FDA approves Mirum’s Livmarli for PFIC patients ages 5 and older

Decision on oral therapy to reduce itching marks 2nd approval in US

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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The U.S. Food and Drug Administration (FDA) has approved Mirum Pharmaceuticals’ Livmarli (maralixibat) to reduce pruritus, or itching, in adults and children, 5 years of age and older, with progressive familial intrahepatic cholestasis (PFIC).

This marks the second approval of Livmarli in the U.S. for liver-related diseases. The therapy was first approved, also to treat itching, in individuals ages 3 months and older with Alagille syndrome, a rare genetic liver disease.

The FDA’s decision comes about a year after Mirum submitted its regulatory application, and following an extended review period that allowed the analysis of new data submitted upon a request from the regulatory agency.

According to the company, Livmarli will now have immediate availability to eligible patients in the U.S.

Mirum also submitted an additional supplemental new drug application for a higher concentration of Livmarli to support a potential label expansion for younger PFIC patients.

“Livmarli has the potential to have a transformational impact for patients with cholestatic pruritus associated with PFIC, and importantly, offers an option for those patients with the rarest of subtypes,” Chris Peetz, CEO at Mirum, said in a company press release.

“Thank you to the patients, families, and clinicians whose study participation made this approval possible,” Peetz added.

Grape-flavored liquid therapy also approved for Alagille syndrome

PFIC is a broad term referring to several rare genetic diseases that are characterized by impaired production and/or secretion of the digestive fluid bile by liver cells. Such impairment leads to stalled bile flow, or cholestasis, in early life.

In PFIC and other forms of cholestasis, bile builds up in the liver and leaks out into the bloodstream, causing a range of symptoms that include itching.

Livmarli, taken as a grape-flavored liquid, is designed to block the activity of IBAT, fully ileal bile acid transporter, a protein that normally helps recycle bile in the intestines so that it can return to the liver and be reused when needed.

By blocking IBAT, the oral medication reduces bile acid reuptake in the intestines and promotes bile excretion in feces. That ultimately helps to battle the buildup of bile that drives cholestasis symptoms.

I am pleased that we will have a well-studied and efficacious option to offer patients whose life has been disrupted by itch.

In the U.S., Livmarli was granted orphan drug status, given to medications for rare diseases, for treating PFIC. It also was awarded breakthrough therapy designation for PFIC type 2, a specific form of the disease characterized by a deficiency of the BSEP protein. Both statuses are meant to help speed the therapy’s clinical development and regulatory review.

“Livmarli’s approval in cholestatic pruritus for patients with PFIC is a result of years of investigation and a collection of a strong body of clinical evidence showing meaningful improvements across a number of important parameters, including pruritus, affecting children with PFIC,” said Richard Thompson, an investigator in a Phase 3 trial testing Livmarli and a professor of molecular hepatology at King’s College London. “I am pleased that we will have a well-studied and efficacious option to offer patients whose life has been disrupted by itch.”

Livmarli had shown effectiveness in PFIC in a global clinical trial

Mirum’s application of Livmarli for PFIC was based primarily on data from a global Phase 3 clinical trial called MARCH-PFIC (NCT03905330), which comprised the largest and most genetically inclusive PFIC study to date.

The trial enrolled 93 children and adolescents, ages 1-17, with different PFIC types. The participants were randomly assigned to receive either Livmarli or a placebo for 26 weeks, or about six months.

The study’s main goal was to test if Livmarli reduced itching in the 31 participants with PFIC type 2. This was measured by changes in the ItchRO(Obs) severity score, with higher scores indicating worse itch.

Previous top-line results showed that, among this group, average ItchRO(Obs) scores dropped significantly more with Livmarli than with the placebo (by 1.7 vs. 0.6 points).  Treatment with Livmarli also led to a significant reduction in blood bile acid levels compared with the placebo.

Data on the trial’s secondary outcome measures came from 64 patients with known PFIC types (1, 2, 3, 4, and 6). These results likewise showed significantly greater benefits with Livmarli than the placebo in terms of reducing itching and blood bile acid levels.

Additional MARCH-PFIC data indicated that most individuals with PFIC achieved complete or near-complete itching resolution with Livmarli. Further, these positive changes were associated with improved sleep.

The therapy was generally safe and well tolerated.

Participants completing MARCH-PFIC could enroll in an ongoing open-label extension study called MARCH-ON (NCT04185363), in which all patients are receiving Livmarli for up to two years.

The MARCH-ON data indicated that the reductions in itching and blood bile acids seen in the original study were maintained with long-term treatment. Patients on the placebo in MARCH-PFIC showed similar improvements when starting Livarmli in the extension study.