Bile acids, traditionally recognized for their role in fat digestion and absorption, are now understood as powerful signaling molecules throughout the body. This expanded understanding has opened new avenues for treating various complex diseases, leading to increased clinical research into bile acid-based therapies.
These investigational treatments aim to modulate specific pathways influenced by bile acids, offering potential solutions for conditions with limited options. Clinical trials focusing on bile acids target underlying biological mechanisms rather than just managing symptoms, bringing developments for patients with chronic illnesses.
Therapeutic Targets of Bile Acid-Based Drugs
Dysregulation of bile acid pathways contributes to several complex diseases, making them primary targets for investigational therapies. These conditions often involve impaired organ function or metabolic imbalances that bile acid modulation addresses.
Cholestatic liver diseases, such as Primary Biliary Cholangitis (PBC) and Primary Sclerosing Cholangitis (PSC), involve impaired bile flow from the liver. In PBC, small bile ducts are progressively destroyed, leading to toxic bile acid buildup and liver damage. PSC involves inflammation and scarring of bile ducts, which can lead to liver failure. Targeting bile acid pathways aims to reduce harmful bile acids and mitigate liver injury.
Metabolic dysfunction-associated steatohepatitis (MASH), previously NASH, is another therapeutic target. This advanced fatty liver disease involves liver inflammation and damage, often linked to obesity and type 2 diabetes. Bile acids interact with receptors regulating glucose metabolism, lipid synthesis, and inflammation. Modulating these interactions can improve liver fat, reduce inflammation, and prevent disease progression to cirrhosis.
Gastrointestinal disorders, particularly Bile Acid Malabsorption (BAM), are also addressed by these therapies. In BAM, excessive bile acids enter the colon, causing chronic watery diarrhea. Normally, most bile acids are reabsorbed in the small intestine; when this process is disrupted, excess bile acids irritate the colon. Therapies managing bile acid levels in the intestine can alleviate these uncomfortable symptoms.
Mechanisms of Action in Investigational Drugs
Investigational drugs targeting bile acid pathways primarily work by interacting with specific receptors or transporters involved in bile acid regulation. These mechanisms restore balance to bile acid signaling, impacting various physiological processes.
One mechanism involves activating the Farnesoid X Receptor (FXR). FXR is a nuclear receptor that regulates bile acid, lipid, glucose metabolism, and inflammatory responses. When activated by drugs, FXR signaling reduces bile acid synthesis and increases excretion, decreasing the overall bile acid pool. This also helps reduce inflammation and fibrosis, common in liver diseases.
Another approach focuses on inhibiting the Apical Sodium-Dependent Bile Acid Transporter (ASBT). ASBT is located in the ileum, responsible for reabsorbing bile acids from the gut back into the bloodstream. By blocking ASBT, drugs prevent efficient reabsorption, leading to more bile acids remaining in the intestine for excretion. This reduction in the circulating bile acid pool is beneficial where high bile acid levels are problematic or increased excretion is desired.
Key Compounds in Recent and Ongoing Trials
Several compounds targeting bile acid pathways have advanced through clinical development, translating scientific insights into potential therapies. These drugs represent different mechanisms of action and are explored for various conditions.
Obeticholic acid, marketed as Ocaliva, is a synthetic FXR agonist. It is approved for Primary Biliary Cholangitis (PBC) in adults not responding adequately to ursodeoxycholic acid, or as monotherapy. The drug works by activating FXR, reducing bile acid synthesis and inflammation in the liver.
Elafibranor is a dual peroxisome proliferator-activated receptor (PPAR) alpha/delta agonist. While not directly a bile acid compound, its mechanism impacts lipid and glucose metabolism and inflammation, closely intertwined with bile acid signaling in metabolic liver diseases. It has been investigated in late-stage clinical trials for Metabolic dysfunction-associated steatohepatitis (MASH).
Cilofexor is a non-steroidal FXR agonist evaluated in clinical trials for MASH and Primary Sclerosing Cholangitis (PSC). Its action is similar to obeticholic acid in activating FXR, reducing liver inflammation and fibrosis.
Volixibat is an Apical Sodium-Dependent Bile Acid Transporter (ASBT) inhibitor. This drug prevents bile acid reabsorption in the intestine, leading to increased fecal excretion. Volixibat has been studied in trials for conditions like Bile Acid Malabsorption (BAM) and chronic diarrhea, where reducing the circulating bile acid pool can alleviate symptoms.
Navigating and Participating in Clinical Trials
For individuals interested in bile acid clinical trials, understanding how to locate and potentially participate is important. Public databases serve as primary resources for identifying ongoing research, providing detailed information about trials, including purpose and eligibility requirements.
The most comprehensive resource is ClinicalTrials.gov, a database maintained by the U.S. National Library of Medicine. This website allows users to search for studies by disease, drug name, or keywords, providing access to a wide range of research protocols. Each trial listing includes information about its phase, locations, and contact details for study sites.
When reviewing trial information, two concepts are inclusion and exclusion criteria. Inclusion criteria are specific characteristics a person must have to be eligible, such as a diagnosis or age. Exclusion criteria are characteristics that would prevent participation, like pre-existing medical conditions or medications. These criteria ensure participants are appropriate for the study’s scientific objectives and safety.
Informed consent ensures potential participants understand the study’s details before agreeing to join. This involves reviewing a document outlining the trial’s purpose, procedures, risks, and benefits. Participants can ask questions and must voluntarily sign the consent form, indicating understanding and willingness to participate. Discussing trial participation with a healthcare provider is recommended to determine if it is a suitable option.