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VIENNA, Austria – Researchers have reported progress in developing new drug treatments to combat primary billiary cholangitis which can lead to cirrhosis of the liver and liver failure – and a disease that disproportionately effects women.
Obeticholic acid, one drug that has already been approved for the treatment of primary biliary cholangitis, also has a side effect that may exacerbate one of the main symptoms of the disease, pruritus or itching, so scientists have been looking for drugs that not only reduce alkaline phosphatase – a marker of disease activity – but do not increase the itching symptoms.
In studies presented here at the International Liver Congress, a meeting of the European Association for the Study of the Liver, the new drugs seladelpar and elafibranor appear to reduce alkaline phosphatase and were not associated with increased pruritus.
In a Phase II, placebo-controlled study that included 45 patients in 3 treatment arms, elafibranor, a peroxisome proliferator-activated receptor (PPAR) alpha and delta agonist lowered alkaline phosphatase, by 41 percent to 4 percent after 12 weeks of therapy, reported Velimir Luketic, MD, professor of medicine at Virginia Commonwealth University, Richmond. In his late-breaker presentation, Luketic noted that there was a minimal rise in alkaline phosphatase among the placebo patients.
Dr. Luketic said that more than 90 percent of the patients on the active drug achieved at least a 10 percent reduction in alkaline phosphatase compared with 13 percent of patients on placebo (P<0.001); that about 90 percent of the patients on elafibranor achieved at least a 20 percent reduction in alkaline phosphatase, compared to about 8 percent of patients on placebo (P<0.001); that about 85 percent of patients on the 80 mg dose of elafibranor achieved at least a 40 percent reduction in alkaline phosphatase, and 55 percent of patients on the 120 mg dose of elafibranor achieved greater than a 40 percent reduction in alkaline phosphatase compared with none of the placebo patients achieving that milestone (P<0.001 for both doses).
The researchers enrolled 15 patients for each of the 3 arms of the study, and 43 of the patients were women. The mean age of the patients in the study was 59 years.
Patients were eligible for the study if they had been taking ursodeoxycholic acid therapy for at least a year, but had not derived what physicians considered an adequate response to the therapy. Following a screening period, the patients were assigned to either dose of elafibranor or placebo and underwent clinical and laboratory examinations at the start of the trial, at Week 2, Week 4, Week 8 and Week 12, and then they were further evaluated 2-4 weeks later at the end of the study.
“Twelve weeks of elafibranor treatment was well tolerated and produced marked improvements alkaline phosphatase and other biochemical markers of primary biliary cholangitis in this Phase 2 study,’ said Dr. Luketic. “These results suggest the treatment has substantial anticholestatic efficacy that we hope will translate into long-term benefits for patients.
He noted that treatment with elafibranor did not exacerbate or induce pruritus.
“These strong alkaline phosphatase/composite results further justify moving elafibranor into a Phase 3 trial of primary biliary cholangitis patients who have inadequate responses to ursodeoxycholic acid treatments,” he said. Dr. Luketic noted that because patients had similar responses to both doses of elafibranor, it was likely that the Phase 3 study would use the 80 mg dose in hopes of preventing drug-related adverse events.
In the study with seladelpar, researchers specifically scrutinized patients who were already diagnosed with advanced primary biliary cholangitis and were cirrhotic – late stages of the disease. In the year-long trial with seladelpar, a selective PPAR-delta agonist, levels of alkaline phosphatase were reduced as much as 43 percent in patients with advance disease, said Marlyn Mayo, MD, professor of internal medicine at the University of Texas, Southwestern Medical Center in Dallas.
In a subset of a large trial, the researchers looked at how 25 compensated cirrhotic patients in Child-Pugh Class A, fared using 5 mg and 10 mg doses of seladelpar.
At 52 weeks, the 14 patients who were started on the 5 mg dose of seladelpar (and could have been titrated to 10 mg if warranted) achieved a 36 percent decrease in alkaline phosphatase production compared to baseline levels, and the 11 patients who initiated treatment at the 10 mg dose achieved a mean 43 percent reduction of alkaline phosphatase levels, Dr. Mayo said.
“We found that seladelpar was equally well-tolerated and efficacious in the cirrhotic patients as in those who had primary biliary cholangitis but had not yet progressed to cirrhosis,” she said.
The current study looked at the subset of patients from an earlier trial that included both cirrhotic and non-cirrhotic patients. The fall in alkaline phosphatase in non-cirrhotic patients was 47 percent to 49 percent, Dr. Mayo reported. Multiple studies have shown that the lower the alkaline phosphatase is, the better is the patient’s prognosis, she said. In this subset, 23 patients were women and 2 were men.”
“The other measurements of successful treatment is how the patient is feeling so that is why we pay attention to itching or pruritus. About half the patients with primary biliary cholangitis with experience itching. We don’t understand exactly why it occurs,” she said. Dr. Mayo said that combined with abnormal laboratory tests, a itching symptom should alert practitioners to suspect primary biliary cholangitis as a diagnosis. She said that about 1 in 2,500 is being diagnosed with primary biliary cholangitis – a number that is increasing as doctors become more aware of the condition.
Dr. Mayo said that in the subset analysis there did not appear to be an association between treatment and pruritus, but she said that since there was no placebo arm in this open label study she could not definitively say that the treatment did not exacerbate itching.In the subset analysis, the 25 patients with cirrhosis were about 60 years old – a year or two older than patients who were non-cirrhotic. The patients had been diagnosed with primary biliary cholangitis for an average of 11 years.
“These findings suggest that seladelpar treatment in primary biliary cholangitis patients with Child-Pugh A cirrhosis maintained a potent anticholestatic effect over 52 weeks,” said Dr. Mayo. “In addition, seladelpar treatment appeared to be safe, was well-tolerated, and was not associated with pruritus or hepatotoxicity which is encouraging given the high unmet need that exists in this population. Confirmation of these findings in the ongoing ENHANCE Phase 3 registration study would be an important advancement in the treatment of primary biliary cholangitis.”
In commenting on the study, Francesco Negro, MD, professor of medicine at the University of Geneva, Switzerland, said, “These are interesting and promising drugs, but these are small early trials. Basically there are 3 drugs to follow if ursodeoxycholic acid does not perform adequately. They are elafibranor and seladelpar – both still investigative – and obeticholic acid which is approved. It is too early to say which would be preferable.”
Dr. Luketic concurred, “We are far away from any decision on the preference among these drugs. There are many doctors who don’t want to prescribe obeticholic acid because we are concerned about pruritus with obeticholic acid.”
The elafibranor trial was sponsored by GENFIT, based in Loos, France The seladelpar trial was sponsored by CymaBay Therapeutics, Newark, California.