Microbiome Drugs: Multiplying Recent Gains

By Duncan Peyton and Charlie Badham

There was a dramatic rise in clinical trial activity in the microbiome industry in 2021. This illustrates the continuing progress and maturation of the field. Positive results have shown the strong therapeutic potential for microbiome therapies in a number of conditions, and this trend is set to accelerate in 2022.

With numerous mid-to-late-stage trials well underway, a host of 2022 readouts, and the first-ever microbiome therapy approval potentially on the cards, interest from big pharma and investors continues to grow.

So, what were the biggest talking points of 2021, and what microbiome developments should key stakeholders be watching in 2022?

The background on the microbiome space

Drug developers are taking different approaches to the microbiome, and one of the interesting features of the space is the wealth of modalities that has opened up. From wholesale modifications of the gut microbiome to dosing specific strains of bacteria as a drug—these differences in scientific approach are important distinctions for industry followers to understand.

Live biotherapeutics, drugs comprised of bacteria with therapeutic effects, have brought the microbiome field from its humble nutrition-focused beginnings to a new era of pharmacologic treatments for a range of diseases. 4D pharma is focused on a particular approach, developing single-strain live biotherapeutic products (LBPs), selecting strains based on their drug-like activity. We are interested in causation not correlation.

Understandably, the field was initially largely focused on gastrointestinal (GI) conditions, which have proven to be an important proof-of-concept steppingstone. We, at 4D pharma, among others, have sought to realize the full potential of the microbiome, by using the systemic impacts of the gut microbiome on human biology to also treat diseases away from the gut—from cancer to inflammatory diseases and neurology, among others.

Throughout 2021, we saw progress across the full range of approaches being pursued within the field. With continued progress, particularly in the clinic, across different drug candidates representing these diverse approaches, these distinctions will, we believe, be increasingly understood and appreciated among the wider pharmaceutical community.

A key benefit of microbiome therapeutics broadly is their expected safety. In previous years and continuing to the present, we have seen this born out in the clinic. This is important validation strengthening one of the key arguments for microbiome therapeutics. But it also accelerates progress and reduces the cost of development. Where the majority of therapies in development have to progress through Phase I trials in healthy volunteers to assess safety, microbiome drug developers are routinely able to go straight to Phase I/II trials in patients, generating that all-important clinical efficacy data much earlier.

Late-stage GI development

Late-stage activity within the microbiome space is being driven in large part by therapies for GI diseases. Late-stage successes are in turn stimulating interest in the sector overall.

In particular, the first wave of pivotal clinical successes were concentrated on different fecal material transplant (FMT) or consortia products for the prevention of recurrent Clostridium difficile infection (CDI). According to the Emerging Infections Program Clostridioides difficile Infection Working Group, C. difficile infection causes almost half a million illnesses in the United States each year, and an estimated 29,300 deaths.¹

Late-stage CDI programs include Seres Therapeutics’ SER-109,² a complex bacterial consortium derived from donor fecal material (the company announced that in 2022 it will begin filing for the therapeutic to receive FDA approval); Finch Therapeutics’ CP101,³ an orally delivered, donor-derived “complete consortium” (the company indicated that the therapeutic’s second pivotal study began in November); Vedanta’s VE303,⁴ an eight-strain consortium (the company announced a Phase II success and advancement to Phase III with the backing of the U.S. Biomedical Advanced Research and Development Authority in October); and Ferring Pharmaceuticals’ RBX2660,⁵ an enema formulation “full-spectrum microbiota restoration therapy” (the formulation is in Phase III development by Ferring’s Rebiotix subsidiary).

Elsewhere in the GI space, we at 4D pharma obtained detailed positive data for our Phase II trial of the single-strain live biotherapeutic Blautix (MRx1234) for the treatment of irritable bowel syndrome (IBS).⁶ The data, which was reported at Digestive Disease Week (DDW) 2021, showed Blautix to be the first and only drug to show potential as a treatment of both IBS with constipation (IBS-C) and with diarrhea (IBS-D). The results have helped lay a path toward Phase III and potentially approval, and the company is now in discussions with regulators about next steps.

It was not all plain sailing for the microbiome in GI in 2021, however. One of the most watched events of the year ended in an unexpected disappointment for Seres Therapeutics’ donor-derived consortium for inflammatory bowel disease (IBD), SER-287, which failed to beat placebo in a Phase II trial after previously posting encouraging Phase Ib results. Seres continues to analyze microbiome and biomarker data from the study to identify potential reasons for the trial results.

Late-stage success is always important for an emerging field. It demonstrates commercial value and, most important, provides validation. With increasing numbers of microbiome therapeutics edging closer to commercialization, led by this GI vanguard, the increasing confidence and backing these late-stage therapies bring will encourage development of “second generation” microbiome therapies for a range of diseases beyond the gut.

Beyond the gut—oncology

Cancer treatment is an area that has seen incredible innovation in recent years, from the establishment of immunotherapies as a cornerstone of treatment, to new targeted therapies and the introduction of cell therapies, to the benefit of patients. The microbiome is widely hoped to be the next source of step-change progress in the treatment of cancer. Last year saw a number of key developments both in the clinic and in pharma collaborations.

In February 2021, we at 4D pharma announced a clinical collaboration with Merck KGaA and Pfizer to combine our single-strain LBP MRx0518 with the anti-PD-L1 immune checkpoint inhibitor (ICI) Bavencio (avelumab) as a first line maintenance therapy for urothelial carcinoma after chemotherapy.⁷

This collaboration expands the MRx0518 clinical portfolio targeting the PD-1 immune checkpoint axis, complimenting 4D pharma’s ongoing collaboration with Merck & Co and its anti-PD-1 Keytruda (pembrolizumab).⁸ The MRx0518-Keytruda combination is currently being studied in heavily pretreated patients with kidney, lung, bladder, melanoma, triple-negative breast, head and neck, and microsatellite-instability-high cancers who have exhausted all other treatment options.

Last year, 4D pharma presented clinical biomarker data at the European Society for Medical Oncology Congress,⁹ further establishing the mechanism of action of MRx0518 in cancer patients, both as a monotherapy and in combination with Keytruda. The preliminary results raise the interesting potential of identifying patients most likely to respond to the combination treatment.

We are continuing to expand our oncology portfolio and the potential of the microbiome in oncology beyond ICIs. Last July, 4D pharma researchers and our collaborators published preclinical research showing the ability of a novel single strain or its metabolites to improve the efficacy of chimeric antigen receptor T-cell (CAR-T) therapy.¹⁰

Genome & Company meanwhile announced in March 2021 the expansion of its own collaboration with Merck KGaA and Pfizer’s Bavencio, in combination its single-strain Lactococcus lactis LBP, GEN-001.¹¹ Genome & Company adds a Phase IIa trial in gastric and gastroesophageal junction adenocarcinoma to an ongoing Phase I clinical trial in patients whose disease progressed while they were on prior anti-PD(L)1 treatment.

Despite these early positive outcomes, and increasing big pharma partnering interest, the field also saw developers of microbiome interventions backing away in 2021, following lukewarm early clinical results. This includes Vedanta Biosciences’ 11-strain consortium VE800,¹² Synlogic’s engineered intratumoural Escherichia coli candidate SYNB1891,¹³ and Seres’ donor-derived consortium SER-401,¹⁴ the latter including the termination of an early-stage collaboration by AstraZeneca.

Evelo Biosciences also set aside its lead oncology LBP EDP1503,¹⁵ halting Phase I/II development to focus instead on a preclinical oncology candidate, EDP1908, a new approach comprised of bacteria-derived extracellular vesicles for which encouraging animal data was presented at the Society for Immunotherapy for Cancer (SITC) meeting.¹⁶

With exciting clinical efficacy data in an expanding number of settings, backed by an ever-growing body of academic research showing the impact of the microbiome on cancer treatment, 4D pharma and others look forward to new trials and further readouts in 2022—and, potentially, pivotal studies thereafter.

Immune-inflammatory diseases

At any one time, the majority of human immune cells are found in the gut. It is perhaps unsurprising, then, that the gut microbiome can downregulate as well as stimulate the immune system, and that microbiome drugs for inflammatory diseases are of interest. In 2021, some of the first clinical evidence of the systemic impacts of live biotherapeutics to treat inflammatory diseases away from the GI tract was produced.

Alongside much of the life sciences industry, many in the microbiome space considered how their therapies might help tackle COVID-19. Kaleido Biosciences reported positive results from its non-IND study¹⁷ of its prebiotic Microbiome Metabolic Therapy (MMT) KB109 in outpatients with COVID-19, showing reductions in healthcare utilization and recovery time in patients with one or more comorbidities. Evelo and 4D pharma also responded to the public health emergency by looking to repurpose our respective clinical-stage immunomodulatory single strains, EDP1815 and MRx-4DP0004, to reduce the hyperinflammatory response which leads to more severe COVID-19.

However, with the swift rollout of vaccines, both developers focused their efforts on the core programs for those candidates (a multiarm COVID-19 study including EDP1815 is ongoing). Evelo reported positive results from its Phase II study of EDP1815 for psoriasis, and the company plans to advance to registrational studies.¹⁸ Last December, 4D pharma announced the first positive clinical results for MRx-4DP0004 for the treatment of asthma in 34 patients and the expansion of its Phase I/II study.

The gut-brain axis

At the same time, there has been growing evidence and clinical activity in microbiome therapeutics for an expanding list of disease areas, including neuroscience. For example, Axial Therapeutics began a large Phase II study of AB-2004, the company’s gut-targeted, small-molecule drug for autism spectrum disorder (ASD)¹⁹; Finch and 4D pharma each also have LBP candidates in development for ASD, an “enriched consortium” and a single-strain LBP, respectively. We at 4D pharma also revealed plans to begin a first-in-human clinical trial in Parkinson’s patients in 2022. The microbiome-gut-brain axis is a hugely exciting area that will contribute significantly to continued innovation in the microbiome field over the coming years.

Big pharma and investor interest

Greater clinical activity and positive data in the field garnered increased interest from big pharma throughout 2021. At 4D pharma, this was evidenced through continued progress with our collaborations with Merck & Co in oncology and vaccines, and a new clinical collaboration in oncology with Merck KGaA and Pfizer.

In January, Pfizer invested $25 million in Vedanta Biosciences through its Breakthrough Growth Initiative to support a Phase II study of VE202, a defined bacterial consortium LBP, for IBD.²⁰ Johnson & Johnson had previously returned the rights to the program in 2020, before the Phase I results were announced.

Meanwhile, Roche signed two research collaboration for the development of novel engineered bacterial IBD treatments. The first was with Synlogic (in June),²¹ and the second was with Novome Biotechnologies (in November).²²

Investor interest is also on the rise. Last March, 4D pharma listed on NASDAQ, in addition to our existing UK listing, raising approximately $40 million in the process. France’s MaaT Pharma completed an initial public offering (IPO) in its home country in November 2021 to support its development of fecal material transplants for cancer-therapy-associated side effects, and Finch Therapeutics raised $128 million in its own NASDAQ IPO. Collectively, public and private microbiome drug developers raised in excess of $700 million during 2021.

In 2021, we made great strides as a field in proving the therapeutic proposition with robust clinical data, and in advancing new candidates into the clinic for an ever-widening range of diseases. And 2022? With a continued increase in mid-to-late-stage clinical activity across a number of therapeutic approaches, an upcoming expected first approval, and greater recognition by the wider life science sector of the microbiome’s potential beyond GI diseases, there are strong indications that 2022 will be an explosive year for the microbiome field.

Duncan Peyton is CEO of 4D pharma, and Charlie Badham is senior manager of corporate development at the company.

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