Kristen Baugher and her daughter, Emmery, of Salem, Oregon. Emmery, 8, has Alagille syndrome. Credit: Kelly Kent Photography

Kristen Baugher of Salem, Oregon, knew almost immediately after giving birth to her daughter, Emmery, that something was wrong. Jaundiced and weak, the baby began itching uncontrollably. Doctors were sure she had biliary atresia, and at 4 months of age, they prepared Emmery for liver surgery at Seattle Children’s Hospital in Washington.

But at the last minute, a gastroenterologist who had recently learned about Alagille syndrome (ALGS) suspected Emmery had that instead. She called off the surgery and ordered more tests, which pointed to Alagille but also left many questions unanswered.

“Had the surgery been completed, it could have put Emmery into possible liver failure,” Baugher told Rare Disease Advisor. “But they couldn’t give us a conclusive answer because genetic testing takes about 3 months. So we left the hospital with a little information packet about Alagille. That was it. I was devastated.”

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Afterward, the itching got worse—to the point where Emmery would scratch herself until she bled. Sometimes, she had to be sedated with tranquilizers just so she, and her parents, could get some sleep.

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“During the day, she did better. But she was in constant pain. There was no relief,” said Baugher, who also has 2 older boys. “We tried everything. I had to quit my job to take care of her. We didn’t know what we were dealing with.”

Eventually, through the Alagille Syndrome Alliance (ALGSA), Baugher learned about a clinical trial being conducted by Mirum Pharmaceuticals for its therapy, maralixibat (Livmarli™), to treat the cholestatic pruritus, or unrelenting itching, that plagues 88% of those with the disease.

Emmery was enrolled in the blind study for maralixibat, a grape-flavored liquid taken 30 minutes before breakfast each morning. The drug, an ileal bile acid transporter (IBAT) inhibitor, works by blocking bile acid absorption in the small intestine, so that more bile acid is excreted in the feces, leading to lower levels of circulating bile acids that cause itching.

“We believe she may have been on placebo in the first part of the trial, but once she actually got the drug, she responded within a few days. She stopped itching and started sleeping for the first time ever,” Baugher said. “Her behavior changed, she started growing exponentially and was no longer covered in scars and blood. It’s been about 6 years now.”

On September 29, 2021, based on the encouraging results seen in children like Emmery, the US Food and Drug Administration (FDA) approved maralixibat as the first-ever treatment for cholestatic pruritus in Alagille patients aged 1 year or older.

Now a third-grader, Emmery is one of 2000 to 2500 children in the United States with the disease, said Mirum’s president and chief executive officer, Chris Peetz.

“The pruritus in Alagille is a devastating symptom, and it’s really hard to put into words how much of a factor it is in the patients and families of those who have Alagille,” Peetz said in a phone interview from Mirum’s headquarters in Foster City, California.

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“You hear heartbreaking reports of children itching their entire lives, scratching until their skin bleeds, and blood on the sheets in the morning. It’s such a defining factor of their lives that it even drives liver transplant decisions,” he said. “Very frequently, you hear stories of divorce or loss of work because care for these children is around-the-clock.”

Mirum Pharmaceuticals chief executive officer Chris Peetz and chief operating officer Peter Radovich. Credit: Mirum

Peetz said maralixibat was originally evaluated as a cholesterol-lowering drug and has been in development for a long time.

“We acquired the rights to this program from Shire, which was questioning whether they would continue it,” he explained shortly after the FDA approval was announced. “We stepped in because we wanted to get this drug approved and available. So today’s a really big day. It’s a major milestone.”

He added: “Our liver disease research has been about a decade in coming and speaks to the real challenges in drug development. It’s been more of a marathon than a sprint. But if we look at transplant rates, we see that patients on Livmarli have an improved transplant outcome. Because they’re not itching, they don’t go to transplant as often.”

Peter Radovich, Mirum’s chief operations officer, said he estimates the market opportunity for Livmarli to be “in excess of $500 million” a year, with the annual cost of therapy for the average patient coming out to $391,000.

“We have invested heavily in a patient access program, with copay support, and we feel very confident that families who need this therapy won’t have to struggle,” he said.

Radovich told investors in a conference call that the drug is now available for prescribing.

“Mirum is fully committed to ensuring Livmarli is accessible to patients who could benefit from this therapy,” he said. “We are focused on product availability and patient support during this important launch period.”

Radovich said Mirum has filed a marketing application for maralixibat before the Brussels-based European Medicines Agency, which regulates drugs across the 27-nation European Union. It’s also signed several licensing agreements, including one with Takeda for Japan, and has an expanded access program in place for Australia, Canada, and the United Kingdom.

“Alagille is just the beginning for us,” Radovich said, adding that maralixibat is being evaluated in clinical trials for other pediatric liver diseases. This includes the MARCH phase 3 study for progressive familial intrahepatic cholestasis (PFIC) and the EMBARK phase 2b study for people with biliary atresia.

Mirum’s second investigational treatment, volixibat—also an oral IBAT inhibitor—is being evaluated in 2 registrational studies, the OHANA phase 2b study for pregnant women with intrahepatic cholestasis of pregnancy and the VISTAS phase 2b study for adults with primary sclerosing cholangitis.

Israeli hepatologist Orit Waisbourd-Zinman belongs to a 3-member team of doctors that treats 30 kids with Alagille syndrome at Schneider Children’s Hospital, located in a suburb of Tel Aviv.

“This is really great news,” she said. “The other medications we have for itchiness resulting from liver diseases are not good, so this is a very promising and important addition to the field.”

In fact, she said, “we’re glad it got approved for pruritus, but actually there are some new data that perhaps it will help with liver disease itself. The thinking is that by reducing the bile acids in the blood, you’ll have less bile acid inside the liver, which contributes to fibrosis of the liver. Perhaps it can also affect the natural history of the disease, but time will tell.”

Rare Disease Advisor Associate Editor Erica Thompson contributed to this article.