A new study shows it may be possible to develop new drugs for progressive liver disease caused by polycystic kidney disease (PBC) that goes undiagnosed because no warning signs show up on a test. Published in Liver Transplantation, the findings suggest there may be a significant pool of patients waiting for diagnostic testing who would benefit from a new class of drugs.
Polycystic kidney disease occurs when the cysts, or deposits, of cysts on the liver develop into large, tangled clusters of cells that obstruct the flow of bile and which may eventually start to form thick scar tissue.
When not treated, PBC is more common in younger women who have diabetes, genetic mutations, or certain medical conditions that can lower the risk of having a healthy liver.
In 2007, the US FDA approved the first drug, MPH-101, to treat PBC, a class of medicines known as proteases inhibitors. However, researchers note that while the drugs improve the appearance of disease in the liver, they do not cure the disease, and new ones are needed.
The study, led by Elizabeth A. Roussell, M.D., Ph.D., of the New York State Office of the Chief Medical Officer, aims to uncover the role of proteases in the disease and to test the safety and efficacy of the new drugs, a class of drugs called exon-skipping-oxalase inhibitors.
They used a twin-blinded, controlled study to evaluate the safety of PB-200023, an experimental exon-skipping-oxalase inhibitor, in 101 patients with PBC and compared it to the performance of PBC patients taking MPH-101, an existing protease inhibitor.
The PB-200023 study compared the adverse events in the PB-200023 arm against those seen in the MPH-101 arm.
Among the PB-200023 patients, three per cent of those taking PB-200023 experienced moderately mild diarrhea, as opposed to six per cent in the group taking MPH-101.
Roussell’s team noted that having diarrhea is a symptom of PBC, so any type of diarrhea could be associated with an adverse event.
It also found that those taking PB-200023 also had nearly half the rash rates and half the blood levels of fluoroquinolones, a widely used class of antibiotics, versus those taking MPH-101.
“The lack of signs and symptoms of PBC typically suggests that patients with PBC have the disease under control, but a debilitating and life-threatening condition that has a profound impact on patients lives – the end stage of advanced PBC,” the authors wrote.
“Potential novel treatments for PBC include new protease inhibitors that in clinical studies have successfully lowered blood levels of glutaraldehyde, a central neurotransmitter in PBC, and transiently decreased the levels of gallstones.
Potential therapeutic exon-skipping inhibitors, such as PB-200023, also have positive effects in lower but important parameters of PBC such as vitamin B12 levels and spleen volume, lowering spleen volume, which is an adverse event in PBC patients.”
“PBC is a silent disease, with only a small proportion of patients suffering from clinical symptoms and a significant majority being undiagnosed.”
“While PB-200023 – the only currently available protease inhibitor approved for PBC – has been promising in clinical trials, it has yet to be seen if its tolerability can be improved in larger animal studies.
“A randomized controlled study to validate PB-200023, in conjunction with low-dose fluoroquinolones, as a therapeutic and acceptable alternative to MPH-101 is an important next step to bring an effective new treatment for PBC to patients.”
PBC Foundation CEO, Dr. Joanna B. Garber, said the new data showed the continuing need for novel treatments to complement and complement the current drug treatment, and that they were encouraged by the prospect of novel drugs to replace MPH-101.
“A PBC patient’s diagnosis can have severe impact on their lives, including the loss of jobs and no way to pay medical expenses. We know that patients with PBC are at risk for metabolic syndrome, a precursor to cardiovascular disease, which in turn can lead to heart attacks, strokes and death,” she said.
“Currently there are no proven agents for the diagnosis of PBC, and medications for the treatment of PBC are limited, costing $25,000 for each person who suffers from PBC.”
Written by Catharine Paddock PhD