DAV132 is a first-in-class product designed to inactivate antibiotics circulating in the colon and disrupting the gut microbiome. DAV132 has already been demonstrated to be safe and to effectively preserve the intestinal microbiome of healthy volunteers and patients in multiple clinical trials without impacting the clinical efficacy of antibiotic treatments.
DAV132 is primarily developed in cancer patients for whom antibiotic use is both life-saving and life-threatening:
To decrease the occurrence of life-threatening complications such as severe infections and graft-versus-host disease in patients with hematological malignancies.
To preserve the efficacy of immune checkpoint inhibitors and increase the survival of patients with solid tumors taking antibiotics.
DAV132 is the world most advanced product protecting against the clinical consequences of intestinal microbiome dysbiosis.
DAV132 mechanism of action
During antibiotic courses, a fraction of the drug remains in the intestinal tract. These active antibiotic residues progress to the colon where they kill numerous bacteria and lead to a profound disruption of the intestinal microbiome of patients. The microbiome balance is disturbed: several bacterial populations are erased while some proliferate. Microbiome disruption, called dysbiosis, is a long-lasting consequence of antibiotics intake and patient’s microbiome can remain disrupted for months.
In the late ileum, cecum and colon, DAV132 delivers a non-specific adsorbent which irreversibly captures antibiotics, before they can significantly alter the microbiome.
DAV132 adsorbent is encapsulated in a specific drug delivery system (smart coating) patented by Da Volterra that permits its targeted delivery in the lower gastro-intestinal tract. That way, DAV132 prevents antibiotic-induced disruption of the intestinal microbiome without interfering with antibiotics and/or other drugs’ efficacy.
DAV132 Regulatory Status
DAV132 is regulated as a drug in the USA and its development plan was validated by the 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.
Why is DAV132 unique?
DAV132 is the first and only microbiome protector currently in Phase 3: DAV132 is the most advanced microbiome protector in development and the only one able to effectively protect the gut microbiome against antibiotics from all classes. DAV132 addresses important unmet medical needs in cancer patients.
DAV132 is very different from other approaches developed in the microbiome space: it protects the microbiome before it gets disrupted by antibiotics, instead of replenishing it partially after it has been disrupted (as what is done with probiotics, live biotherapeutic products and fecal microbiota transplantation).
DAV132 is easy to prescribe and use: DAV132 is administered orally and works with all antibiotics, regardless of their class and route of administration.
DAV132 manufacturing is well mastered and reproducible: although complex and hard to copy, Da Volterra has developed the know-how required to execute DAV132 manufacturing reliably in high quantity.
Clinical Benefits of DAV132
Effect of antibiotic treatments taken without DAV132 in patients with hematologic malignancies
Patients with hematologic malignancies such as leukemia, myeloma or lymphoma receive numerous courses of antibiotics during the neutropenic phases that are induced by their cancer treatment. These massive and prolonged antibiotic treatments lead to an important disruption of their gut microbiome resulting in the occurrence of life-threatening complications such as severe infections, cancer relapse, delayed recovery, all ultimately leading to a poor quality of life and reduced survival (Peled et al. N Engl J Med. 2020). This is even more true for patients who receive a transplantation and for whom the perturbation of the microbiome also increases the occurrence and severity of Graft-versus-Host Disease (GvHD) (Taur et al. Blood. 2014).
Protecting the microbiome of hemato-oncology patients is essential to increase their chances of survival. DAV132 is the world-first product capable of preventing the life-threatening gut microbiome disruption in patients with hematologic malignancies.
The MICROCARE Phase 3 study is currently ongoing to evaluate the safety and clinical benefits of DAV132 in patients with hematologic malignancies. More details about the MICROCARE study below.
Effect of antibiotic treatments taken without DAV132 in cancer patients treated with immune checkpoint inhibitors
Cancers are traditionally treated with surgery, radiation and/or chemotherapy, with limited results. In recent years, a new approach has emerged and revolutionized cancer treatment: immunotherapy, which boosts patient’s own immune system response to help fight cancer. Immune checkpoint inhibitors (ICIs) are considered to be one of the most promising types of immunotherapy as they have shown unprecedented efficacy in several types of cancer.
Because cancer patients are particularly vulnerable to infections, they rely on antibiotics for their treatment. The medical community has been aware of the deleterious impact of antibiotics on the intestinal microbiome for many years. In the past 2 years, above 50 independent studies and 7 meta-analyses (Lurienne et al. J Thorac Onco. 2020; Cervesi J et al. ESMO Virtual Congress 2020) have shown that, by altering the microbiome, antibiotics may severely reduce the efficacy of ICIs and consequently the survival of cancer patients. As cancer care and antibiotics go together, it is impossible for physicians not to prescribe antibiotics and leave patients vulnerable to life-threatening infections. To ensure that cancer patients do not have to choose between the efficacy of their cancer treatment and the management of complications related to their disease, it is necessary to protect their gut microbiome from antibiotics, thus keeping their microbiome healthy.
By protecting the intestinal microbiome of cancer patients treated with ICIs and antibiotics, DAV132 will improve their survival.
A Phase 2 study is currently in preparation to evaluate the safety and clinical benefits of DAV132 in cancer patients for which antibiotic-induced dysbiosis is life-threatening.
SHIELD was a multicenter, randomized, parallel-group comparative trial in which 260 patients were recruited in 4 European countries (Germany, Romania, Bulgaria, and Serbia). The study was designed to investigate the safety and efficacy of DAV132, taken during antibiotic treatment, to protect the intestinal microbiome. The patients enrolled had a median age of 71 years and 96% of them had at least one chronic comorbidity. They received oral or intravenous fluoroquinolone antibiotics for the treatment of lower respiratory tract infections, complicated urinary tract infections or for prophylaxis of febrile neutropenia.
The study met its primary endpoint and demonstrated positive results:
DAV132 was shown to be safe for use in hospitalized patients with several comorbidities and concomitant medications. Notably, DAV132 did not interfere with the treatment of patients’ infections or with the control of their underlying diseases, confirming the favorable safety profile demonstrated in previous studies conducted in healthy volunteers.
DAV132 was shown to be highly efficient in capturing antibiotics in the colon and in protecting the intestinal microbiome from antibiotic-induced disruption.
DAV132 was shown to maintain the function of the microbiome: resistance to colonization by pathogenic bacteria was preserved in patients taking DAV132 in addition to the antibiotics whereas it was lost in patients taking antibiotics only.
Da Volterra received first regulatory approvals to start enrolling patients in a Phase 3 clinical trial evaluating DAV132. The trial, named MICROCARE, is conducted in collaboration with partners of the COMBACTE-NET consortium and is co-funded by the Innovative Medicines Initiative (IMI).
MICROCARE is an interventional, randomized, placebo-controlled, parallel-group (DAV132 vs. Placebo) trial. 900 patients newly diagnosed with acute myeloid leukemia or high-risk myelodysplastic syndrome and treated with intensive chemotherapy will be enrolled from clinical sites across the world.
The overarching objective of the trial is to demonstrate that DAV132 decreases the occurrence of life-threatening complications and increases survival of patients with hematologic malignancies undergoing several cycles of chemotherapies.