Welcome to the market, FMT

On Wednesday 30 November 2022, the U.S. Food and Drug Administration (FDA) authorised the first microbiome-based drug to go onto the US market. Initially developed by Rebiotix Inc. (part of the Ferring Pharmaceuticals Group), Reybota offers a much-needed biotherapy for reducing the recurrence of Clostridioides difficile infection after antibiotic treatment. This news closely follows the approval by the Australian Therapeutic Goods Administration (TGA), on 09 November 2022, for BiomeBank to market a similar product in Australia.

Reybota (also termed ‘RBX2660’) is a type of faecal microbiota transplant (FMT), which contains a mixed consortia of beneficial bacteria from stool samples of healthy donors. These “good bacteria” suppress damaging C. difficile populations in the gut, to help restore a healthy gut microbiome and break the vicious cycle of recurring infection. This is the theory behind Ferring’s Microbiota Restoration Therapy (MRT^TM) platform, which aims to capture the power of the microbiome in an off-the-shelf product.

What is C. difficile infection (CDI) and why treat it with FMT?

C. difficile is a highly infectious gut bacterium responsible for causing serious illness, usually manifesting in recurrent episodes of debilitating and potentially life-threatening diarrhoea. CDI is estimated to cause ~20-30% of antibiotic-associated diarrhoea in the UK¹. Antibiotics deplete both the “good” and “bad” bacteria from the gut, making space for damaging strains of C. difficile to populate.

CDI is the most common healthcare-associated infection, presenting an “urgent” threat to antibiotic resistance with an estimated attributable cost in the US of $1 billion in 2017². In the UK, ~25% of patients experience recurrent infections after initial antibiotic treatment³.

Conventional treatments for CDI involve further rounds of antibiotics, but this approach weakens the broader gut microbiome and leaves the patient vulnerable to further rounds of CDI. Alternative treatment options are desperately needed. Despite NICE not currently recommending it, FMT can be considered for patients who have experienced more than two recurring CDI episodes and for whom surgery is not feasible³.

Enter Rebyota: the FDA approves

Several clinical trials, including two Phase 3 trials, which examined efficacy in a large clinical cohort (n=978 subjects), suggest that a single dose of Rebyota prevents recurrent CDI at 8 weeks in 70.4% of subjects, a significantly better response than placebo⁴. Rebyota is administered via enema by a one-time dose.

While the FDA concluded that FDA criteria for efficacy had not been met in the broader sense, considering the lack of alternatives for patients and the healthcare burden of recurring CDI, the efficacy, in combination with its safety profile, was sufficient to gain a positive recommendation from the FDA’s Vaccines and Related Biological Products Advisory Committee on September 22 of this year. The Advisory Committee is an independent panel, including scientific experts and at least one patient representative, which, at the request of the FDA review division provides scientific and medical advice regarding a product or treatment in question. While the Advisory Committee’s role is just that – advisory - in this instance, the committee’s positive recommendation led directly to the⁵ recent approval of Rebiotix’s Biologics License Application (BLA) and subsequent market entry.

Helping out the competition

Although Rebyota is the first to achieve FDA approval, BiomeBank had beaten it to become the first microbiome-based drug to gain marketing approval in a major jurisdiction. The TGA approved BiomeBank’s frozen CDI treatment for colonic and enema administration just weeks before the FDA’s approval of Rebyota¹⁰. These successes may well accelerate the approval of similar therapies and boost confidence in the biotherapy industry as a whole. Hot on Ferring’s heels are Seres Therapeutics and Finch Therapeutics, both offering alternative microbiome-based treatments that are currently in Phase 3 trials.

Seres Therapeutics has been making headlines for some years, most notably for forming a co-commercialisation agreement in the US and Canada with Nestlé Health Science, securing a $175m investment with an additional $125m earmarked upon FDA approval for their lead product, SER-109⁶. On 26 October 2022, the FDA granted 'Priority Review' status on the Biological Licence Application for SER-109, with a decision on approval from the regulatory agency expected April 2023. SER-109 is an oral therapeutic containing live, purified spores produced by Firmicutes, originally isolated from healthy donors. Recent Phase 3 results showed that recurrence of CDI was prevented in 88% of patients, compared to 60% in the placebo group 8 weeks post-treatment⁷, a result that appears to indicate a higher efficacy than Rebyota demonstrated in its Phase 3 studies.

The oral route of SER-109 administration also represents an advantage over Rebyota, which is administered by enema. Already alive to this drawback, Ferring have completed Phase 1 trials for RVX7455, an oral capsule alternative.

Finch Therapeutics is another company that is developing FMT-related products for a variety of diseases, including those not typically associated with the gut, such as Autism Spectrum Disorder and Chronic Hepatitis B. Finch have received Fast Track and Breakthrough Therapy designations by the FDA for prevention of recurrent CDI with their product; a single dose, oral capsule-containing complete bacterial consortia, CP101. However, the trials for CP101 are currently on clinical hold.

Controversy

Despite dramatic improvements in extensive screening, purification and inactivation of material with pathogenic potential, FMT continues to raise eyebrows amongst healthcare professionals, regulators and the public. Six incidences of serious infection following FMT therapy reported by the FDA in 2020 raised understandable doubts about the safety profile of this type of treatment. Alternatives offered by Destiny Pharma (NTCM-M3) and Vedanta (VE303)⁹ contain defined microbial species from clonally isolated bacteria, rather than relying on those from human donors. Such options avoid the human donor aspect, potentially being less controversial if safety concerns surrounding stool screening and scale-up are removed.

Regarding Rebyota, Ferring claims that the manufacturing and testing processes involved in its MRT platform differ from more traditional methods of faecal transplantation, reducing the risk of infection.

What does FDA approval mean for Europe?

In our blog Regulatory challenges for microbiome therapeutics in the EU and beyond – focus on FMT, we explored the divergent regulatory approaches taken by different jurisdictions that further complicate the commercialisation of FMT. In Europe, some EU Member states consider FMT to be a medicinal product, others say it falls in the Tissue and Cells category, whilst others fail to classify it at all. Many are hopeful that the recent FDA approval for Reybota and the Australian approval for BiomeBank should give Europe the confidence and ambition it needs to push for a more centralised, consistent procedure. Indeed, commercialisation for Ferring’s product will certainly be turning the heads of investors, and with the global microbiome therapeutic market estimated to be worth $3.2 billion by 2032, Europe cannot afford to be left behind.

References

1. NICE (2021). Diarrhoea – antibiotic associated. https://cks.nice.org.uk/topics/diarrhoea-antibiotic-associated/
2. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention (2019). Antibiotic Resistance Threats Report, Clostridioides Difficile. https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf
3. U.K. Health Security Agency (2022). Clostridioides difficile infection: updated guidance on management and treatment. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1097425/UKHSA-CDI-guideline-july-2022_DRAFT.pdf
4. Rebiotix (2021) Ferring and Rebiotix Present Landmark Phase 3 Data Demonstrating Superior Efficacy of Investigational RBX2660 Versus Placebo to Reduce Recurrence of C. difficile Infection. https://www.rebiotix.com/efficacy-rbx2660-vs-placebo-reduce-recurrence-c-difficile-infection/
5. Campbell, K. (2022) A microbiome therapeutic is closer than ever to market authorization in the US. What does it mean for the industry? Microbiome Times. https://www.microbiometimes.com/a-microbiome-therapeutic-is-closer-than-ever-to-market-authorization-in-the-us-what-does-it-mean-for-the-industry/
6. Pharmaceutical Technology (2021) Seres and Nestlé enter up to $525m deal for microbiome therapeutic. https://www.pharmaceutical-technology.com/news/seres-nestle-microbiome-therapeutic/
7. Feuetstadt, P., Louie, T. J., Lashner, B., Wang, E. E. L., et al. (2022) SER-109, an Oral Microbiome Therapy for Recurrent Clostridioides difficile Infection. The New England Journal of Medicine. https://www.nejm.org/doi/full/10.1056/NEJMoa2106516
8. Food and Drug Administration (2020) Fecal Microbiota for Transplantation: Safety Alert - Risk of Serious Adverse Events Likely Due to Transmission of Pathogenic Organisms.
9. Brown, A. (2022) The year the regulators meet the microbiome. Evaluate Vantage. https://www.evaluate.com/vantage/articles/analysis/spotlight/year-regulators-meet-microbiome
10. BusinessWire “BiomeBank Announces World First Regulatory Approval for Donor Derived Microbiome Drug” https://www.businesswire.com/news/home/20221108006340/en/BiomeBank-Announces-World-First-Regulatory-Approval-for-Donor-Derived-Microbiome-Drug

About the authors

This article was written by Eliot Ward and Alice Jefferies, in collaboration with Mark FitzGerald of Nixon Peabody.

Alice Jefferies

Alice is a trainee patent attorney working in the Life Sciences sector. She has industrial experience, which was gained at a drug delivery start-up, and more recently has experience working in collaborative academic research at the Francis Crick Institute. Alice has a BSc in Biochemistry and a MSc in Immunology from Imperial College London. Her undergraduate research project focused on the use of potassium channel blockers as therapeutics for inflammatory diseases. During her Masters, Alice carried out a project investigating the impact of immunotherapy on the haematopoietic stem cell niche in Acute Myeloid Leukaemia.

Email: alice.jefferies@mewburn.com