat severe Clostridioides difficile gastrointestinal infections due to the nature of the disease: oral treatments struggle to reach the intestine because of frequent bowel movements, colitis or intestinal paralysis, and intravenous (IV) antibiotics fail to efficiently penetrate the gastrointestinal barrier to reach the site of infection. As a result of this urgent medical need, the CDC and the World Health Organization (WHO) have both declared Clostridioides difficile a priority pathogen that poses great threat to human health.
Anticipating bioterrorist attacks
Bacillus anthracis and Francisella tularensis are pathogenic bacteria designated by the US government as Tier 1 agents, which include the most dangerous biological weapons. Bacillus anthracis is a gram-positive bacterium whose highly resistant spores cause anthrax, an infection that affects either the skin, the gastrointestinal tract or the respiratory tract, with the latter having a mortality of up to 80% . Francisella tularensis, on the other hand, is a highly virulent gram-negative bacterium that causes tularemia – or rabbit feaver –, an infection that attacks the skin, eyes, lymph nodes and lungs, and is often lethal without treatment.
The standard of care against both Bacillus anthracis and Francisella tularensis is currently Ciprofloxacin, a synthetic large spectrum antibiotic from the fluoroquinolone family. However, a number of pathogenic bacterial species have developed resistance against this family of antibiotics, highlighting the urgent need to develop alternative treatments. In vitro analysis performed in collaboration with the USAMRIID has now shown that DNV3681 (The active metabolite of DNV3837) is effective against these two pathogenes, and its activity is exceptionnaly high against Bacillus anthracis (see poster ASM Microbe 2019 below). Preclinical studies on animal models of the diseases will follow to evaluate DNV3837 as a treatment in vivo against these major bioterrorist threats.
A dual mechanism of action to counter pathogens
DNV3837 is a water soluble prodrug that is rapidly dephosphorylated after intravenous administration in humans to produce DNV3681, the active form of the drug. Its structure results from the combination of two active moieties: a fluoroquinolone that inhibits bacterial DNA gyrase to interfere with replication of the bacterial genome and an oxazolidinone that inhibits initiation of bacterial protein synthesis.
Proven safety, promising efficacy
Preclinical studies have demonstrated that DNV3837 is highly efficient against 114 different clinical isolates of Clostridioides difficile, and its efficacy is actually superior to that of most standard of care antibiotics, including Vancomycin, Metronidazole and Fidaxomicin. This observation was in particular true against the hypervirulent C. difficile strain NAP1, which caused a peak of healthcare-associated CDIs across Europe and North America in the early 2000s, providing strong arguments to support the clinical development of DNV3837.
Three phase I clinical trials were performed on a total of 90 healthy volunteers to evaluate the safety and pharmacology of DNV3837. The results raised no safety concerns, and the prodrug was found to be efficiently converted into its active form, DNV3681. The antibiotic then crossed the gastrointestinal barrier and accumulated in the intestinal lumen, demonstrating its ability to precisely target the site of infection. Importantly, one trial performed on 12 healthy volunteers who received intravenous DNV3837 for 5 consecutive days showed a clear overall decrease in gram-positive bacteria in stool samples after infusion, suggesting an efficacy in vivo against Clostridioides difficile, without affecting the gut microbiota, which was fully restored between days 12 and 19. Following these promising preclinical and clinical data, DNV3837 was granted the Qualified Infectious Disease Product (QIDP) designation and Fast Track status by the US Food and Drug Administration (FDA) for accelerated product development .
DNV3837 has now entered a multicenter phase II clinical trial to evaluate its efficacy, safety and pharmacokinetics in 40 patients with moderate to severe Clostridioides difficile gastrointestinal infections (NCT03988855). Thanks to clinicians and patients, the clinical trial still runs in the United States despite the COVID-19 pandemic and preliminary results are still expected by S1 2021.
 Cassini, A., Plachouras, D., Eckmanns, T., Abu Sin, M., Blank, H.-P., Ducomble, T., Haller, S., Harder, T., Klingeberg, A., Sixtensson, M., Velasco, E., Weiß, B., Kramarz, P., Monnet, D. L., Kretzschmar, M. E., & Suetens, C. (2016). Burden of Six Healthcare-Associated Infections on European Population Health: Estimating Incidence-Based Disability-Adjusted Life Years through a Population Prevalence-Based Modelling Study. PLOS Medicine, 13(10), e1002150.
 Hendricks, K. A., Wright, M. E., Shadomy, S. V., Bradley, J. S., Morrow, M. G., Pavia, A. T., Rubinstein, E., Holty, J.-E. C., Messonnier, N. E., Smith, T. L., Pesik, N., Treadwell, T. A., & Bower, W. A. (2014). Centers for Disease Control and Prevention Expert Panel Meetings on Prevention and Treatment of Anthrax in Adults. Emerging Infectious Diseases, 20(2).
 ‘Fast Track’ status facilitates the development of the molecule through a faster and more flexible regulatory review of the application. The QIDP designation gives the drug exclusive access to the market for an additional five-year period. These designations are granted by the FDA to drugs under development that meet critical and unmet therapeutic needs.