From The Editor | August 14, 2019

Rebiotix Works With Regulators To Define A New Clinical Pathway

Ed Miseta

By Ed Miseta, Chief Editor, Clinical Leader
Follow Me On Twitter @EdClinical

regulations compliance (002)

Rebiotix, a Ferring company, hopes to revolutionize the treatment of debilitating diseases by harnessing the power of the human microbiome. Your microbiome is the trillions of bacteria living on and within you. It is also necessary for a healthy life and plays a huge role in an individual’s intestines and digestive health. Researchers have found that restoration of a healthy gut microbiota is also necessary for the effective treatment of disease. This is the area where Rebiotix is focused.

The company is developing their proprietary MRT drug platform, which uses a defined manufacturing process and quality control parameters to assess the impact of human-derived microbiota therapies on patient health and disease. The platform uses live microbiota as a therapy to replace or replenish disrupted microbial communities.

The lead investigational MRT drug formulation, RBX2660, is currently recruiting a Phase 3 clinical trial for the prevention of recurrent Clostridioides (Clostridium) difficile (C. diff) infection. C. diff is responsible for nearly 30,000 deaths in the U.S. every year. Even when successfully treated, C. diff will re-occur in roughly 20 percent of patients, impacting their quality of life.

The clinical trials for RBX2660 are being conducted under the FDA’s Investigational New Drug (IND) application. Rebiotix was the first microbiome company to engage the FDA in defining a regulatory pathway for microbiota-based therapies and believes regulation of these therapies is imperative for patient safety and efficacy. It has also been granted FDA Fast Track status, as well as Orphan Drug and Breakthrough Therapy designations.

Human But Not Human

Lee Jones
Human cell donations are taken from healthy donors, from which it extracts and develops formulations of live microbes. The live microbes may be used to replenish or replace a disrupted microbial community. This is a new area of medicine supported by an ever-growing body of data connecting the importance of human microbiota to the maintenance of health. 

“What is unusual about this is there are no other products that use human derived microbes currently on the market,” says Lee Jones, the founder, president and CEO of Rebiotix who started the company in 2011. “There were only antibiotic therapies available for this disease and they were not very effective. By bringing in a whole new class of drugs, we believe that we can solve a tremendous unmet medical need and finally bring some relief to this patient population.”

Jones does not come from a drug development background. When approaching the FDA for the IND application, she felt the regulator would treat the microbiome product like a tissue transplant, organ transplant, or blood infusion. Upon further evaluation by the FDA, the decision that this strategy would not take hold resulted in defining a new pathway.

The first step of the journey involved writing a letter to the FDA that discussed the product and included relevant background information. The letter explained why the company felt the therapy should be regulated as a tissue transplant. A committee reviewed the information and responded to the company stating that they disagreed with the assessment. They explained that the best route for the product would be through the Center for Biologics Evaluation and Research (CBER) in the vaccine division.

RBX2660 involves collecting donor stool material from humans who possess healthy digestive tracts. Fecal material contains a vast number of organisms that aid with the digestion of food. It also grows in humans. Still, it’s those organisms the FDA determined were not human in origin. They cannot be classified as either a human tissue or a human organ. That is the reason the FDA transferred the treatment over to CBER.

“These organisms did not meet the FDA’s criteria for a human tissue transplant,” says Jones. “This was actually a new category of treatment. As a result, neither the FDA nor Rebiotix had an established pathway to follow. This created an interesting journey that we would undertake with the FDA, since no clinical studies had been conducted in this arena before. There were many new things we had to invent along the way.”

Establish A New Pathway

After being transferred to CBER, Rebiotix began working with the agency to develop and define a new regulatory pathway for the product that encompassed pathogen safety concerns. This involved regular interactions with the Agency, sometimes meeting monthly or even weekly to ensure the safety components were assessed.  The communications involved a mix of phone calls, emails, and face-to-face meetings to provide as much data oversight as possible.

“They have been incredibly helpful by keeping the focus on the science and patient safety,” says Jones. “We submitted our first IND in 2013. They reviewed it and provided us with very helpful feedback. Part of our challenge is that we had to test the human donors for disease. If someone donates blood for transfusions, those donors must be tested for HIV and Hep C. That is to prevent diseases from getting into patients receiving the blood. For our products, we must do something similar, but the requirements were (and in some cases, remain) not fully defined. Since we are using human stool as the raw material for our product, we similarly need to ensure we do not transfer any diseases into our patients.” Jones went on to mention that through regulatory guidance and expert input, Rebiotix has built a program that not only screens for potential pathogens, but also has the ability to evolve if new concerns arise.

Rebiotix and CBER worked together to define a donor screening and testing panel that is now performed on every single donor and every stool provided to Rebiotix. The company and agency also worked together to define how the products would be regulated and define the testing methods for the donors and RBX2660.

Jones notes Rebiotix made the decision early on to not use a CRO, as is common for many sponsor companies. “Our product was so new we simply did not know what to expect,” she says. “For that reason, we hired our own clinical employees to work with the sites and physicians. That has been a benefit for our company. Being a start-up in a new field, we were able to get immediate feedback if a question on the therapy or a safety issue arose.”

A Working Partnership

In working with the FDA and CBER, Jones states she did not feel like she was being micro-managed by the agency. In fact, she notes the FDA cannot, and will not, tell companies what they need to do, but rather focuses on the quality of the information that sponsor companies provide to the Agency. That is because they work with other companies, including competitors in the microbiome space, that are also submitting INDs. Each company may present novel approaches to addressing drug requirements which ensures a fair assessment for each sponsor company’s technology. The agency will simply inform you of whether your idea will meet their requirements, and occasionally offer suggestions.   

“In that respect, they have been cooperative and very much a partner,” states Jones. “Through this entire journey, they have been quick to respond to questions. They could not tell us what we should and shouldn’t do. That is something we had to figure out on our own. Still, when we had meetings with them to discuss our pathway proposals, they had many individuals take part, including folks with chemical, clinical, and statistical expertise. There were times when they had 20 people on the discussion with us. Since we worked with the same people over those six years, we developed a very good personal and working relationship with them. I fully expected the FDA to be far more standoffish and the discussions to be more difficult and with more limitations to what we could discuss. I was very pleased to find they were just the opposite.” In fact, Jones found that the FDA made patient safety the focus throughout their discussions.

For small companies that are about to undergo a similar journey, Jones recommends seeking help for some of the heavy lifting you cannot perform yourself. Being a small company prior to joining forces with Ferring Pharmaceuticals in 2018, Jones shares that a small staff supported a lot of the groundwork, and she relied heavily on consultant and contractor help to provide the expertise needed at an affordable price. Since 2018, the Ferring acquisition of Rebiotix has provided the opportunity to combine leadership efforts to continue to drive innovation and make a lasting impact with microbiota-based technologies.

Finally, Jones recommends that company leaders remain mindful of the skills and experience possessed by the regulators you work with. “One of our regulatory contractors kept reminding me of something over and over again,” adds Jones. “The FDA has many skilled scientists on their staff. Those scientists possess a lot of knowledge that you may not be aware of. When they ask you a question about something, you really need to pay attention to what the intention of the question is. Think about what they asked and what that might mean. You may not always be thinking about things the same way but understanding what the other side is thinking can help the relationship with the FDA, as well as your product, move forward. The FDA has seen and done more than any individual company could ever hope to do. Always try to look at them as a partner and a source of information, not an adversary.”

Rebiotix has conducted three Phase 2 trials and is now recruiting for its first Phase 3 trial for RBX2660. The trial consists of a one-time treatment with the primary efficacy endpoint measured at eight weeks. Some patients in the Phase 2 trials were followed for as long as two years to ensure there were no significant changes in health over time.