Wave after wave of microbiome therapeutics are said to be on their way. The first wave has already appeared, rather like a pair of blips on a radar screen. Each blip corresponds to a fecal microbiome product for treating recurrent Clostridioides difficile infection (rCDI). One of them is Rebyota, a rectally delivered product developed by Ferring Pharmaceuticals, that secured FDA approval in November 2022. The other is Vowst, an orally delivered product developed by Seres Therapeutics that secured FDA approval in April 2023. Both products are derived from donor-supplied material. Whereas Rebyota is a fecal microbiota suspension, Vowst contains purified bacterial spores.

The expectation is that successive waves of microbiome therapeutics will sweep across a wider range of conditions while employing increasingly varied modalities. They will also involve more standardized and scalable manufacturing techniques. Perhaps our radar screen for microbiome therapeutics will soon be crowded with blips—and not just in the most obvious region—that is, the region corresponding to gastrointestinal infections—but also in regions corresponding to other kinds of disorders. Possibilities include microbiome therapeutics to treat inflammatory bowel disease, graft-versus-host disease, and myriad skin conditions. Microbiome therapeutics are also being developed that are meant to work in combination with checkpoint inhibition and thereby improve antitumor immunity.

How intently should we be staring at the radar screen, awaiting changes? It has been looking fairly static of late, but appearances can be deceiving. Yes, the COVID-19 pandemic has heightened concerns about adequately screening infectious agents from donor-supplied materials. Also, donor-derived products tend to be manufactured in small and variable batches, constraining supplies, complicating quality control, and raising costs. Finally, as some developers have noted, the microbiome therapeutics industry has seen reductions in funding.

We might suppose that the industry is in a holding pattern. But before we do that, let’s try looking into development work that isn’t quite on the radar yet. Let’s hear what a selection of industry experts have to say about the industry’s prospects.

One of the experts in this article represents a company developing therapeutics based on defined consortia of bacteria, another represents a company addressing immune conditions, and another represents a company developing therapeutics for dermatological conditions. Finally, we hear from a contract development and manufacturing organization (CDMO) about services that could facilitate commercial-scale production.

A shift to defined consortia

Bernat Olle, PhD, CEO of Vedanta Biosciences, emphasized the potential of live biotherapeutic products (LBPs), that is microbiome products based on defined consortia of bacteria isolated from the human microbiome and grown from pure clonal cell banks. The company recently reported progress for two defined bacterial consortium candidates. VE303, for preventing rCDI, will soon enter a Phase III registrational trial. VE707, for preventing Gram-negative infections, has received support from the Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator and is being readied for a first-in-human study.

Vedanta Biosciences' Anaerobic Workstation
During the production of microbiome therapeutics that consist of living microorganisms, difficulties are encountered at every stage: isolation and banking of individual strains; fermentation; formulation and lyophilization; and blending, fill, and finish. This image, from Vedanta Biosciences, depicts a particular fermentation challenge—working with anaerobic strains.

Olle acknowledged that LBPs still pose challenges with respect to chemistry, manufacturing, and controls (CMC): “Manufacturing has to navigate a series of challenges including media variability, minimizing exposure to oxygen, and preserving the viability of bacterial cells during freeze-drying and storage.”

He also cited risks related to pharmacology and biological complexity: “The pharmacokinetics of gastrointestinal-targeted LBPs has some key differences from small molecules, proteins, or oligonucleotide-based drugs: on the one hand, the classical processes of absorption, distribution, metabolism, and excretion largely do not apply. On the other hand, new measures such as the abundance and durability of the colonization of LBP strains in the intestine are a relevant way to quantify exposure.”

“The most formidable challenge for development of LBPs,” he continued, “is the complexity of the biology being uncovered. Even as the field advances, this risk will likely remain as the hardest of all to discharge. The mechanisms by which bacteria affect the host are highly pleiotropic and poorly understood. Both limitations make bottom-up approaches to rational development of LBP candidates a challenging, largely empirical exercise. Engineered LBPs pose the additional technical challenge that the functions engineered into the organism may not be stable in vivo or may be transferred to unintended organisms, which is believed to have been a contributor to clinical failures in the field.”

Vedanta Biosciences' Lab Shot
Vedanta Biosciences maintains a large-scale current Good Manufacturing Practice (cGMP) facility to ensure the clinical and commercial supply of the company’s product candidates. Capabilities span from master cell banking to drug substance and drug product manufacturing, and from early clinical phase to commercial launch. Also, the facility can accommodate the production of multiple candidates and the handling of both spore-forming and non-spore-forming bacteria.

Nonetheless, Olle also highlighted reasons for optimism. “The mechanisms of action by which LBPs restore colonization resistance against pathogens are unlikely to elicit antimicrobial resistance, which should obviate the need for stewardship and remove downward pressure on sales volumes,” he suggested. “These attributes of LBPs are not well appreciated by the pharma industry or investors yet, but in the long term could bring renewed interest to the field of anti-infectives.”

Olle also offered another take on the “most formidable” challenge for LMPs: “The pace of exciting research continues unabated in academia, painting a progressively clearer picture of the complex biology that defines the field.”

Immunomodulatory agents

“Since our inception 10 years ago, we have been committed to leveraging microbiome-based therapies to restore immune homeostasis in cancer patients, potentially reshaping cancer treatment paradigms and positioning microbiome-therapies as the fifth pillar of cancer treatment,” declared Hervé Affagard, co-founder and CEO, MaaT Pharma. He added that areas of growing interest among microbiome researchers and industry players include hemato-oncology applications (specifically, preventing graft-versus-host disease) and immuno-oncology applications (specifically, boosting the immune response to tumors).

Affagard noted that Maat Pharma’s efforts included the development of MaaT013, an alternative to immune-suppressive graft-versus-host therapies such as corticosteroids and ruxolitinib, and the development of MaaT033, a concomitant to immune checkpoint inhibition.

“MaaT013’s immuno-restorative approach offers significant hope, as evidenced by reduced infectious complications and improved survival rates in recent data presented at the 2024 annual conference of the European Society for Blood and Marrow Transplantation,” he reported. “MaaT013 is currently being evaluated in Phase III trial in acute graft-versus-host disease, with the topline results expected for mid-Q4 2024.

MaaT013 production facility
In September 2023, MaaT Pharma, a clinical-stage biotechnology company, and Skyepharma, a contract development and manufacturing organization, completed construction of a manufacturing facility for microbiome ecosystem therapies. The facility, located near Lyon, spans over 17,200 square feet. The facility’s first tasks are the production of MaaT013, a treatment to prevent graft-versus-host disease, and MaaT033, a treatment to improve survival in patients receiving allogeneic stem cell transplantation.

“In March 2024, we completed patient recruitment for an investigator-sponsored Phase IIb study evaluating MaaT013 in combination with immune checkpoint inhibition in metastatic melanoma. We also announced on May 7th our participation in a clinical trial in the IMMUNOLIFE program dedicated to solving primary resistance to immune checkpoint inhibition observed in advanced non–small cell lung cancer patients following antibiotic uptake. As part of this Phase II randomized multicenter clinical trial, our second drug candidate, MaaT033, an oral, pooled fecal microbiotherapy, will be tested as a concomitant treatment to anti-PD1 therapy.”

Affagard also discussed manufacturing challenges. “Microbiome-based therapy manufacturing requires specialized expertise and infrastructure,” he explained. “Most CDMOs lack the necessary know-how to maintain microorganism viability throughout production, a critical factor for success. At MaaT Pharma, we’ve opted for a dedicated cGMP manufacturing facility, operated in partnership with Skyepharma, to ensure full control and scalability. The building was built in 12 months, and production started in September 2023.”

Skin in the game

“There are a number of companies pursuing a range of non-CDI indications,” observed Daniel Brownell, senior director of R&D at AOBiome. “We’re preparing to begin Phase III trials in atopic dermatitis.” These trials involve AOBiome’s B244, a microbiome therapeutic based on a live single strain of Nitrosomonas eutropha.

The “AOB” in AOBiome stands for ammonia-oxidizing bacteria. When AOB such as N. eutropha metabolize ammonia, they reduce local pH and produce nitric oxide, which has anti-inflammatory and vasodilatory properties, and nitrite, which has anti-infective properties. Indeed, according to AOBiome, the presence of AOB is correlated with reductions in bacteria such as Staphylococcus aureus and Propionibacterium acnes, which are commonly associated with eczema and acne, respectively.

“We anticipate readouts from [the atopic dermatitis] studies in the next few years,” Brownell remarked. “We are also interested in advancing our programs in other indications such as acne, rosacea, and pruritus, where our previous trials have shown promising results.”

Brownell looks forward to technology developments that will help clarify the “incredibly complex interactions between microbes and humans, microbes and microbes, as well as the influence of all of the microbially produced products.” He stated, “The first generation of microbiome therapeutics was borne out of the ability to sequence human bacterial communities to determine what was missing/overrepresented in the healthy and diseased states, allowing for construction of consortia to correct these dysbioses. While there have been successes using this approach, there have also been high-profile failures. The field has moved beyond merely sequencing-based approaches, incorporating a range of new technologies such as metabolomics, proteomics, and bioinformatics.”

Passing the acid test

When asked about the specialized development and manufacturing expertise needed to produce microbiome therapeutics, Vincent Jannin, PhD, director of R&D and head of capsule application lab services at Lonza emphasized the need for delivery vehicles that could protect sensitive therapeutics from acid stomach conditions. “LBPs belong to this category,” he said. “They need to bypass acidic conditions to reach the intestines while retaining their activity.”

To address this market requirement, Lonza has developed Capsugel Enprotect capsules. “Our capsules work well for donor-derived fecal microbiota transplants that prevent rCDI,” Jannin asserted. “We have also been collaborating with APHP Sorbonne Université–Saint Antoine (Paris, France) to demonstrate the stability of our enteric capsules with fecal microbiota transplant formulations during storage.”

Capsugel Enprotect capsules take advantage of Lonza’s proprietary technology for the production of bilayer modified release capsules. “The capsules simplify the manufacturing process and supply chain of our customers and shortens the timeline from clinical development to market entry,” Jannin added. “Customized bilayer capsules can also be developed through the Capsule Application Lab Services that enable the development of microbiome therapeutics with new capsule sizes or drug release profiles.”

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