Finch Therapeutics is developing microbial therapies designed to alter the microbiome for treatment of patients suffering from diseases as varied as bacterial infections and autism.

In 2019, the company received a Breakthrough Therapy designation from the US Food and Drug Administration (FDA) for its microbial therapy CP101, a treatment for recurrent Clostridium difficile (C. difficile) infections (CDI), which can cause extreme diarrhea and life-threating inflammation of the colon.

CP101 is the lead drug candidate derived from a technology platform designed to explore the microbiome, the community of micro-organisms that exists throughout the human body, particularly in the gastrointestinal tract. Imbalances and disruptions of the microbiome are linked to a wide variety of diseases.

Finch CEO Mark Smith, Ph.D., said C. difficile infections are usually treated with antibiotics, “which often disrupt the balance of the gut microbiome, leaving patients susceptible to additional CDI episodes.”

A 2017 clinical trial showed CP101 prevented recurrence of CDI in 88 percent of the 49 patients enrolled, earning the drug its breakthrough designation. A Phase 2 trial of CP101 is underway and, if successful, could serve as a pivotal study expediting FDA approval.

As part of an exclusive series spotlighting the insider perspectives of thought leaders on topics shaping the future of new medicines, WuXi AppTec Communications spoke with Smith about the company’s new CDI therapy, the impact of the FDA’s Breakthrough Therapy designation and the role of the human microbiome in diseases.

Smith co-founded Finch to develop the next generation of microbiome-based therapies. He earned his Ph.D. in microbiology from Massachusetts Institute of Technology and his B.A. in biology from Princeton University.  

WuXi: How did CP101 qualify for Breakthrough Therapy designation?

Mark Smith: CP101, our microbiome-based investigational drug for recurrent C. difficile infections (CDI), received the FDA’s Breakthrough Therapy designation because it is intended to treat a serious or life-threatening condition, and the preliminary clinical evidence indicates that CP101 may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.

CDI is certainly a serious and sometimes life-threating condition. CDI is the most common hospital-acquired infection in the US, but it also affects individuals with limited or no contact with a hospital setting. In the US alone, an estimated 500,000 individuals suffer from CDI each year, and sadly, CDI is associated with close to 30,000 deaths per year. The US Centers for Disease Control and Prevention (CDC) categorizes CDI as an “urgent threat” to public health, the highest possible threat categorization.

CP101 is intended to prevent recurrent CDI; in other words, it is designed to prevent patients from experiencing additional CDI episodes. After an initial CDI episode and treatment with antibiotics, up to 20 percent of patients will experience a second episode. After a patient has experienced two or more CDI episodes, 40-65 percent experience yet another episode. With antibiotics alone it can be extremely difficult to break the cycles of CDI, and the negative impact on patients, their families and the health care system is enormous.

The preliminary evidence for CP101 is very exciting — in a preliminary clinical study, 88 percent of patients battling recurrent CDI that received CP101 did not experience a CDI recurrence over a two-month period. Beyond this study, other clinical studies have also shown that transferring a diverse microbial community into the gut of patients suffering from recurrent CDI may be significantly more effective than utilizing antibiotics alone to treat recurrent CDI.  

WuXi: How does your drug candidate differ from existing therapies for clostridium difficile infection? What is the mechanism of action?

Mark Smith: CDI has traditionally been treated with antibiotics alone, which often disrupts the balance of the gut microbiome, leaving patients susceptible to additional CDI episodes. To combat this, many clinicians are now using fecal microbiota transplants (FMT), an investigational treatment derived from the stool of human donors, to treat patients with recurrent CDI that have failed antibiotic therapy.

While many of the FMT treatments used in the US come from OpenBiome, a nonprofit stool bank that rigorously screens its donors, there is wide variation in the donor screening protocols and processes used by other organizations preparing FMT treatments. FMT treatments are often delivered using clinically invasive methods, such as naso-enteric tubes, enemas, or most commonly in the US, via colonoscopy, which requires bowel preparation beforehand, a process that can be quite uncomfortable and difficult for patients. 

We consider CP101 the next generation of microbiome-based therapies because it addresses the limitations of currently available options. Specifically, CP101 is an oral capsule, produced under applicable GMP (Good Manufacturing Practices) controls, which contains a diverse community of lyophilized microbiota from human donors that have undergone rigorous screening and testing.

The oral delivery method has the potential to significantly improve the patient experience. And, unlike FMT treatments that must generally be kept frozen, the lyophilization of the microbiota avoids the need for CP101 to be kept frozen, simplifying the supply chain and making it much easier for hospitals to store CP101.

WuXi: How did you demonstrate the potential clinical benefit beyond existing treatments to secure the breakthrough designation?

Mark Smith: We submitted data from a clinical study conducted at the University of Minnesota, which describes the clinical experience with CP101 used to treat patients with recurrent CDI.

In the study 88 percent of patients achieved clinical success, defined as no recurrence of CDI over a two-month period. Compared to the published recurrence rates seen after antibiotic therapy, this is a large, and very clinically relevant, decrease in the rate of recurrence. This data allowed us to meet the FDA’s requirement that breakthrough therapies must have preliminary clinical evidence that indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.

WuXi: What impact does the breakthrough designation have for your company?

Mark Smith: The increased communication and support that the FDA offers to companies with Breakthrough Therapy designation is incredibly valuable and will enable us to accelerate our efforts to make CP101 available to patients fighting recurrent CDI. Just recently, we had a very productive conversation with the FDA in which we learned that it may be possible for PRISM3, our currently enrolling Phase 2 clinical trial, to be considered a single pivotal trial if the statistical results meet the FDA’s highest bar. If we meet this very high, but achievable bar we would be able to submit for FDA approval without needing to conduct a Phase 3 clinical trial.

Having a therapy with Breakthrough Therapy designation was also helpful during our last fundraising round, where we raised $53 million dollars to advance our portfolio of therapies.

WuXi: What role, if any, have patients played in your drug development and clinical trials, aside from participating in clinical trials, of course?

Mark Smith: Patients are always at the center of our work. They inspire us and motivate us to work with tenacity and urgency. We’ve worked closely with many individuals that have battled C. difficile as well as C. difficile patient advocacy groups to understand the needs of those we seek to serve. Their input has helped inform the design of our product and clinical trials.

WuXi: What other drugs are you developing based on your technology platform?

Mark Smith: We use our Human-First Discovery™ platform to develop therapies for a wide range of diseases and conditions linked to a disrupted gut microbiome.

Rather than following the traditional drug discovery process, we begin with proof-of-concept data from human interventional studies to identify meaningful microbial signatures. We have a Full-Spectrum Microbiota® (FSM®) product platform that allows for the development of therapies that contain a diverse community of microbiota from healthy human donors, as well as a Rationally-Selected Microbiota® (RSM™) product platform that allows for the development of therapies containing select microbes, grown in pure culture, that we believe are driving successful clinical outcomes.    

In addition to recurrent CDI, we also have a pediatric Autism Spectrum Disorder program that recently received Fast Track designation from the FDA, and a partnership with Takeda Pharmaceutical Company to develop a Rationally-Selected Microbiota therapy for ulcerative colitis. Beyond that we continue to evaluate and advance microbiome research to identify additional areas where our platform can address unmet patient needs.

WuXi: What role does the microbiome play in diseases and what kinds of diseases are linked to it?

Mark Smith: Scientists are discovering that the microbes inside us are having a much bigger impact on our health than previously thought.

In addition to the areas we are currently focused on, researchers have found that the microbiome is linked to the response patients have to cancer therapies, as well as the development of autoimmune conditions, such as rheumatoid arthritis and multiple sclerosis, central nervous system disorders such as Parkinson’s disease, and even the development of food allergies and obesity, just to name a few areas of promising research.

To further our understanding of the microbiome’s therapeutic potential, we are currently supporting a number of investigator-initiated clinical studies that span a wide variety of neurological, hepatic, infectious disease, and gastrointestinal conditions.    

WuXi: What lessons can other companies learn from your drug development experience?

Mark Smith: We believe that focusing on bringing clinical data into the development process as early as possible is critical to retire risk and inform product strategy.

Because of the favorable safety profile of our microbial therapies we have been able to rapidly generate proof-of-principle clinical data. This approach enabled us to quickly move into the clinic with CP101 and obtain data that allowed us to secure Breakthrough Therapy designation and initiate a potentially pivotal trial. While other companies may not share the unique features of our discovery platform, the principle of tying decisions to clinical data early in development is an important one.

WuXi: Have FDA initiatives such as Breakthrough Therapy and Fast Track designations, changed the paradigm of clinical drug development? If so, how?

Mark Smith: The FDA plays a pivotal role in the development of effective therapies. Fast Track and Breakthrough Therapy designations increase our ability to interact with the FDA’s multidisciplinary team of experts. These designations allow sponsors to design better trials and more smoothly navigate the necessary regulatory processes that exist to ensure that safe, effective drugs reach patients.

WuXi: What are the top three major impediments in our delivery of better medicines, faster and cheaper to patients?

Mark Smith: If you consider the biopharma industry as a whole, there are a few main challenges. As we all know, it’s very costly and time consuming to identify a promising drug candidate. And, many drug candidates that show promise in a pre-clinical setting are found to be ineffective once clinical trials start. These factors drive up the cost of drugs and increase the time it takes for new therapies to enter the market.

With our product platform and strong partnerships with clinicians studying the gut microbiome in a clinical setting, we are uniquely positioned to overcome many of the traditional challenges.

By starting with microbial data sets from human interventional studies, we can reverse engineer successful clinical outcomes to identify the microbial community driving patient outcomes, significantly decreasing the time, cost, and risk associated with our drug discovery process.