Ri-CoDIFy

Phase 3 clinical program*

Targeting C. difficile with the aim to sustain cures for patients

CDI (C. difficile Infection)

Clostridium difficile (sometimes called Clostridioides difficile), or C. difficile, is a type of bacteria (germ) that produces toxins which can cause infections of the colon. CDI is a common infection characterized by severe diarrhea; there are over one million cases of CDI each year in the US and Europe.

CDI can result in serious disease complications, including bowel perforation, toxic megacolon and sepsis, and in the most serious cases, CDI can be fatal.

Many patients who become sick from CDI do so in the hospital; however, it is becoming more common to get CDI in one’s community. Risk factors for getting CDI include current or recent antibiotic use, length of hospital stay and being over 65 years old. Patients who get CDI have a 25% chance that it will come back for a second time, which is called recurrent CDI. Recurrent CDI is the main challenge in treating CDI.

CDI symptoms include:

Watery diarrhea

(at least three bowel movements per day for two or more days)
Fever
Loss of appetite
Nausea
Abdominal pain/tenderness

The Role of the Gut Microbiome in CDI

One of the main protectors against CDI is the gut microbiome. A healthy gut microbiome is made up of many different bacteria that perform different functions to maintain health, most of which are not yet fully understood. When the diversity of the protective gut microbiome changes, it leaves the gut vulnerable to CDI.

Researchers believe bacteria play two different roles in protecting against CDI

Bacteria compete for food and nutrients within the gut.

By having a diverse and large quantity of bacteria in the gut, each type of bacteria occupies a particular space and uses up available food and nutrients, leaving no room for the intruding bacteria to grow.

Bacteria promote an environment that is unsuitable for C. difficile to grow.

A full complement of healthy and protective gut bacteria is essential to prevent CDI. Many things can change the diversity of a gut microbiome, but the onset of CDI is most often linked to taking a course of broad-spectrum antibiotics. Patients who get CDI have typically taken broad-spectrum antibiotics for unrelated bacterial infections or to prevent infections after surgeries or dental procedures prior to getting CDI. Broad-spectrum antibiotics can kill many different types of bacteria, including ones that can make you sick and ones that make up a healthy gut microbiome.

Current Treatments for CDI

In clinical practice, most patients receive a broad-spectrum antibiotic with activity against C. difficile to treat an initial episode of CDI, and it is considered the standard of care. Broad-spectrum antibiotics may cause further damage to the gut microbiome and are associated with high rates of recurrent CDI. As mentioned above, reducing disease recurrence is the key challenge in CDI, as repeat episodes are typically more severe and associated with increased mortality rates and healthcare costs. In addition, with each recurrence, there is a higher risk of CDI returning again.

25% CDI recurs in approximately one in four patients.
>1 million cases per year in the US and Europe

Ridinilazole, an Investigational Antibiotic for CDI

Ridinilazole is a new investigational antibiotic being studied, but not yet approved, for the treatment of CDI. Ridinilazole is highly specific for C. difficile.

A Phase 2 clinical trial called CoDIFy showed ridinilazole treated CDI as well as vancomycin and had lower rates of CDI recurrence compared to vancomycin. The primary endpoint, the trial’s main measure of success, was sustained clinical response (‘SCR’). In this trial, SCR meant a patient was free from disease after ten days of treatment and remained free from disease for 30 days after treatment ended.

Ridinilazole was well tolerated, with an adverse event profile similar to that of vancomycin. Of all participants, 82% in the ridinilazole group and 80% in the vancomycin group reported treatment-emergent adverse events, the most common (≥ 10% of patients) of which for ridinilazole were nausea, abdominal pain, abdominal distension, vomiting and decreased appetite and for vancomycin were abdominal pain, nausea, abdominal distension, vomiting, diarrhoea, nasopharyngitis, headache and dizziness.

The results from these clinical trials led us to design two randomized, double-blind Phase 3 clinical trials, called Ri-CoDIFy 1 and Ri-CoDIFy 2.

SCR

Ridinilazole 66.7%
Vancomycin 42.4%

Cure at End of Treatment

Ridinilazole 77.8%
Vancomycin 69.7%

Recurrence 30 Days Post Treatment

Ridinilazole 14.3%
Vancomycin 34.8%

SCR
90% CI: 3.1, 39.1
Cure Rates
90% CI: -9.3, 25.8
Recurrence Rates
90% CI: -35.5, 3.0

SCR is defined as the percentage of patients who were cured after the end of treatment (days 12-14), defined as ≤3 unformed bowel movements in 24 hours or <200ml of unformed stool in rectal collection devices, and did not have a recurrence in the 30 days following treatment. The graph also shows the percentage of patients cured and the percentage of patients who had a subsequent episode of CDI between days 10-40 in a Phase 2 clinical trial.

Clinical Trials

Clinical trials are a part of a carefully planned and legally required process to move from the identification of a potential new drug in the laboratory to making it available on the market. Clinical trials mark the beginning of testing a product candidate in humans and are only conducted after undertaking appropriate experiments in the laboratory to determine whether such a candidate is suitable for testing in humans for the disease being studied. There are several steps to the clinical trial process, called “phases.” Each phase is designed to answer specific questions that help the researchers decide whether or not the product candidate should continue in development.

Phase 1

Phase 1 is the first step, and the primary goal of this phase is to determine the safety of the product candidate being tested. Phase 1 is usually conducted in a small group of healthy volunteers but can also include patients with the disease for which the product candidate is being tested.

Phase 2

If Phase 1 trials are successful, the product candidate moves to Phase 2. Phase 2 trials are designed to evaluate the efficacy of a product candidate in the patients with the disease for which the product candidate is being tested. In addition, the Phase 2 trial will continue to assess the safety of the product candidate. These trials are often slightly larger than Phase 1 trials.

Phase 3

If the Phase 2 trials are successful, the product candidate moves to Phase 3. The objective of Phase 3 is to confirm the efficacy and safety findings of Phase 2 in an even larger group of patients with the disease for which the product candidate is being tested. If there is a standard of care treatment for the disease being studied, the new product candidate will often be compared to the efficacy and safety of that standard of care treatment. Regulatory agencies use the findings from all of these phases to decide whether the product candidate should be approved for use in a specific disease indication outside of clinical trials.

Ri-CoDIFy Clinical Trials

Ri-CoDIFy 1 and Ri-CoDIFy 2 are global, Phase 3 clinical trials designed to test how well ridinilazole works in CDI compared to vancomycin. A positive Phase 3 outcome has the potential to support the regulatory approval of ridinilazole and may allow it to be used to treat the first episode of CDI and reduce CDI recurrence.

Both clinical trials are testing for SCR as the primary endpoint, or main measure of success. Just as in the Phase 2 clinical trial, SCR means a patient is free from disease after ten days of treatment and remains free from disease for 30 days after treatment ends.

The Phase 3 clinical trials will also measure the safety and tolerability of ridinilazole, as well as various health economics and outcomes research measures, including hospital readmission rates, lengths of hospital stays, and patient-reported outcomes.

Am I eligible for these trials?

Patients must be 18 years of age or older
Patients must have signs and symptoms of CDI, including diarrhea, in the 24 hours prior to entry into one of the trials and a positive toxin test on a stool sample produced within 72 hours of entry into the trial
Patients cannot have had more than one prior episode of CDI in the previous three months or more than three episodes in the past 12 months
Patients cannot have had more than 24 hours of CDI antibiotic treatment prior to entry into one of the trials
There are additional entry criteria and considerations; the study doctors will ultimately decide whether a patient is eligible for entry into one of the clinical trials and the patient will be required to give consent

What can I expect from these trials?

Each trial is expected to enroll up to 680 patients
Patients will be randomized to receive either ridinilazole or vancomycin, and neither the patients nor the study doctors will know which drug they receive
Participation will involve about seven study visits over approximately 100 days to track the safety and effectiveness of each drug
Patients or their caregivers will be asked to complete an electronic diary each day they are enrolled in the trial to help the study doctors monitor their patients’ progress
Patients who participate receive free trial-related CDI medical care and medication and may be reimbursed for travel expenses associated with trial site visits

For further detail about the clinical trials, please visit:
‍
https://clinicaltrials.gov/ct2/show/NCT03595553
‍
https://clinicaltrials.gov/ct2/show/NCT03595566

The Phase 3 clinical and regulatory development of ridinilazole is being funded in part with federal funds from the US Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority (‘BARDA’), under Contract No. HHS0100201700014C.

Clinical Trial Locations

Locations that are currently enrolling patients into Ri-CoDIFy 1 and 2:

Faqs

How does ridinilazole work?

In studies done in a scientific laboratory, ridinilazole killed C. difficile by stopping the bacteria from reproducing. Ridinilazole is highly specific for C. difficile.

How many clinical trials of ridinilazole have you completed and what have you found in these trials?

Ridinilazole has been tested in one Phase 1 clinical trial and two Phase 2 clinical trials.

Our Phase 1 clinical trial was conducted in 56 healthy male volunteers. In this study ridinilazole was well-tolerated, retained in the gastrointestinal tract (the site of CDI) and selective for Clostridia family bacteria with minimal impact on other gut bacteria.

Our Phase 2 clinical trial called CoDIFy enrolled 100 patients, half of which received vancomycin and the other half of which received ridinilazole. This study showed that 66.7% of patients treated with ridinilazole had a sustained clinical response compared to 42.4% of patients treated with vancomycin. A sustained clinical response means that patients were cured after the end of treatment (days 12-14), defined as ≤3 unformed bowel movements in 24 hours or <200ml of unformed stool in rectal collection devices, and did not have a recurrence in the 30 days following treatment. Sustained clinical response was the primary endpoint, or main measure of success. Ridinilazole was shown to be statistically superior to vancomycin in this measure. The difference between ridinilazole-treated patients and vancomycin-treated patients was driven by a reduction in recurrence rate – 14.3% of patients on ridinilazole had a recurrence, whereas 34.8% of patients on vancomycin had a recurrence. Ridinilazole was well tolerated, with an adverse event profile similar to that of vancomycin. Of all participants, 82% in the ridinilazole group and 80% in the vancomycin group reported treatment-emergent adverse events, the most common ((≥ 10% of patients) of which for ridinilazole were nausea, abdominal pain, abdominal distension, vomiting and decreased appetite and for vancomycin were abdominal pain, nausea, abdominal distension, vomiting, diarrhea, nasopharyngitis, headache and dizziness.

A second exploratory Phase 2 clinical trial was conducted in 27 patients, in that trial, ridinilazole was found to be well-tolerated.

At what stage of development is ridinilazole?

Ridinilazole is being tested in two global Phase 3 clinical trials.

Where are the clinical trials taking place?

Sites are currently active in North America, Australia, Asia, Europe and South America. Please see the maps above for further information.

Why should I consider taking part in a clinical trial?

While no personal benefit can ever be guaranteed by participation in a clinical trial, there are other potential benefits, including allowing you to play an active role in your healthcare and helping others by contributing to the better understanding of CDI.

How can I get involved in Ri-CoDIFy 1 and 2?

You can contact one of the actively enrolling sites to inquire about participating in the trials. The study doctors will review inclusion and exclusion criteria with you to help decide whether you would be eligible for the trials.

Where can I find more information about your clinical trials?

You can find more information at https://clinicaltrials.gov/ct2/show/NCT03595553 and https://clinicaltrials.gov/ct2/show/NCT03595566, or by signing up for our email list below

When will ridinilazole be available on the market?

If the Phase 3 clinical trial results are positive, we expect to file for regulatory approval in the US in 2022. Timing to market would be dependent upon regulatory review. Ridinilazole does have the potential to receive priority review with the US Food and Drug Administration, which shortens the review time to six months. However, this is not guaranteed.

Is it possible to get access to ridinilazole under compassionate use?

Running clinical trials that can support regulatory approvals is the best way to ultimately ensure wide access for patients to our drug candidates. All of our efforts are therefore focused on conducting rigorous clinical trials to establish the safety and potential clinical benefits ridinilazole may have. At this point in the development, we cannot support any use of ridinilazole, or any of our product candidates, outside of our clinical trials.

Ri-CoDIFy

Phase 3 clinical program*

CDI (C. difficile Infection)

CDI symptoms include:

Watery diarrhea

Fever

Loss of appetite

Nausea

Abdominal pain/tenderness