Livmarli led to ‘dramatic responses’ in PFIC trial, Mirum exec says

The Phase 3 trial that supported the U.S. approval of Livmarli (maralixibat) for progressive familial intrahepatic cholestasis (PFIC) involved the broadest range of patients, by underlying genetic cause, in a PFIC clinical study to date — with the treatment leading to “dramatic responses,” according to the CEO of Mirum Pharmaceuticals, which developed the therapy.

The MARCH-PFIC trial (NCT03905330) — whose data supported Livmarli’s approval in the U.S. earlier this month to ease itch in PFIC patients 5 years and older — included not only participants with known forms of PFIC but also those without a defined genetic type.

The response in itch scores was “quite consistent and broad across all” groups of patients, including those with “unknown or novel genetics,” Chris Peetz, Mirum‘s co-founder and CEO, said in an interview with Liver Disease News.

“That was really exciting data to come out in this study,” he added.

Livmarli already is available to eligible U.S. patients with PFIC, and Mirum is offering an assistance program that may help to cap out-of-pocket costs for some families, according to Peetz.

Mirum offering assistance program to patients and families

Livmarli’s approval means that most individuals with this group of rare genetic diseases now have a second therapeutic option for treating itch, following the U.S. clearance of Ipsen’s Bylvay (odevixibat) in 2021. Bylvay is indicated to treat itch in PFIC patients ages 3 months and older.

While both therapies are taken orally at a weight-based dose, Livmarli comprises a grape-flavored liquid and Bylvay is available in oral pellets and capsules.

This is a major milestone for PFIC, which causes itching and other symptoms in childhood.

“To have another treatment option for a rare disease is quite meaningful,” Peetz said, noting that “it’s not always possible to even have one treatment available” for such conditions.

This is the second U.S. approval for Livmarli, which already had been authorized to treat itching in another rare genetic liver disease called Alagille syndrome. According to Peetz, the therapy’s reception in the Alagille community has been “overwhelmingly positive.”

Mirum originally had applied for approval of Livmarli for PFIC patients as young as 3 months of age, but the current indication covers only those ages 5 and older. The reason for this discrepancy is that, due to dosing considerations, younger children in the MARCH-PFIC trial received a higher concentration formulation of Livmarli that’s different than the one currently approved.

The U.S. Food and Drug Administration (FDA) has asked Mirum to submit a separate application for the high-concentration formulation for use in younger children.

“We didn’t fully expect [a separate application] to be needed,” Peetz said, but “we’ve already submitted [it] with the FDA.” The company expects Livmarli to be available for these younger children before year’s end, he noted.

Still, Livmarli was made available for eligible PFIC patients as soon as the approval was secured, and the company offers an assistance program called Mirum Access Plus to support patients and their families in accessing the treatment.

Our strategy is that, for families, the cost for Livmarli is $10 a month or less out of pocket. … We work through all of the different types of insurance coverage that these families may have to make sure that that we’re doing what we can to enable that.

According to Peetz, the program includes resources to help healthcare providers in prescribing the therapy, and a call center with trained nurses that can help families “if they have any questions or any needs as they’re going through treatment.”

The program also offers financial support resources, with the company actively working to ensure that “affordability is not an issue for families,” Peetz added.

“Our strategy is that, for families, the cost for Livmarli is $10 a month or less out of pocket,” Peetz said. “We work through all of the different types of insurance coverage that these families may have to make sure that that we’re doing what we can to enable that.”

Peetz added that this goal is possible “in almost all cases,” noting also the existence of a supportive program for uninsured families that “really cannot afford therapy.”

Livmarli approval based mainly on Phase 3 MARCH-PFIC trial results

According to its label, Livmarli is not recommended for people with PFIC type 2 who carry mutations that result in a non-working or absent bile salt export pump (BSEP) protein. This limitation is due to how the therapy works in PFIC, Peetz explains.

PFIC is characterized by cholestasis, or reduced flow of bile, a digestive fluid made in the liver and shipped to the intestines through tubes called bile ducts. As a consequence, bile builds up in the liver and leaks into the bloodstream, causing itching and liver damage.

Chris Peetz is the CEO and a cofounder of Mirum Pharmaceuticals. (Photo courtesy of Mirum)

Livmarli works by reducing bile acid reuptake in the intestines and promoting its excretion in feces, thereby helping to lower bile buildup in the liver. But in the absence of a working BSEP protein, bile isn’t able to get out of the liver into the intestines at all.

As such, “if there’s no bile acids [in the intestines] to act on, [Livmarli is] not going to have an effect,” Peetz said.

Mutations resulting in a non-working or absent BSEP are “very rare,” and therefore affect only a “very small percentage” of PFIC patients, Peetz noted, adding that patients can talk to their physician to determine if this restriction applies to them.

Livmarli’s approval for PFIC was based mainly on findings from MARCH-PFIC, which tested the therapy against a placebo for six months in 93 children and adolescents with known and undefined PFIC types.

The results showed Livmarli significantly outperformed the placebo at reducing itch, as measured by the ItchRO(Obs) severity score. This caregiver-rated score assesses itching severity on a 4-point scale, and “anything over a 1-point reduction is considered clinically meaningful,” Peetz explained. 

At the start of the study, most patients had scores around 3, indicating severe itch. After about six months of Livmarli treatment, average scores decreased by just shy of two points — which Peetz called “a game-changing impact.” 

According to Peetz, more than 60% of Livmarli-treated patients had itch scores of 0, indicating no itching, or 1, indicating mild itching, by the end of the study.

“The impact on the day-to-day life is really tremendous when you get the scores to that level,” he said.

Livmarli found to work for patients with different genetic profiles

Importantly, Livmarli was found to have “an impact across all [the] different genetic profiles, which is unique and new data for [PFIC] patients,” Peetz said.

Exploratory trial data indicate that Livmarli also may help normalize levels of bilirubin, a marker of liver damage. Among patients with high bilirubin levels at the study’s start, 40% of those given Livmarli and none in the placebo group saw their levels normalize after six months.

“The early data is really promising, already at six months to see bilirubin improvements,” Peetz said, adding there were also signals that Livmarli improved patients’ growth. These early findings suggest the therapy could help improve long-term liver health, such as delaying the need for a liver transplant.

Peetz noted Mirum is hoping to further explore these data and do outcome comparisons between Livmarli-treated patients and historical groups of untreated PFIC. Such work would help the company to better understand Livmarli’s effects on long-term liver health.

The company also is exploring potential uses for the therapy in other cholestatic diseases beyond PFIC and Alagille, its CEO said.

In addition, Mirum is developing a medication called volixibat that’s now in clinical trials for primary biliary cholangitis and primary sclerosing cholangitis, which are inflammatory bile duct diseases that cause cholestasis and typically affect adults.

“We have a team that’s really ambitious and looking for other rare disease medicines to bring in and work on. [We] hope to find many more of these medicines that can change the course of rare disease,” Peetz said.

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