New medications show promise for children with rare liver disease
Review: Bylvay, Livmarli may have broader efficacy across several PFIC types
While different types of progressive familial intrahepatic cholestasis (PFIC) vary in their genetic cause and clinical profile, new medications like Bylvay (odevixibat) and Livmarli (maralixibat) have shown promise across several PFIC types, including rare ones, in children.
That’s according to a review study, titled “New hope in treating progressive familial intrahepatic cholestasis in children,” which was published in the World Journal of Hepatology.
Bylvay and Livmarli belong to a class of medications called ileal bile acid transporter (IBAT) inhibitors, which aim to increase excretion of bile, the digestive fluid that builds up in the liver in PFIC, through feces.
“New hope exists with ileal bile acid transporter receptor inhibitors, however, more data is still required,” the researchers wrote.
Each PFIC type caused by mutations in different genes
PFIC refers to a group of rare liver diseases typically manifesting in infancy or early childhood that are marked by cholestasis, or stalled flow of bile from the liver, where it is produced, to the intestines, where it helps digest fats and fat-soluble vitamins.
As bile accumulates, it can damage the liver and leak into the bloodstream, resulting in symptoms like itchiness, malnutrition, and jaundice, or the yellowing of the skin and white parts of the eyes.
There are several PFIC types, each caused by mutations in different genes that ultimately interfere with bile transport. Researchers previously categorized PFIC into three types depending on the impacted genes. However, “recent advancements in genetic research have revealed up to 13 key proteins involved in bile transport, clarifying the underlying mechanisms,” the researchers wrote.
Broadly, the 13 PFIC types fit into five categories of mechanisms. For example, in PFIC types 1 and 3, mutations affect mechanisms that protect cells lining the tubes that transport bile against bile toxicity, leading to damage and slowing bile flow.
In contrast, mutations that cause PFIC types 2 and 6 lead to problems in the proteins that transport bile acids, bile’s main components, out of liver cells or that reabsorb, or recycle, bile acids from the intestine back to the liver.
Other types of mutations alter how molecules move through cells, affect the localization of transport proteins in the cell membrane, disrupt liver cell structure, or affect primary cilia, which is a cellular structure that in liver cells is involved in sensing bile flow and regulating bile production.
Currently, there are no curative therapies for PFIC.
“The management of PFIC in pediatric patients involves a multifaceted approach aimed at controlling symptoms, slowing the progression of liver damage, and addressing related complications such as malnutrition, intense itching (pruritus), and liver injury,” the researchers wrote.
Bylvay, Livmarli found effective in multiple types of rare liver disease
Some medications and surgeries to improve bile flow or ease pruritus work better in specific PFIC types, the team noted.
Ursodeoxycholic acid (UDCA), a therapy sold under the brand names Urso and Actigall and commonly used off-label for PFIC, varies in efficacy across types, but is most effective in PFIC type 3. The antibiotic rifampicin, sold as Rimactane and Rifadin, among others, and sometimes used off-label with UDCA, has lower efficacy in types 2 and 3.
Cholestyramine (sold as Prevalite and Locholest, among others) and colesevelam (sold under the brand name Welchol) are “commonly used off-label to manage pruritus associated with cholestasis,” the researchers wrote. These medications work by preventing bile acids from being reabsorbed after reaching the intestine.
Still, “there is limited evidence supporting their efficacy and long-term outcomes in the pediatric population,” the researchers added.
IBAT inhibitors like Bylvay and Livmarli, which have been approved for treating PFIC-associated pruritus in the last few years, may have broader efficacy across disease types, according to the researchers.
These oral medications reduce the amount of bile acid that the intestines reabsorb. This means the digestive system can excrete more bile in feces, lowering the burden on the liver.
These findings support the potential role of odevixibat as a safe and effective adjunct in managing [treatment-resistant] pruritus associated with atypical or genetically undefined cholestatic liver disorders, particularly when introduced early in the disease course.
Most clinical trials of Bylvay, sold as Kayfanda in some countries, initially focused on individuals with type 1 and 2 PFIC. However, a recent real-world study and case series found the medication was effective in rarer types.
“These findings support the potential role of odevixibat as a safe and effective adjunct in managing [treatment-resistant] pruritus associated with atypical or genetically undefined cholestatic liver disorders, particularly when introduced early in the disease course,” the researchers wrote.
In clinical trials, Livmarli also proved effective across several PFIC types, including rare ones.
“Both agents have shown promising results in reducing pruritus and [blood] bile acids and are generally well tolerated with minimal adverse effects,” the researchers wrote.
Because of their distinct molecular mechanisms, emerging experimental therapies aldafermin and obeticholic acid (sold as Ocaliva) may have particular impacts in people with more unusual PFIC types, the researchers hypothesized.
As more information emerges about the mechanisms and relative efficacy of IBAT inhibitors and other treatments across disease types, understanding individuals’ genetic mutations and disease types may help tailor therapeutic strategies, the researchers noted.
“Identifying the underlying genetic disorder allows better understanding of the clinical [disease features] and associated complications,” they concluded.
