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Pharmabiotics – Spreading Culture to Therapeutic Drugs

In the therapeutic toolbox, there is a multitude of drug categories. For decades, small molecules have been the cornerstone of pharmacology. In recent years, biological products have ushered in a wave of therapies, and forged the path for other cell- and genetic- based treatments. Greater understanding of the microbiome in association with dysbiosis and associated diseases have led to the advancement of pharmabiotics.

How Microbes can Treat Diseases

Pharmabiotics or live biotherapeutic products (LBP) refers to live microbes administered to patients to treat a disease. Gut dysbiosis is an imbalance of digestive track bacteria species that may contribute to a host of diseases including depression, Alzheimer’s disease, diabetes, irritable bowel disease (IBD) and nonalcoholic fatty liver disease (NAFLD) and even cancer.  Replenishing the so-called “good” bacteria may return balance and revert or alleviate symptoms of the conditions. Gut-brain-, gut-lung- and gut-liver- axes research has expanded our understanding of the microbiome and fostered a new branch of drug development. Dysbiosis has also been described in other organ systems such as the skin, mouth, vagina and placenta [1], all which may benefit from LBP treatment.

Pharmabiotics are validated through clinical trials with safety and efficacy endpoints for a given indication and follow the same regulatory pathway to approval as other novel drugs. In that respect, pharmabiotics differ from prebiotic and probiotic products. Prebiotics are fermented fibers that supports the growth of certain gut bacteria, while probiotics are live microorganisms that support or show potential for health benefits. For the most part, these two products are considered a dietary supplement or a medical food and do not require FDA premarket approval.

LBP can be derived from a human host or genetically modified or engineered to express a specific trait. According to ClinTrials.gov several LBP are in development [2]. This includes pharmabiotics for cancer adjuvant therapy, asthma, IBD and prevention from recurrent infection such as Clostridium difficile and bacterial vaginosis.

FDA Guidance on Pharmabiotics

The FDA defines LBP as a product that [3]: i) contains live organisms, such as bacteria; ii) is applicable to the prevention, treatment, or cure of a disease or condition of human beings; and iii) is not a vaccine.

The FDA guidance, which was updated in 2016, outlines requirements for describing the LPB and the manufacturing process as well as adjuvant substances if necessary. For non-clinical studies, the FDA recommends pharmacological and toxicological studies of the LBP in laboratory animals, or in vitro, to support a proposed clinical trial evaluating the investigational LBP. Similar to small molecule or biological drug development, non-clinical studies for LBP may include general toxicity; target organs or systems of toxicity; teratogenic, carcinogenic, or mutagenic potential of any ingredient in the product; and relationship of dosage and duration to toxic response and pharmacological activity. In addition, during early clinical Phase I studies, emphasis should be placed on subject safety. Early studies with healthy volunteers can be important to identify common LBP-associated adverse events before proceeding to studies in more vulnerable populations, such as those with the disease of interest. Currently, there is no EMA guidance for pharmabiotics as the agency does not regard LBP as a drug; however this stance may change as the field continues to grow.

LPB Dosing and Monitoring

Commonly, dosing units for LPB are based on a colony forming unit (CFU). According to the FDA, CFU is the measurement of viable microbial cells that are capable of replicating on agar plates and forming colonies which are then counted [3]. Depending on the targeted tissue, delivery of LBP may be orally ingested, administered via the urogenital track or other methods.

While traditional PK assessments may not apply to the field of pharmabiotics; microbiota diversity, taxonomic composition as well as the microbiome are important pharmacological endpoints. LPB bacterial strain colonization in stool and fecal metabolomic profile, including short chain fatty acids and bile acids, may be evaluated for LBP targeting gut disorders, while sputum may be obtained for microbe count and bacterial DNA for an asthma indication. Supporting serum biomarkers such as inflammatory cytokines, chemokines, and hormones can also demonstrate systemic pharmacodynamic changes.

Safety Considerations

While probiotics are generally considered safe for consumption, there has been reported instances of adverse events which can include systemic infections, deleterious metabolic activities, excessive immune stimulation in susceptible individuals and gene transfer [4].  Pharmabiotics may results in similar adverse effects, therefore close monitoring may be warranted. An excellent recent invited review by LeBegue et al. describes the history and study design considerations for pharmabiotic products [5].

The Celerion Advantage

Celerion clinics have experience with LPB and the unique challenges in sampling and handling key matrices such as feces, urine, sputum and other fluids for pharmabiotic studies. Our team of highly skilled Regulatory and Drug Development Service associates can support your LBP from IND through Phase II. In addition, we have a vast database of healthy volunteers as well as access to patient populations such as asthma, NAFLD and irritable bowel disease patients.

References

  1. Belizario JE, Napolitano M. Human microbiomes and their roles in dysbiosis, common diseases, and novel therapeutic approaches. Front Microbiol. 2015;6:1050.
  2. ClinTrials.gov. Live biotherapeutic products search. https://clinicaltrials.gov/ct2/results?cond=&term=live+biotherapeutic+product&cntry=&state=&city=&dist= Accessed March 9 2020.
  3. Early Clinical Trials With Live Biotherapeutic Products: Chemistry, Manufacturing, and Control Information; Guidance for Industry. . Food and Drug Administration; 2016.
  4. Doron S, Snydman DR. Risk and safety of probiotics. Clin Infect Dis. 2015;60 Suppl 2:S129-34.
  5. LeBegue CE, Love BL, Wyatt MD. Microbes as Drugs: The Potential of Pharmabiotics. Pharmacotherapy. 2020;40(2):102-6.