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. This is why CDI is labelled as an Urgent Threat by the US CDC. The majority of CDI cases (65%) are considered to be healthcare-associated and in the US, nearly 223,900 people with CDI required hospital care in 2017. CDI is characterized by its 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 recurrences per year in the USA. Patients with recurrence are at higher risk for subsequent recurrences, leading to an exhausting cycle of repeated infections.
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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 around 6%.In 2017, CDI has resulted in 12,800 deaths in the United States.
  • CDI has a high and long lasting physical and psychological impact on patients’lives.94% of CDI patients admit that their daily activities are impacted by the infection and almost all (97%) are afraid of taking antibiotics again.What patients said about CDI:
    “Mentally this has destroyed me”
    “I have never regained my strength.”
  • In the US, the hospital costs associated to CDI range from $8,911 per infection up to $36,113 in some particularly severe patient populations (i.e. patients with hematologic malignancies).The US CDC estimate that in-hospital CDI cases were responsible for $1 billion excess healthcare costs in 2017 nationwide.In some accounts, the total costs of CDI almost reach $6.3 billion a year in the US.

Most common word cited by patients when talking about consequences of CDI:

Who is at risk of Clostridioides difficile infection?

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  Recent use of antibiotics

  Antibiotic exposure is associated with a 1.5 to 17.8-fold increased risk of developing CDI.

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  Advanced age

  Almost 2/3 of patients with CDI are aged 65 or more.

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  Chronic underlying illness

  CDI is a particular risk in patients with kidney disease, hematologic malignancies, solid cancer and more generally, in patients with immune deficiency.

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  Recent hospitalization

  Hospitalization is associated with higher exposure to antibiotics and 
C. difficile spores.

References

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

6. CDC. Antibiotic Resistance Threat in the United States, 2019. Atlanta, GA: U.S. Department of Health and Human Services, CDCC; 2019 Link to the report

7. Lurienne L, Bandinelli P-A., Galvain T, Coursel C-A., Oneto C. Feuerstadt P. (2020) Perception of quality of life in people experiencing or having experienced a Clostridioides difficile infection: a US population survey. JPRO Link to the article

8. Duhalde L, Lurienne L, Wingen-Heimann SM, Guillou L, Buffet R, Bandinelli PA. (2019) Excess burden associated with Clostridioides difficile infection in haematological patients occurring during hospitalization with induction chemotherapy in the USA, J Hosp Infect. Link to PubMed

9. Furuya-Kanamori L, Stone JC, Clark J et al. (2015), Comorbidities, Exposure to Medications, and the Risk of Community-Acquired Clostridium difficile Infection: a systematic review and meta-analysis.Infect Control Hosp Epidemiol. Link to PubMed

DAV132 and GvHD

Graft-versus-Host Disease (GvHD) is a medical complication 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. In GvHD, the donated bone marrow or peripheral blood stem cells recognize the recipient’s body as foreign, which results in the aggression of the transplanted patient by the donor’s immune system.

Acute GvHD occurs in 25%-40% of allo-HSCT recipients and is a leading cause of graft failure and post-graft mortality.

Patients undergoing allo-HSCT frequently receive antibiotics during the neutropenic period before engraftment. Recent literature has established that GvHD is further exacerbated by antibiotic exposure and low-diversity microbiota.

DAV132 co-administered with antibiotics when they are needed could decrease the development and severity of GvHD.

References

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

3. Johnson BH, Taylor A, Gilwan K et al. (2019), Clinical Outcomes and Healthcare Resource Utilization for Gastrointestinal Acute Graft-versus-Host Disease after Allogeneic Transplantation for Hematologic Malignancy: A Retrospective US Administrative Claims Database Analysis. Link to PubMed

4. Han L, Zhang H, Chen S, Zhou L et al. (2019), Intestinal Microbiota Can Predict Acute Graft-versus-Host Disease Following Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant Link to PubMed

5. Lee SE, Lim JY, Ryo DB, Kim TW et al. (2019) Alteration of the Intestinal Microbiota by Broad-Spectrum Antibiotic Use Correlates with the Occurrence of Intestinal Graft-versus-Host Disease. (2019), Biol Blood Marrow Transplant. Link to PubMed

6. Peled JU, Gomes, ALC, Devlin SM, Littman ER et al. (2020), Microbiota as Predictor of Mortality in Allogeneic Hematopoietic-Cell Transplantation, N Engl J Med. Link to PubMed

DAV132 as an add-on therapy to preserve the efficacy of anti-cancer treatment

• In the last decade, advancements in cancer immunotherapies (immune checkpoint inhibitors or ICI) have dramatically revolutionized the treatment of a variety of cancer, and much improved outcome for patients.The intestinal microbiota has been thought to regulate the host immune system for some time, and it has recently emerged as a potential predictor or modulator of response to ICI. Research also suggests that antibiotic-induced disruption of the microbiota may impact anticancer therapies negatively.
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More than 30 studies have been published showing that patients with Melanoma, Non-Small-Cell Lung Cancer, Renal Cell Carcinoma or Urothelial Carcinoma treated with ICI and receiving antibiotics had poorer outcomes than patients not receiving antibiotics.

Systematic review and meta-analyses demonstrate that progression-free-survival (PFS) and overall survival (OS) are significantly reduced in patients receiving antibiotic around immunotherapy initiation. On average, OS is reduced by around 7 months in non-small cell lung cancer patients.

We develop DAV132 to protect the intestinal microbiota from antibiotic-induced disruption and guarantee 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. A high share of patients with cancer are prescribed antibiotics while under anti-cancer treatment.

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.

References

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. Vetizou M, Pitt JM, Daillere R, Lepage P, Waldschmitt N, Flament C, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015 Link to PubMed

5. Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, et al. Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients. Science. 2018 Link to PubMed

6. Huang XZ, Gao P, Song YX, Xu Y et al. (2019), Antibiotic use and the efficacy of immune checkpoint inhibitors in cancer patients: a pooled analysis of 2740 cancer patients. Oncoimmunology. Link to PubMed

7. Lurienne L, Cervesi J, Duhalde L, de Gunzburg J et al. (2020) Non-small-cell lung cancer immunotherapy efficacy and antibiotic use: a systematic review and meta-analysis. J Thorac Onco. Link to PubMed

8. Xu H, Xu V, Wang H, Ge W, Cao D et al. (2020), The association between antibiotics use and outcome of cancer patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis, Crit rev onc. Link to PubMed

9. Wilson BE, Routy B, Nagrial A, Chin VT (2019), The effect of antibiotics on clinical outcomes in immune-checkpoint blockade: a systematic review and meta-analysis of observational studies. Cancer Immunol Immunother. Link to PubMed

DAV132 to tame antibiotic resistance

When the intestinal microbiota is disrupted by the use of antibiotics, it becomes permissive to selection and colonization of multi-resistant bacteria, resulting in the emergence and spread of antimicrobial resistance. The development of bacterial resistance to antibiotics is caused by rapid evolution of the bacterial genome under selective antibiotic pressure and by the selective pressure of the environment. A continuous selective pressure of routinely used antibiotics is an important precondition for the increase in multi-resistant strains.

Antibiotic-resistant bacteria such as Carbapenem-resistant Enterobacteriaceae (CRE), Extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-PE), or Vancomycin-resistant Enterococci (VRE), are a global emerging threat increasingly identified worldwide as causative agents both in community and nosocomial infections. These pathogens cause a broad range of infections that are difficult to treat and often associated with increased morbidity, mortality and healthcare costs. This is particularly concerning in certain clinical settings such as cancer, as cytotoxic chemotherapy alters the gut microbiome and destroys the mucosal barrier, facilitating translocation of colonising microbes into the bloodstream.

Left unchecked, the current trend in rising antimicrobial resistance is a crisis of global scale, already resulting in more than 700,000 deaths from drug-resistant infections worldwide, and expected to be responsible for 10 million deaths each year by 2050.

Thus, 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. Physicians are also actively looking for solutions to limit the risk of selecting and spreading resistant bacteria.

DAV132 may be used to prevent intestinal colonization by multi-drug resistant organisms and subsequent infections.

In the long run, considering the rising threat posed by antibiotic resistance, DAV132 may be used more generally with all antibiotic prescriptions in order to quench the selection of resistant bacteria and the spread of resistance genes in the environment. By doing so, DAV132 could prevent intestinal colonization by multi-drug resistant organisms and subsequent infections which threaten medical practice.

References

1. European Commisssion, A European One Health Action Plan against Antimicrobial Resistance (AMR) Link to PDF

2. World Health Organization, Antimicrobial resistance Link to the report

3. Centers for Disease Control and Prevention, Antibiotic / Antimicrobial Resistance (AR / AMR) Link to the report

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

6. CDC. Antibiotic Resistance Threats in the United States, 2019. Atlanta, GA: U.S. Department of Health and Human Services, CDC; 2019. Link to PDF

7. Interagency Coordination Group on Antimicrobial Resistance (IACG). No Time to Wait: Securing the future from drug-resistant infections. Report to the Secretary-General of the United Nations. 2019. Link to PDF

8. Alevizakos M, Karanika S, Detsis M, Mylonakis E. Colonisation with extended-spectrum β-lactamase-producing Enterobacteriaceae and risk for infection among patients with solid or haematological malignancy: a systematic review and meta-analysis. Int J Antimicrob Agents. 2016. Link to PubMed

9. Tischendorf J, de Avila RA, Safdar N. Risk of infection following colonization with carbapenem-resistant Enterobactericeae: A systematic review. Am J Infect Control. 2016. Link to PubMed

10. Detsis M, Karanika S, Mylonakis E. ICU Acquisition Rate, Risk Factors, and Clinical Significance of Digestive Tract Colonization With Extended-Spectrum Beta-Lactamase-Producing Enterobacteriaceae: A Systematic Review and Meta-Analysis. Crit Care Med. 2017. Link to PubMed

11. Zacharioudakis IM, Zervou FN, Ziakas PD, Rice LB, Mylonakis E. Vancomycin-Resistant Enterococci Colonization Among Dialysis Patients: A Meta-analysis of Prevalence, Risk Factors, and Significance. American Journal of Kidney Diseases. 2015. Link to PubMed