Live Biotherapeutics ‒ A Novel Way To Treat Disease

Our bodies contain complex microbial ecosystems composed of bacteria, archaea, fungi, protozoa and viruses, which collectively are referred to as the microbiota. The intricate and intertwined nature of the host‒microbiota connection has garnered increasing interest from the scientific community in recent years, due to its known role in the development and progression of various diseases.

4D pharma has leveraged growing knowledge in the field, by creating a novel class of medicines called live biotherapeutic products (LBPs), which are defined by the US Food and Drug Administration (FDA) as being biological products “that (1) contain live organisms, such as bacteria; (2) is applicable to the prevention, treatment or cure of a disease or condition of human beings; and (3) is not a vaccine”.

Unlike conventional therapeutic approaches that target a specific biological target or signaling pathway within the body, LBPs exert their effect by either directly interacting with the native microbiota or by modulating the host‒microbiota relationship, indirectly leading to biological effects within the patient.

To learn more about the various LBPs being developed by 4D pharma and the indications they are designed to treat, Technology Networks spoke with the company’s CEO, Duncan Peyton.

Laura Lansdowne (LL): Interest in how the microbiome influences health and disease has increased in recent years. How do bacteria found in the gut interact with the body and how is 4D pharma exploiting knowledge of the gut–brain connection to treat disease?

Duncan Peyton (DP): 4D pharma is developing LBPs, a defined new class of drug comprising live bacteria. Specifically, 4D is developing single strain LBPs – each of our drug candidates is one particular strain, originally isolated from the gut microbiome of a healthy human donor. We select strains for development based on their specific activity against disease pathways of interest. The microbiome is well known to be key for digestion and metabolism, but also over 70% of the immune system is in and around the gut and the microbiome has a major role in the development and proper functioning of the immune system. We are tapping into this in two ways – by regulating the immune system to manage inflammatory diseases (e.g., asthma) and stimulating the immune system to fight cancer. There is also an increasing awareness of the gut‒brain axis and how the microbiome directly influences neurological diseases (e.g., multiple sclerosis), neurodevelopmental disorders (e.g., autism) and neurodegenerative diseases (e.g., Parkinson’s disease).

LL: What are some of the benefits of using LBPs compared to synthetic small molecule drugs?

DP: LBPs as non-engineered commensal bacteria isolated from a healthy human, are expected to have very favorable safety profiles, and we are seeing this play out in clinical trials in patients across our pipeline in diverse diseases from irritable bowel syndrome (IBS) to cancer to asthma. The microbiome also offers a new way to access human biology, for example, the close two-way interaction with the immune system, and the gut‒brain axis as a new way to access and treat diseases of the CNS. Bacteria as drugs also have the potential to exert new or different activity to traditional drug classes like small molecules or biologics. Furthermore, LBPs as drugs have already been optimized by thousands of years of co-evolution.

LL: Two of 4D Pharma’s live biotherapeutics (MRx0005 and MRx0029) recently received investigational new drug (IND) clearance by the FDA for Parkinson’s disease. Could you tell us more about these two biotherapeutics and comment on next steps in terms of clinical testing?

DP: Both MRx0005 and MRx0029 have been shown preclinically to reduce neuroinflammation including inflammation induced by α-synuclein, a key protein in Parkinson’s pathology. Both have also been shown to protect neurons from oxidative stress-induced neuronal death. MRx0005 has been shown to upregulate the expression of neuroactive molecules and their receptors in vivo and protected against loss of dopamine metabolites in the brains of mice with induced parkinsonian syndrome. MRx0029 has been shown to improve intestinal epithelial integrity, which is important because impaired intestinal barrier function and intestinal permeability or “leaky gut” is a common symptom of Parkinson’s disease thought to potentially contribute to the onset or progression of the condition. MRx0029 has also been shown to induce the differentiation of dopaminergic neuronal phenotype in vitro and in an animal model of Parkinson’s disease protected against the loss of dopaminergic neurons.

We expect to commence a Phase 1 clinical trial of both MRx0005 and MRx0029, separately, in people with Parkinson’s in 2022. This first-in-human study will be primarily focused on safety, but because we are able to conduct the study in patients, we will also be collecting a suite of biomarkers relating to the two candidates’ mechanisms of action.

LL: You are also developing live biotherapeutics for numerous other indications as part of your broader R&D pipeline, could you highlight a few of these?

DP: Our MRx0518 oncology program currently has multiple ongoing studies. We are collaborating with:

• MSD (Merck & Co.) to investigate the use of MRx0518 in combination with Keytruda^® (pembrolizumab)
• University of Texas MD Anderson Cancer Center to explore MRx0518 in combination with radiotherapy for pancreatic cancer

We will also shortly be starting a study of MRx0518 in combination with Merck KGaA & Pfizer’s anti-PD-L1 immune checkpoint inhibitor Bavencio^® (avelumab) in patients with locally advanced or metastatic urothelial carcinoma that has not progressed with first-line platinum-containing chemotherapy.

We have completed a successful Phase 2 trial of Blautix^® (MRx1234) in IBS; uniquely Blautix showed activity in both of the major subtypes ‒ constipation-predominant (IBS-C) and diarrhea-predominant (IBS-D).

We recently announced the first clinical data for our asthma program (MRx-4DP0004) and this Phase 1/2 study is now progressing into Part B. We have also identified other LBPs with promising activity in IBD, MS, arthritis and autism. Lastly, we are working with MSD using our MicroRx platform in the vaccines field.

Duncan Peyton was speaking with Laura Elizabeth Lansdowne, Managing Editor for Technology Networks.