DAV132 is a novel microbiota protective therapy developed to prevent antibiotic-induced dysbiosis. Co-administered with antibiotics, it has demonstrated its ability to selectively and safely target antibiotics. Multiple clinical trials have already been performed successfully in healthy volunteers and a Phase 2 in patients is ongoing.
Protecting the intestinal microbiota during antibiotic treatments
DAV132 is regulated as a drug in the USA and its development plan was validated by FDA in Pre-IND and Type C meetings. In Europe, due to its unique mechanism of action, DAV132 is regulated as a medical device and obtained a first CE mark in 2015.
DAV132 mechanism of action
During antibiotic courses, a fraction of the drug remains in the intestinal tract due to either partial absorption or recycling via the hepatobiliary route from the blood into the small intestine. These active antibiotic residues progress to the colon and provoke a profound dirsuption of the intestinal microbiota of patients. The microbiota balance is disturbed: several bacterial populations are erased whereas some strains proliferate. Microbiota disruption, called dysbiosis is a long-lasting consequence of antibiotics intake and patient’s microbiota will take months to recover.
In the late ileum, cecum and colon, DAV132 delivers a non-specific adsorbent which irreversibly captures antibiotics, before they could alter significantly the microbiota.
DAV132 adsorbent is encapsulated in a specific drug delivery system (specific coating) patented by Da Volterra that permits a targeted delivery to the lower gastro-intestinal tract. DAV132 prevents the antibiotic-induced disruption of the intestinal microbiota without interfering with the antibiotic or other drugs efficacy.
Video of the mechanism of action
DAV132 is protected by more than 100 patents worldwide and the team is committed to file additional patent. applications on improvements and new discoveries around the product.
Clinical Benefits of DAV132
DAV132 in the prevention of C. difficile infection
Clostridioides (Clostridium) difficile is well recognized as the leading cause of antibiotic-associated diarrhea, having a significant impact in both healthcare and community settings. By binding with and neutralizing common antibiotics in the gut, DAV132 preserves the integrity of the intestinal microbiota during antibiotic cures and is indicated to prevent Clostridioides difficile infections and their consequences.
C. difficile infection, a growing medical need
The incidence, severity and mortality of Clostridioides difficile infection (CDI) have been increasing in the United States of America and the European Union, since 2000, with a steady rise over the last decade. In 2012, of the total estimated 453,000 incident cases in the USA, a majority (64.7%) were considered to be healthcare-associated.CDI are characterized by their high rate of recurrence. Up to around 25% of patients treated for CDI have recurrence of the infection within 1 to 3 months after treatment completion, resulting in approximately 83,000 reccurences per year in the USA. Patients with recurrence are at higher risk for subsequent recurrences, leading to an exhausting cycle of repeated infections.
The burden of Clostridioides difficile infection
High Clinical Burden
Decreasing Patients Quality of Life
High Economic Burden
The clinical symptoms of CDI range from asymptomatic colonization, to mild or moderate diarrhea, but can also include fulminant colitis with toxic megacolon and death.
CDI can be devastating, with an estimated 30-day mortality ranging from 5.7% to 6.9%. In 2011, CDI has resulted into 29,300 deaths in the United States.
Consequences of CDI have a high and long lasting impact on patients lives
Most common word cited by patients when talking about consequences of CDI
In the US, the costs associated to CDI in the hospital range from $8,911 to $30,049 per infection.
In some accounts, the total costs of CDI almost reach US $6.3 billion a year.
In Europe, the costs due to CDI are estimated at over 3.7 billion euros per year
Who is at risk of Clostridioides difficile infection?
Recent use of antibiotics
Patients have a 7 to 10-fold increased risk of CDI during antibiotic therapy.
Almost 2/3 of patients with CDI are aged 65 or more.
Chronic underlying illness
CDI is a particular risk in patients with kidney disease, cancer and in patients with immune deficiency.
Hospitalization is associated with higher exposure to antibiotics and C. difficile spores.
1. Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol. 2010. Link to Pubmed.
2. Johanesen P. A., Mackin K. E., Hutton M. L., et al. Disruption of the gut microbiome: clostridium difficile infection and the threat of antibiotic resistance. Genes 2015 Link to Pubmed.
3. Zhang, S. et al. Cost of hospital management of Clostridium difficile infection in United States, a meta-analysis and modelling study.BMC Infect. Dis.16,447 (2016) Link to Pubmed.
4. Kuijper EJ et al. Emergence of Clostridium difficile– associated disease in North America and Europe. Clin Microbiol Infect 2006;12(Suppl 6):2 –18. Link to Pubmed.
5. Dubberke ER, Olsen MA, Stwalley D, Kelly CP, Gerding DN, Young-Xu Y, et al. (2016) Identification of Medicare Recipients at Highest Risk for Clostridium difficile Infection in the US by Population Attributable Risk Analysis. PLoS ONE Link to Pubmed.
DAV132 and cancer immunotherapies
For some time, the intestinal microbiota has been thought to regulate the host immune system. Recent research suggests that the composition of intestinal microbiota impacts the efficacy of anticancer therapies and in particular immuno-oncology treatments such as inhibitors of PD1 and PD-L1. Recently published studies have shown that patients with Melanoma, Non Small-Cell Lung Cancer, Renal Cell Carcinoma or Urothelial Carcinoma treated with immunotherapies and receiving antibiotics had poorer outcomes than patients not receiving antibiotics.
These publications show that antibiotic use during immunotherapy reduces the median overall survival by several months (from 9.1 to 16.7 months) depending on the type of cancer. We develop DAV132 to protect the intestinal microbiota from antibiotic-induced disruption and garantee the best efficacy of immunotherapies for patients with cancer.
Cancer is Progressing Worldwide
The international Agency for Research on Cancer has recently estimated that 1/5 men and 1/6 women worldwide will develop cancer in their lifetime. According to the World Health Organization, 18.1 million new cases of cancer are expected worldwide in 2018, including 2.1 million of lung cancer cases, the most common cancer.
Burden of Cancer
Cancer is the second leading cause of death globally, and is responsible for an estimated 9.6 million deaths in 2018. Globally, about 1/6 deaths is due to cancer.
The economic impact of cancer is significant and is increasing. The total annual economic cost of cancer in 2010 was estimated at approximately US$ 1.16 trillion worldwide.
1. M.P. Francino. Antibiotics and the Human Gut Microbiome: Dysbioses and Accumulation of Resistances. Frontiers in Microbiology. Jan 2016. Link to Pubmed.
2. Vylyny Cha. Autoimmune genetic variants as germline biomarkers of response in melanoma immunotherapy treatment. Poster presented to ASCO 2018. June 2018 Link to the abstract.
3. B. Routy and al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. Jan 2018. Link to Pubmed.
4. L. Derosa. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Annals of Oncology. June 2018. Link to Pubmed.
DAV132 and GvHD
Graft-versus-Host Disease (GvHD) is a condition that can occurs after an allogenic Hematopoietic Stem Cell Transplant (allo-HSCT), which is performed for patients in the treatment of hematological diseases such as leukemia, myeloma or lymphoma. GvHD is a major life-threatening complication of allo-HSCT occuring in 30% to 60% of patient with a mortality rate of approximately 50%.
In GvHD, the donated bone marrow or peripheral blood stem cells view the recipient’s body as foreign, and the donated cells/bone marrow attack the body. Antibiotic use has been correlated to higher risk of developing GvHD, and most of transplanted patients receive a lot of antibiotic treatments during the path of transplant.
DAV132 given with those antibiotics could decrease the development of GvHD.
1. Shono Y, Docampo MD, Peled JU, et al. Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice. Sci Transl Med 2016 Link to Pubmed
2. Hidaka D, Daisuke E, Hayase S, et al. The association between the incidence of intestinal graft-versus-host disease and antibiotic use after allogeneic hematopoietic stem cell transplantation. Clin Transplant 2018 Link to Pubmed
DAV132 to tame antibiotic resistance
Antibiotic resistance is more than ever considered a top priority of public health and considerable efforts are being engaged to develop new solutions to combat multi-drug resistant bacteria. In its recent Action Plan against Antimicrobial Resistance, the European Commission pointed out the need to “support SMEs in their R&D efforts towards […] alternative therapeutic approaches for the treatment or prevention of bacterial infection”.
In some hospital wards, the transmission of resistant bacteria from patients to patients is particularly worrisome. Physicians are looking for solutions to limit the risk of selecting resistant bacteria and spread them in the patient environment.
DAV132 may be used in these wards to limit the dissemination of resistant bacteria.
In the long run, considering the threat of antibiotic resistance, DAV132 may be used more generally with all antibiotic prescriptions in order to quench the selection of resistant bacteria and spread of resistance genes in the environment with the final objective to slow the emergence of deadly multi-drug resistant bacteria which threaten medical practice.
1. European Commisssion, A European One Health Action Plan against Antimicrobial Resistance (AMR) Link to PDF.
2. World Health Organization, Antimicrobial resistance Link.
3. Centers for Disease Control and Prevention, Antibiotic / Antimicrobial Resistance (AR / AMR) Link.
4. O’Neil J, Review on Antimicrobial Resistance,Tackling Drug-Resistant Infections Globally: Final Report & Recommendations (2016) Link to PDF.
5. Carlet J, The gut is the epicentre of antibiotic resistance (2012).Link to Pubmed.