Summary Basis of Decision for Rebyota

Clinical Pharmacology

The exact mechanism of action of Rebyota has not been established. Defining a clear mechanism of action is challenging, as the action is believed to occur through multiple simultaneous pathways which can be directly mediated by interactions with the immune system, or indirectly mediated by gut microbiome modulation and production of active metabolites.

Rebyota is comprised of live microbiota and is not systemically absorbed. Consequently, no pharmacokinetic studies have been conducted.

In Study 1, treatment success was associated with increased bacteria from the Clostridia and Bacteroidia classes, and decreased bacteria from the Gammaproteobacteria and Bacilli classes. Fecal sequencing analysis showed that the microbiome composition in patients with treatment success was significantly shifted to more closely resemble the composition of Rebyota by one week following the study treatment. This shift continued through at least six months post treatment. These changes were significantly more extensive among patients responding to Rebyota treatment compared to placebo-treated responders.

For further details, please refer to the Product Monograph for Rebyota, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Rebyota was evaluated through a Bayesian analysis of data from Study 1 (NCT 03244644), a double-blind, placebo-controlled Phase III study, which formally integrated treatment success rates from Study 2 (NCT02299570), a placebo-controlled Phase II study. Both studies enrolled patients 18 years of age and older, with a confirmed diagnosis of recurrent Clostridioides difficile infection (CDI), or had at least two episodes of severe CDI resulting in hospitalization within the last year. Recurrent CDI was defined as diarrhea (passage of three or more loose stools within a 24-hour period for two consecutive days) and a positive stool test for C. difficile toxin or toxigenic C. difficile. Patients in Study 1 had one or more episodes of recurrent CDI, and patients in Study 2 had two or more episodes of recurrent CDI.

Patients enrolled in the study were required to have completed at least 10 consecutive days of antibiotic therapy and their CDI had to be under control (less than three unformed/loose stools [i.e., Bristol Stool Scale type 6-7] per day, for two consecutive days). An antibiotic washout period of 24 to 72 hours was required prior to the administration of the assigned study treatment in Study 1.

Patients enrolled in Study 1 were randomized 2:1 to receive either a single dose of Rebyota or placebo. Patients enrolled in Study 2 were randomized 1:1:1 to receive two doses of Rebyota, two doses of placebo, or one dose of Rebyota and one dose of placebo, administered 7 ± 2 days apart. Only the data from the Rebyota one-dose group and the placebo group from Study 2 were integrated with the efficacy data from Study 1, through a Bayesian hierarchical modelling approach.

In the integrated efficacy analysis set, the demographic profile and baseline recurrent CDI characteristics of treated adults were similar in the Rebyota and placebo groups. In Study 1, 32.8% of patients had one previous CDI and the remaining patients had two or more previous CDIs. In total, 262 patients were randomized and treated, with 177 patients receiving Rebyota and 85 patients receiving placebo. Patients had a mean age of 60.1 years and 45.4% of patients were 65 years and older. The majority of patients were White (92.0%) and female (69.1%). In Study 1, 87.4% of patients had received vancomycin alone prior to treatment.

In Study 2, 39 patients received one dose of Rebyota and one dose of placebo, and 43 patients received two doses of placebo. Patients in these two groups had a mean age of 59.8 years, and 42.7% of patients were 65 years and older. The majority of patients were White (97.6%) and female (63.4%). In this study, 89.0% of patients had received vancomycin prior to treatment.

Treatment success was defined as the absence of CDI diarrhea within eight weeks of blinded treatment. The results of the Bayesian analysis, which integrated the treatment success rate from Study 2, indicated a higher estimated rate of treatment success in the Rebyota group (70.6%) than in the placebo group (57.5%) through eight weeks after completing blinded treatment (difference of 13.1%; 95% credible interval: 2.3, 24.0). The posterior probability that Rebyota is superior to placebo was 99.1%.

Study 1 also evaluated sustained clinical response, which was defined as treatment success at 8 weeks and no CDI event through 6 months after the last dose during the blinded period. The sustained clinical response rates were 65.5% in the Rebyota group and 56.5% in the placebo group.

Indication

Sponsor's proposed indication	Health Canada-approved indication
Prevention of recurrence of Clostridioides difficile infection (CDI) in adults following antibiotic treatment for recurrent CDI.	Rebyota (fecal microbiota) is indicated for the prevention of recurrence of Clostridioides difficile infection (CDI) in adults following antibiotic treatment for recurrent CDI. Rebyota is not indicated for the treatment of CDI.

For more information, refer to the Product Monograph for Rebyota, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Rebyota was evaluated in Study 1 and Study 2 (both randomized, double-blind clinical studies, described in the Clinical Efficacy section), and in three open-label clinical studies (NCT01925417, NCT02589847, and NCT03931941). Altogether, these studies enrolled 978 patients, 595 of whom received a single dose of Rebyota. Patients had a history of one or more recurrences of CDI, and symptoms were controlled for 24 to 72 hours following antibiotic treatment.

In Study 1 and Study 2, 131 patients were originally randomized to receive placebo and 48 patients crossed over to receive an open-label dose of Rebyota after additional CDI recurrence. Across the five studies, the median age of patients was 64 years, 67.2% of patients were female, 93.8% were White, and 2.4% were of Hispanic or Latino ethnicity. There were no meaningful differences in demographic characteristics across the treatment groups.

Study 1 and Study 2 excluded individuals with celiac disease, inflammatory bowel disease, irritable bowel syndrome, and chronic diarrhea. Individuals with these conditions were not excluded from one of the open-label studies (NCT03931941), and individuals with food allergies were not excluded from any of the five clinical studies.

Across the five clinical studies, patients recorded solicited adverse events in a diary for the first seven days after each dose of Rebyota or placebo. Patients were monitored for all other adverse events by queries during scheduled visits, with duration of follow-up ranging from 6 to 24 months after the last dose.

In Study 1, 180 patients received a single dose of Rebyota and 87 patients received placebo. Patients with recurrent CDI during the first eight weeks after receipt of Rebyota or placebo were censored from analysis at the time of the recurrent CDI. During the first two weeks of the follow-up period, 34 Rebyota recipients (18.9%) and 24 placebo recipients (27.6%) were censored from analysis. Overall, during the eight-week follow-up period, 47 Rebyota recipients (26.1%) and 30 placebo recipients (34.5%) were censored from analysis.

The most common adverse reactions in Study 1, reported by 3% or more of Rebyota recipients and at a rate greater than that reported by placebo recipients, were abdominal pain, (8.9%), diarrhea (7.2%), abdominal distention (3.9%), flatulence (3.3%), and nausea (3.3%). Adverse reactions were defined as adverse events assessed by the investigator as definitely, possibly, or probably related to the investigational product.

Most of the adverse reactions were reported during the first two weeks following treatment, whereas the proportion of patients with adverse reactions declined in the subsequent two-week intervals. Beyond the first two weeks following treatment, only a few single adverse reactions were reported. Most adverse drug reactions were mild to moderate in severity. No life-threatening adverse reactions were reported. In a pooled analysis of the five clinical studies, 60 of 595 Rebyota recipients (10.1%; one dose only) and 6 of 83 placebo recipients (7.2%) reported a serious adverse event within six months of the last dose of the investigational product. None of these events were considered related to the investigational product.

For more information, refer to the Product Monograph for Rebyota, approved by Health Canada and available through the Drug Product Database.

Rebyota is a microbiota suspension consisting of human fecal material from qualified donors containing viable fecal microbes suspended in a solution of polyethylene glycol 3350 and 0.9% saline.

No non-clinical studies were conducted in the product development program for Rebyota, which was justified due to multiple factors. Standard pharmacokinetic and toxicology studies compliant with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines are not considered necessary, as human stool transplants are not absorbed into the body. Additionally, there are no standardized and validated models where host-microbiome interactions can be accurately simulated. Animal models to study Clostridioides difficile infection (CDI) recurrence in the presence of a human-derived microbiota are inadequate and are not considered to provide translational data that would add to the efficacy and safety assessment in humans. Due to the unique nature of the drug substance, the known properties of the excipients, and the lack of animal models for recurring CDI, the rationale for not conducting non-clinical studies is considered acceptable. Overall, the submission relied on a substantial amount of clinical data to support efficacy and safety in humans, with a focus on the extensive pathogen screening of donors and donations.

Considering the intended use of Rebyota, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Product Monograph for Rebyota, approved by Health Canada and available through the Drug Product Database.

Characterization of the Drug Substance

Rebyota is a fecal microbiota therapy (FMT) for the prevention of recurrent Clostridioides difficile infection (CDI). The drug product is manufactured from donor human stool (DHS) collected from qualified donors. The DHS and donors undergo a rigorous screening and testing process to ensure that the product is free from adventitious agents. The DHS is resuspended into a microbial slurry in 0.9% saline/polyethylene glycol 3350 solution, which acts as a cryoprotectant to support microbial viability.

Manufacturing Process of the Drug Substance and Drug Product and Process Controls

The drug substance manufacturing process involves the collection, inspection, and testing of DHS and preparation of the polyethylene glycol/saline solution, followed by formulation, mixing, and filtration. The drug substance is then immediately processed to produce the drug product. Each DHS is processed into one drug substance lot, and DHS batches are never pooled to manufacture a drug substance lot. The drug substance does not undergo release testing.

The drug product manufacturing process begins with sampling of the drug substance for quality testing, followed by filling of the drug substance into an ethylene vinyl acetate (EVA) bag equipped with a spike port and a fill port. The bag is then sealed and inspected. The drug product is stored at -60 °C to -90 °C. Upon successful completion of the quality testing, the drug product is labelled, placed into the secondary packaging, and returned to -60 °C to -90 °C for long-term storage.

Rebyota is manufactured in a facility compliant with current good manufacturing practices (cGMP). The drug substance and drug product manufacturing processes, including donor screening, process parameters, in-process controls, critical quality attributes, analytical methods, and specifications were set based on overall experience from product development and knowledge gained in the field of FMT. Analytical methods were validated or verified appropriately. The specifications were supported by the quality attributes of the materials shown to be safe and efficacious in clinical studies. The available batch analysis and stability data demonstrate the ability of the commercial manufacturing process to produce drug product lots of consistent quality.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations. The compatibility of the fecal microbiota with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

Consistency testing was not performed on Rebyota for several reasons. Rebyota is manufactured from DHS collected from different donors. As each batch is unique to the donor and significantly different between donors, consistency testing would have limited value. Additionally, FMT material is microbiologically diverse and due to the complexities of characterizing such an ecosystem, testing is limited to standard microbiological techniques. These include testing to verify that the FMT material meets the minimum specifications of very general microbiological parameters, such as the total number of colony-forming units (CFU), microbial diversity, or the percentages of Bacteroidetes. Although the quality control release testing is based on these parameters, they have not been identified as important factors for the therapeutic effect of FMT material and are measures believed to be more common among healthy individuals.

The most important parameter contributing to the consistency and quality of the FMT material is the health status of the donor, which is strictly monitored at the time of donation. This is expected to provide more assurance of the consistency and quality of the FMT material than the consistency testing methods typically used for other biologic drug products.

Rebyota is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs. For post‑approval monitoring, Rebyota has been assigned to Lot Release Evaluation Group 4. The sponsor is required to notify Health Canada when a lot is to be sold in Canada. A Release Letter is not required prior to sale. At the discretion of Health Canada, products in Evaluation Group 4 may also be subjected to periodic testing. The risk level associated with a drug product is determined by factors including the nature of the product, its indication and target patient population, and the manufacturer's production and inspection history.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 36-month shelf life at -60 °C to -90 °C for Rebyota is considered acceptable.

Facilities and Equipment

An on-site evaluation (OSE) was not recommended for Rebyota, following a risk assessment conducted by Health Canada and the consideration of several mitigating factors. The manufacturing facility has a history of cGMP compliance, and had recently been inspected by the United States Food and Drug Administration (FDA) with a satisfactory outcome. Additionally, the manufacturing process is straightforward, with no intermediates and with few processing steps, which minimizes the risk of errors.

The final product is a microbiota suspension and is not sterile by nature. However, the raw material is extensively tested for pathogens and donors undergo stringent and continuous screening and testing to ensure their suitability. Collectively, the information in the submission provided sufficient assurance that the process and conditions of manufacture are suitable, and that the drug product will not be unsafe for use as required by the Food and Drugs Act.

Adventitious Agents Safety Evaluation

The manufacturing process of Rebyota has no capacity for viral clearance. Instead, the donors and starting materials (the DHS) undergo extensive screening and testing to minimize potential contamination of the drug product with infectious pathogens. Qualified donors undergo an initial qualification comprised of the donor qualification questionnaire and testing of the blood and DHS. The suitability of the donor and DHS is monitored on an ongoing basis. Suitability is assessed by completion of a donation questionnaire at every donation, pathogen testing of every DHS, and periodic testing of the donor blood. The sponsor provided reasonable justifications for the inclusion or exclusion of certain pathogens in the testing, based on prevalence of infection and route of transmission. The donor and DHS screening strategy is considered sufficient for the control of adventitious agents.