番茄社区

WASHINGTON -- Another ileal bile acid transporter inhibitor has demonstrated in a phase III trial the ability to reduce pruritus and serum bile acids for kids with progressive familial intrahepatic cholestasis (PFIC).

In children with PFIC2, meaning those with severe bile salt export pump (BSEP) deficiency, observer-reported change on the ItchRO scale significantly improved with maralixibat (Livmarli) versus placebo at 12 weeks, meeting the study's primary endpoint, reported Richard Thompson, MD, PhD, of King's College London.

From baseline, itch severity dropped by 1.7 points in the maralixibat arm versus a 0.6-point decline in the placebo arm, a full 1-point difference on the 5-point scale (95% CI -0.81 to -0.27, P=0.0098), he said at the annual Liver Meeting sponsored by the American Association for the Study of Liver Disease.

Treatment with maralixibat also led to a significant reduction in serum bile acids at 12 weeks compared with placebo (-176 vs 11 µmol/L change from baseline, P=0.0013), according to his presentation here.

"The majority of these children historically had to have a liver transplant because of the low quality of life that is induced by their pruritus," Thompson told 番茄社区.

"Now we have orally available, non-absorbed drugs which can do the same thing as surgery," he said. "There's a good chance that we are going to rescue 50% of patients, who will ultimately not require transplant in the future."

In patients with other types of PFIC, including those with FIC1 deficiencies or mutations in TJP2, MDR3, or MYO5B, observer-reported ItchRO scores declined 1.9 points with maralixibat and 0.5 points with placebo at 12 weeks (P=0.0029). Serum bile acid levels were also significantly reduced with maralixibat in these patients (-132 vs -6 µmol/L, P<0.0001).

"We see improvement in bile acid and in pruritis; this is very nice, but the biggest question is, Does this change the outcome for the children's overall liver health?" said Rohit Kohli, MD, of Children's Hospital Los Angeles.

"That is yet to be determined," added Kohli, who was not involved in the study but serves as a consultant to the company developing the drug.

Maralixibat is currently approved for Alagille syndrome. If approved for PFIC, it would be the second oral medication for the rare liver disease. Odevixibat (Bylvay), also an ileal bile acid transporter inhibitor, was approved in July 2021 to treat PFIC-related pruritus in children ages 3 months and up.

"With these new drugs, we have light at the end of the tunnel," said Kohli.

"These children had debilitating itching; scratching themselves to bleed," he said. "If you weren't trained in pediatrics to recognize this, you would think these children were abused -- the itching could be that bad."

Maralixibat is taken twice a day, and odevixibat once a day. Thompson pointed out that the drugs would need to be taken for the rest of kids' lives, "which is why we want to know [and continue to study them to see], what change will be there for them in the long term?"

Study Details

MARCH-PFIC enrolled 93 patients (ages 1 to 17 years) and randomized them 1:1 to either maralixibat or placebo. Participants had an average age of 5 years, and 43% were male. This included 31 patients with PFIC2; another 33 patients with PFIC involving FIC1 deficiencies or mutations in TJP2, MDR3, or MYO5B; and an exploratory cohort of 29 patients.

At baseline, observer-rated pruritus on the ItchRO scale was a mean 2.8 in treatment group and 2.9 in the placebo group. Mean serum bile acids were an average 263 µmol/L and 243 µmol/L, respectively.

Other analyses showed improvements in weight and bilirubin with maralixibat for the full study population, according to Thompson.

He said the therapy was generally well tolerated, with no new safety signals observed. Treatment-emergent adverse events (TEAEs) occurred in 100% of patients on maralixibat and 94% of those on placebo. The most common TEAE with maralixibat was diarrhea (57% vs 20% with placebo). One patient stopped maralixibat due to diarrhea.

Severe TEAEs occurred in a similar proportion of patients (6.4% vs 6.5%) while serious TEAEs were slightly higher in the maralixibat group (10.6% vs 6.5%).

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