NEW YORK – French biotech EverImmune is attempting to reverse immunotherapy resistance across several cancer types using a single species of bacteria called Akkermansia.
The firm recently announced the start of its first-in-human clinical trial, EV 2101, evaluating targeted administration of the bacteria — which it has named Oncobax AK — in certain patients with lung and kidney cancer receiving standard-of-care immune checkpoint inhibitor therapy.
The trial, which is expected to enroll 19 patients with non-small cell lung cancer and 41 patients with renal cell carcinoma across Phases I and IIa, is taking a biomarker-selected approach to the microbiome treatment. To partake in the study, patients must submit stool samples that undergo PCR-based screening for Akkermansia deficiency, which allows researchers to gauge if the Oncobax AK approach might improve their immunotherapy responses.
Romain Daillere, CSO of EverImmune, explained that the PCR-based screening step is done within 24 hours. "This was very important for us, because we can't forget that we are working with cancer patients [who] cannot wait several weeks," he said.
Patients at one of four trial sites in France and Belgium provide a stool sample for PCR-based screening. Those that have the bacterial deficiency are eligible for the trial and go on to receive Oncobax AK, an oral pill, for seven days prior to beginning standard-of-care immune checkpoint inhibitors and continue to take the pills daily through the immunotherapy course. Metastatic non-small cell lung cancer patients receive Merck's PD-1 inhibitor Keytruda (pembrolizumab), for example, whereas metastatic renal cell carcinoma patients get combined treatment with Bristol Myers Squibb's PD-1 inhibitor Opdivo (nivolumab) and CTLA4 inhibitor Yervoy (ipilimumab).
The goal of the trial is to determine the toxicity and efficacy of Oncobax AK plus immunotherapy. EverImmune will be measuring patients' objective response rates as the trial's primary endpoint, then tracking nine-month progression-free survival rates as a secondary endpoint. The preliminary results from the Phase I portion of the trial are expected in June, said EverImmune CEO Jean-Luc Marsat, allowing EverImmune to immediately begin the Phase IIa part of the trial.
If and when that happens, Marsat said EverImmune, a Gustave Roussy Cancer Center spinout based in France, is hoping to open study sites in North America. To accomplish this, the firm will need to submit an investigational new drug application with the US Food and Drug Administration. Most likely, EverImmune will seek permission to conduct human trials in the US either in NSCLC or renal cell carcinoma, depending on the activity seen in early data, and enroll an additional 50 patients in that indication.
Single bacteria versus microbiome consortia
The concept of therapeutic microbiome modulation to improve immunotherapy response isn't unique to EverImmune. Other biotechs and academic researchers have been focusing on the role of the microbiome in immunotherapy response, and several have begun to develop and clinically evaluate oral therapies. That said, EverImmune's approach is unique in that it is using just one bacteria — Akkermansia — to treat a population of patients with a documented deficiency. While many of the other microbiome therapies under development comprise several bacteria strains, EverImmune sees its single-bacteria approach as a key advantage.
"Developing a consortium [of bacteria] is complex in terms of manufacturing," Daillere said. "You have to be able to characterize all the unique bacteria in the product." Then, there is the difficulty of evaluating a bacteria consortium from a safety standpoint. In a clinical trial, it would be difficult to isolate which bacteria in the consortium is causing toxicity, let alone home in on the strain driving efficacy if they were all administered in a single capsule.
Use of a single bacteria limits the therapy only to those who have a deficiency in that specific bacteria, but Marsat also sees this as an advantage.
"This is the beauty of our clinical demonstration," he said. "The competitors are very often taking all the patients and adding a consortium of bacteria. In our case, we are not targeting all the patients. We are targeting the patients with the deficiency, so we create what we call a compensation."
While it varies according to line of treatment, Daillere estimated that some 60 percent of patients with metastatic, immunotherapy-refractory NSCLC and renal cell cancer are likely deficient in Akkermansia.
Potential for earlier intervention
While EverImmune is focusing its early clinical development efforts in patients who haven't responded to immune checkpoint inhibitors, there's a chance Oncobax AK could play a role in the first-line setting as a way to preemptively overcome checkpoint inhibitor resistance.
This would require determining whether patients are Akkermansia deficient from the start to gauge whether the initial treatments they received contributed to the deficiency. "This is something we are working on," Daillere said. "The condition of the gut microbiome is very dynamic … It's a complex ecosystem."
EverImmune is also hoping that it will be able to adapt its approach for additional cancer types, including breast cancer. For patients with breast cancer, Marsat said that the firm has identified a different, undisclosed bacteria that it wants to develop in tandem with immunotherapy, similar to how it is developing Akkermansia. The firm has already identified this bacteria's mechanism of action but wants to finish developing a test to screen for the deficiency before announcing which bacteria it is. According to Marsat, the firm wants to ensure initial results from the Oncobax AK trial validate its approach before expanding it into other cancer types. In the meantime, EverImmune is trying to attract investors who will see the promise of its approach and support its clinical research efforts.