Experimental ICP drug volixibat shows early promise for mothers, babies
Report: Oral treatment may ease itch in pregnant woman, but data still limited
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Volixibat, Mirum Pharmaceuticals’ experimental oral treatment, may help reduce circulating bile acids and ease itch in pregnant women with intrahepatic cholestasis of pregnancy (ICP), without causing adverse effects on the baby, according to a report.
The report presents data from four women who participated in OHANA (NCT04718961), a Mirum-funded Phase 2 clinical trial evaluating the safety and efficacy of the therapy in pregnant women with ICP.
OHANA was planned as a larger clinical trial with a placebo-controlled portion, but the study ended early “due to challenges in enrollment in this high-risk pregnancy population,” researchers wrote.
“This study provided early signals of volixibat’s potential as a treatment in ICP, but further research needs to be conducted in order to adequately determine the impact of the medication,” researchers added.
The data were detailed in a brief report titled “Efficacy, Safety and Tolerability of Volixibat, an IBAT Inhibitor, in Patients With Intrahepatic Cholestasis of Pregnancy,” which was published in Liver International. Most of the researchers who authored the study work for or have worked for Mirum or consult for the company.
Treatments that reduce bile acids during pregnancy needed
ICP is a type of cholestasis — a condition marked by slowed flow of bile from the liver to the intestines — that arises during pregnancy. As a result, bile acids build up to toxic levels in the liver and leak into the mother’s bloodstream, leading to symptoms such as intense itch, or pruritus. Bile acids are the main components of the digestive fluid bile.
High levels of bile acids in the blood increase the risk of complications such as preterm birth (before 37 weeks of gestation) or stillbirth. Alongside efforts to identify ICP risk factors and protect both mothers and their babies from complications, there is a strong need for treatments that safely reduce circulating bile acids during pregnancy.
A promising treatment approach for diseases marked by cholestasis is to block the ileal bile acid transporter (IBAT), which recycles bile acids from the intestines back to the liver. IBAT suppression is expected to increase bile acid excretion in stool, preventing their accumulation in the liver and bloodstream, and easing pruritus and other symptoms.
Livmarli (maralixibat), an approved IBAT blocker developed by Mirum, has resulted in “not only statistically significant and clinically meaningful reductions in pruritus, [blood bile acid] levels and bilirubin [a liver damage marker] but also improvements in quality of life across several cholestatic disorders, including progressive familial intrahepatic cholestasis (PFIC), Alagille syndrome (ALGS), primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC),” the researchers wrote.
Livmarli’s development has focused mainly on pediatric cholestatic diseases such as PFIC and ALGS, for which the therapy is approved. Mirum’s second IBAT blocker, volixibat, is being tested primarily in adult cholestatic disorders, including chronic forms of cholangitis (PSC and PBC), a condition marked by inflammation of the tubes that transport bile.
All four women on volixibat showed reductions in circulating bile acids
The Phase 2 OHANA trial was launched to test volixibat in pregnant women with ICP, ages 18-45. The study was recruiting at 25 sites in the U.S., New Zealand, and the U.K., and was designed to have two parts. The first was meant to test different doses of volixibat, and the second would compare the optimal dose with a placebo.
The trial’s main goal was to assess the therapy’s safety and tolerability, while secondary goals included changes in the Adult Itch Reported Outcome, a measure of pruritus severity. Exploratory goals included assessing changes in maternal blood bile acid levels and levels of volixibat in maternal and fetal blood, as well as the therapy’s effect on other maternal and fetal outcomes.
OHANA did not proceed to the second part because it ended early “due to lack of enrollment,” the researchers wrote.
More than 1,000 women were invited to participate in the trial, but only 11 were enrolled, and four received the therapy. These four women, ages 20 to 38, received 20 mg or 80 mg of volixibat, twice daily from enrollment until delivery.
Treatment duration ranged from less than a week to more than five weeks. Dose reductions or pauses were allowed at the clinician’s discretion.
All four women showed reductions in circulating bile acids after starting volixibat, with levels falling below 6 micromoles per liter, which is within the normal range. In three women, these reductions were sustained over time.
Patients with ICP appear more susceptible to the gastrointestinal side effects of the medication than those with chronic cholestatic disease; hence, future strategies may necessitate gradual dose increases.
Three women also experienced a clear reduction in pruritus, regardless of the dose used. Notably, itch returned when treatment was briefly stopped, and eased again when dosing resumed.
All four pregnancies resulted in healthy live births, with two babies born at term and two preterm, and short neonatal unit stays.
Volixibat was detected only at low levels in maternal or umbilical blood. The most common adverse event was diarrhea, occurring in all women, and it eased when the dose was reduced or treatment stopped.
“Patients with ICP appear more susceptible to the gastrointestinal side effects of the medication than those with chronic cholestatic disease; hence, future strategies may necessitate gradual dose increases,” the researchers wrote.
Although the data come from only four women and volixibat was not compared with a placebo, as initially planned, the researchers concluded that “given the absence of any effective alternative treatment for ICP beyond premature delivery, the potential value of this as a novel treatment warrants further research.”
