DNV3837

A new 2-in-1 antibiotic against high priority superbugs

DEINOVE’s proprietary antibiotic molecule, 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 evaluated in a phase II clinical trial for the treatment of severe Clostridioides difficile infections, a pathogen responsible for certain healthcare-associated infections, representing a major threat to human health and recognized as a priority by the World Health Organization. DNV3837 is the only antibiotic-candidate developed by a French company, among the 43 antibiotics in the clinic globally [1] and the only administered intravenously (no others in development or commercialized).

In parallel, and in collaboration with the United States Army Medical Research Institute of Infectious Diseases (USAMRIID), the compound is under preclinical evaluation against two of the most dangerous potential biological weapons, Bacillus anthracis and Francisella tularensis.

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.

More than 40% of hospitalized patients with Clostridioides difficile infection (CDI) have been classified as severe disease associated with higher morbidity and mortality [2]. The Centers for Disease Control and Prevention (CDC) identifies CDI as one of the leading causes of hospital-acquired infections, ahead of even MRSA infections [3]. In the United States, it is estimated that CDI causes nearly half a million disease cases each year, and approximately 29,300 deaths [4]. This condition is not limited to the United States and recent studies [5] show that the incidence of this type of infection is greatly underestimated in other parts of the world, such as Europe and Asia.

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.

Anticipating bioterrorist attacks

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% [6]. Francisella tularensis is a highly virulent gram-negative bacterium that causes tularemia – or rabbit fever –, 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 shown that DNV3681 (the active metabolite of DNV3837) is effective against these two pathogens, with an exceptionnaly high activity against Bacillus anthracis (see poster ASM Microbe 2019 below). Preclinical studies on animal models of the diseases are evaluating 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.

DNV3837

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 [7].

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).

The independent Data Safety Monitoring Board (DSMB)[8] has completed its review of the safety data from the first part of the trial and considered that the benefit/risk balance of antibiotic therapy with DNV3837 was in favor of continuing the recruitment in this trial.

It should be noted that, due to the Covid-19 pandemic, the first phase of the trial was limited to 9 patients instead of 10.

The design of the second part of the trial has been modified to improve its protocol thanks to the investigators' feedback during the first part, with a reduction in dose by a factor of 4 and a reduction in the duration of administration by a factor of 2, reducing the intravenous treatment from 12 to 6 hours per day.

Lastly, in order to accelerate patient recruitment, DEINOVE has expanded its study in Canada with the opening of 5 new sites, in addition to those already active in the US. Dr. Thomas Louie, Professor of Microbiology and Infectious Diseases at the University of Calgary (Canada) and a world expert on Clostridioides difficile, will be the medical lead of the study in Canada.

Due to the impact of the COVID-19 pandemic, the results of the second part of the trial are expected to be published at the end of the first half of 2023.
 

[1] The Pew Charitable Trusts - Tracking the Global Pipeline of Antibiotics in Development, March 2021

[2] Zar FA et al. Clin Infect Dis. 2007 Aug 01; 45(3):302-7.

[3] SARM : staphylocoque doré résistant à la méticilline

[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. J Glob Health 9:010407

[6] 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).

[7]  ‘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.

[8] The Data and Safety Monitoring Board (“DSMB”) is an independent group of experts responsible for monitoring the patient safety data of a clinical trial, and when appropriate, balancing it against the efficacy data. It may make recommendations regarding the continuation, modification or discontinuation of the trial.

DNV3837 at the Peggy Lillis Foundation's Virtual C.diff Advocacy Summit - April 2021

DNV3837, a new parenteral treatment for C.diff Infection Presented by Yannick Pletan, MD, MSc, HEC, Chief Medical Officer

Poster ASM Microbe 2019