In Lyon, the promises of the intestinal microbiota

This article was published in issue 843 of Lyon Capitale, May 2024.

From a -80°C freezer, Carole Schwintner holds up a rectangular cardboard box: "This is MaaT013, our first drug," introduces MaatPharma's technology director. At the end of 2023, the Lyon-based biotech opened its first factory in Saint-Quentin-Fallavier (Isère), in partnership with pharmaceutical subcontractor SkyePharma. Located in the heart of the ZAC (Production Zone), the production site is ideally located, "close to the motorway, the train station, and the airport." This is a major advantage, as the drugs produced here require the daily delivery of a very fresh ingredient: human fecal matter. The newly inaugurated factory is one of the few, and the largest in Europe, to manufacture microbiota-based treatments. At this stage in the world, "only three drugs of this type, two in the United States and one in Australia, are on the market," and MaatPharma positions itself as one of the pioneers in the sector. This field of therapeutic innovation, which consists of re-implanting the microbial community of healthy donors via stool into patients who need it, is still in its infancy on a global scale. But it opens up very promising therapeutic horizons.

Let's go back to the origins to understand it, by entering the Cité de la Gastronomie in Lyon. On display is an interactive epic dedicated to the intestinal microbiota, the ecosystem of bacteria, viruses, fungi, and archaea found in the intestine and colon. It is in this part of the body that the microbial community finds the most fertile ground: each individual, we learn as we walk through the grounds, is home to 40 billion bacteria, from 250 to 300 different species. This community specific to each individual, like a fingerprint, is “a synthesis of our life history, which interacts and evolves with our body over time depending on our genes, our birth, our environment, our diet, our health,” explains Dr. Nicolas Benech, a gastroenterologist at the Croix-Rousse hospital who co-founded the Microbiota Study Group, bringing together around thirty specialists on the subject in the Auvergne-Rhône-Alpes region in order to “pool expertise on the subject in different medical disciplines to build effective research that leads to clinical application.”

Over the past twenty years, our knowledge of the intestinal microbiota has leaped forward “thanks to technological advances in metagenomics, which make it possible to identify all the bacteria in a community at once through DNA sequencing,” explains Carole Schwintner. Research has gradually discovered the countless functions that this ecosystem plays in our bodies, not only in digestion, but also in moderating the central nervous system, modulating neuronal activity, and especially regulating the immune system. Very closely linked to the latter, which is built up through contact with the microorganisms our body encounters, the state of the microbiota – which depends on the quantity and diversity of microorganisms present – ​​therefore also influences the development or not of certain diseases. And can contribute to aggravating them… or to containing them.

This opens up major therapeutic perspectives. “The idea is to use the microbiota as a health co-factor to prevent and treat,” continues Dr. Benech. For a healthy individual, maintaining the richness of their microbiota primarily involves nourishing it with a diet rich in fiber, low in meat and processed foods. But in sick people, other avenues sometimes need to be explored to rebuild a microbiota that has become depleted. This is where therapeutic innovations based on the microbiota come in. They can involve the creation of personalized foods for malnourished cancer patients, as promoted by the Onco-Nutribiota project, or the development of new-generation probiotics, two ambitions shared by Dr. Benech. In other cases, the solution involves directly re-implanting a microbiota from elsewhere; this is known as fecal microbiota transfer. Already practiced at the Croix-Rousse Hospital, which now has its own stool bank, it is only authorized for routine care in very specific cases, and sometimes on compassionate grounds for patients who have reached a therapeutic impasse. But its scope is gradually expanding as clinical trials are rolled out, particularly in oncology.

This field—and in particular oncohematology, blood cancers—has been the main strategic focus of MaatPharma from the outset, created in 2014 based on a technology transfer from INRAE. “In these cancers, patients see their microbiota and therefore their immunity weakened by the disease and the very heavy treatments (chemotherapy, antibiotics) they undergo. Reimplanting a diverse microbiota helps combat both the effects of the treatment and the cancer,” explains Carole Schwintner. Their most advanced drug, MaaT013, is used in the treatment of graft-versus-host disease, which generally occurs in patients suffering from leukemia. After chemotherapy and antibiotics, it is sometimes necessary to transplant a new immune system into the patient. The latter sometimes turns against its host, in a reaction causing very aggressive skin, liver, and especially gastrointestinal symptoms. “We intervene in the third line, on patients whose life expectancy at two months is 20%.”

Administered three times over ten days by enema, this treatment is manufactured in the new Isère factory from a mixture of stools from four to eight donors – to maximize the quantity of bacteria – hand-picked (only 1% of candidates become donors), and suspended in a cryoprotectant solution. This expertise requires infrastructure dedicated exclusively to this type of treatment: the 650 m2 factory houses the development laboratory upstairs and the production rooms on the ground floor, subject to strict containment – ​​level 2 – to prevent any pathogenic elements from escaping. The manufacturing process also requires the material to be protected from oxygen because “where bacteria live, there is no oxygen” .

For this drug, the clinical trial is currently in its third phase, conducted on 75 patients, and MaatPharma is aiming for a market launch in 2026, with a commercial target in Europe of approximately 2,000 to 3,000 patients. “In phase 2, 38% of patients responded to the treatment, meaning they survived 28 days after the start of treatment, with a reduction in diarrhea.” Prospects are also emerging for the possibility of using the treatment on solid tumors such as metastatic melanomas. “The literature shows that the quality of the microbiota affects the response to immunotherapies, which are the treatments used against this type of cancer.” Another formulation of the drug is currently being developed, in phase 2 of clinical trials, and will be manufactured at the Saint-Quentin site: this capsule containing the same mixture, dried and lyophilized, which only opens at the colon, will, if validated, be offered as an accompaniment to treatments for blood cancers and could target 40,000 people per year – a study is also evaluating its potential use in Lou Gehrig's disease. A third generation of drugs is under consideration. To continue its momentum, the biotech, which has already raised €115 million, is preparing a new round of funding in 2024.