An obituary on DAV-132—authors’ viewpoint on the current limits of pivotal trials in clinical microbiome research

Abstract

There is an urgent need for novel approaches to reduce the spread and clinical impact of infections with MDR bacteria. Da Volterra (Paris, France) is a biopharmaceutical company specializing in the development of microbiota-protective therapies. In 2010, they introduced DAV-132, an active charcoal preparation designed to protect the gut microbiota from antibiotic selection pressure, without affecting antibiotic pharmacokinetics, at the Superbugs and Superdrugs Conference in London, UK.1 In 2016, Da Volterra joined the EU Innovative Medicines Initiative (IMI) to further develop this promising product in close cooperation with academic partners. Phase I and II trials were completed successfully, confirming the protective effect of DAV-132 on the human gut microbiota.2,3 Consequently, a Phase III trial—MICROCARE—was planned and initiated. On 2 December 2022, however, the company Da Volterra was declared bankrupt. Given the significant clinical potential of DAV-132, this turn of events can be considered tragic. Could it have been avoided? The authors of this letter were closely involved in the design and conduct of the Phase III trial necessary for registration of DAV-132, which was classified as a medical device by the competent authorities. Many hurdles had to be overcome to design and implement a trial that would be feasible to execute. To meet EMA and FDA registration criteria, it was necessary to show that DAV-132 could confer a health benefit. Protecting the microbiota is a very useful property, but is not considered a health benefit per se and is not recognized as a surrogate endpoint. Therefore, an alternative clinical endpoint had to be identified. The evidence on potential health benefits associated with a balanced human microbiota seems to be growing exponentially.4 At the same time, very little of that evidence is quantifiable and directly relatable to endpoints recognized by regulators. For the Phase III trial, we needed patients with considerable antibiotic exposure. These would have to experience a measurable clinical outcome associated with their antibiotic exposure. In addition, the frequency of this outcome to occur would need to be high enough to result in a feasible sample size. The only indication that seemed to fit these criteria was the prevention of Clostridioides difficile infections (CDI). Even though CDI is considered the most frequent healthcare-associated infectious cause of diarrhoea, its overall incidence is declining. Predicting which individual patient might develop CDI remains a major challenge, despite the identification of age and intense antibiotic exposure as key risk factors for CDI.5,6 In patients undergoing induction chemotherapy for AML or high-risk myelodysplastic syndrome the frequent co-occurrence of the latter risk factors results in a relatively high cumulative incidence of CDI, ranging from 9.4% to 23.8% within the first 120 days after initiation of induction chemotherapy.7–10 Even in this selected population, a sample size of 900 was deemed necessary to show the prophylactic efficacy of DAV-132, while assuming a clinical efficacy of DAV-132 of 50% reduction in CDI cases. At the same time, selecting such a seriously ill patient population involves risks. Chemotherapy-associated side effects can significantly impair patient compliance with trial protocols, and an increased number of serious adverse events is to be expected in this population. However, given that the sample sizes calculated for all other populations were not within a realistic range, we were left with the choice of no trial versus a trial with a considerable risk of failure.