Medications known as IBATIs are safe, effective in Alagille: Analysis
Livmarli, Bylvay both ease itching, improve quality of life in children
Livmarli (maralixibat) and Bylvay (odevixibat) not only offer significant relief from severe itching in children with Alagille syndrome, but also improve quality of life for youngsters with the genetic condition, according to a new analysis that combined the results of four independent clinical trials.
That meta-analysis, which aimed to provide stronger conclusions than any single study could, was conducted by a research team from Brazil and Portugal to learn more about the safety and effectiveness of a class of medications known as ileal bile acid transport inhibitors, or IBATIs. Both Livmarli and Bylvay are in the IBATI therapy class.
The results showed that both medications were generally safe and well-tolerated when used to treat children. There were no treatment discontinuations in the trials due to adverse events, pooled data showed.
The researchers concluded that “IBATIs are effective and well tolerated in pediatric ALGS [Alagille syndrome], providing meaningful improvements in pruritus [itching] and quality of life.”
Still, “longer trials are needed to confirm durability, safety, and transplant-free survival impact” of these medications, the team noted.
The results of the meta-analysis were detailed in a study titled “Efficacy of ileal bile acid transport inhibitors in children with Alagille syndrome: a meta-analysis,” published in the European Journal of Pediatrics.
In Alagille syndrome, the normal flow of the digestive fluid bile from the liver is disrupted. When bile cannot flow properly into the intestine, it builds up in the liver and leaks into the bloodstream, causing cholestatic pruritus, or severe itching linked to slowed or stalled bile flow (cholestasis).
IBATIs, such as Livmarli and Bylvay, work by blocking the action of IBAT, a protein that reabsorbs bile acids, the main components of bile, from the intestine back into the liver. Suppressing IBAT reduces the amount of bile acids in the liver and prevents them from leaking into circulation in the body, potentially easing liver damage and cholestatic pruritus.
Despite ‘growing interest,’ there’s scant data on IBATIs
Livmarli, an oral solution from Mirum Pharmaceuticals, is approved in both the U.S. and the European Union to reduce itching in Alagille patients. In the U.S., it’s indicated for individuals as young as 3 months of age, while in the EU, it can be prescribed for patients at 2 months.
Ipsen’s Bylvay, available as a once-daily capsule, is also approved for easing pruritus in people with Alagille. It is cleared for use by patients ages 1 and older in the U.S., and for those 6 months and older in the EU. In Europe, the medication is sold under the brand name Kayfanda.
In this analysis, the researchers sought to learn more about the therapy class.
“Despite growing interest in IBATIs, evidence regarding their efficacy and safety in ALGS remains limited due to the rarity of the syndrome and the [variability] of clinical presentations,” the scientists wrote.
Here, the team systematically reviewed studies published through November 2024 that reported on data from placebo-controlled clinical trials testing IBATIs in Alagille patients.
A total of four trials, covering 138 children diagnosed with Alagille, were used in the meta-analysis. In three Phase 2 trials — ICONIC (NCT02160782), ITCH (NCT02057692), and IMAGO (NCT01903460) — children were assigned to Livmarli or a placebo for up to 204 weeks, or nearly three years. In a Phase 3 study, called ASSERT (NCT04674761), children received either Bylvay or a placebo daily for 24 weeks, or slightly less than six months.
The children’s mean age was 6.1 years, and slightly more than half were boys. The placebo-controlled parts of the studies lasted up to 24 weeks; ICONIC had a subsequent extension portion in which all participants received Livmarli for up to nearly 2.5 years.
The main goals of the meta-analysis were to assess how IBATIs affected itching severity and blood bile acid levels after six months of treatment. Secondary goals included changes in quality of life — as assessed with Pediatric Quality of Life Inventory — and blood levels of liver damage markers. Rates of adverse events and treatment discontinuations were also evaluated as secondary goals.
Significantly less itching seen for children given Livmarli, Bylvay
The pooled data showed that children who received an IBATI had significantly less severe itching compared with those given a placebo. Pruritus was measured using Itch-Reported Outcome (ItchRO) in Livmarli studies and PRUCISION in the Bylvay trial.
“Consistent improvements were observed across both instruments; however, as these scales differ in design and scoring, they should not be regarded as interchangeable, and no conclusions can be drawn regarding relative efficacy between agents,” the team wrote.
Treatment with IBATIs also significantly reduced levels of bile acids in the blood relative to the placebo. When considering only the three studies of Livmarli, the reduction remained significantly greater with Livmarli compared with the placebo.
These findings support the potential role of IBATIs as promising therapeutic options for children with [Alagille syndrome] and severe [itching linked to slowed or stalled bile flows].
Itching can disturb sleep and interfere with a child’s daily life and emotional well-being. However, IBATI therapy significantly increased Pediatric Quality of Life Inventory scores, indicating better quality of life.
IBATIs were “generally well tolerated,” the researchers wrote. The most frequently reported adverse events were diarrhea, abdominal pain, and vomiting, and these were mild to moderate in severity and resolved on their own.
“These findings support the potential role of IBATIs as promising therapeutic options for children with ALGS and severe cholestatic pruritus,” the researchers wrote.
Several study limitations were noted by the scientists, however. Among them were the small number of studies, the fact that not all used the same tool to measure itching, and the short placebo-controlled periods (up to six months).
“Additional studies with larger sample sizes and longer follow-up are needed to confirm these benefits, better characterize long-term safety, … and inform optimal clinical use,” the team concluded.
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