Alagille Syndrome

The FDA greenlit Mirum Pharmaceuticals’ Livmarli (maralixibat) for the treatment of cholestatic pruritus in patients aged five years and older with progressive familial intrahepatic cholestasis (PFIC), marking the oral ileal bile acid transporter inhibitor’s second US approval after its initial clearance for Alagille syndrome (ALGS) in 2021.“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,” remarked Mirum CEO Chris Peetz. The company, however, noted that Livmarli is not intended for the treatment of patients with PFIC type 2 characterised by a severe impairment in the bile salt export pump (BSEP) protein.The expanded label approval was based on findings from the Phase III MARCH trial, involving 93 patients with multiple PFIC genotypes, including those with unidentified mutations. In the study, Livmarli demonstrated significant improvements in pruritus, serum bile acid, bilirubin, and growth compared with placebo in a cohort comprising combined genetic subtypes. The application was also backed by favourable transplant-free survival outcomes seen with Livmarli in the Phase II INDIGO study.Livmarli is rivalled by Ipsen’s Bylvay (odevixibat), the latter having secured US approvals for both ALGS and PFIC in 2021. Although Bylvay has an edge in PFIC owing to an earlier approval and a younger eligible population from three months old, Mirum hopes to tackle it by seeking approval of a higher-strength version for younger patients with PFIC, later this year. Alongside the US, Livmarli has been approved for ALGS in the EU, Canada and other countries. The drugmaker has also filed with the European Medicines Agency for approval in patients with PFIC aged two months and older. Livmarli generated sales of $141.8 million last year.

Pictured: FDA signage at its Maryland campus/iStock, hapabapa The FDA on Wednesday approved Mirum Pharmaceuticals’ Livmarli (maralixibat) for the oral treatment of cholestatic pruritus in patients with progressive familial intrahepatic cholestasis that are five years of age and older. The California-based biotech also announced that it has filed a supplemental New Drug Application (sNDA) seeking approval for a higher concentration formulation of Livmarli for younger patients with progressive familial intrahepatic cholestasis (PFIC), a rare genetic disorder that causes progressive liver disease and can lead to significant morbidity and mortality. Mirum hopes to introduce this higher-concentration regimen later this year, according to its announcement. Mirum CEO Chris Peetz said in a statement that Livmarli could have “transformational impact for patients with cholestatic pruritis associated with PFIC” and provides an effective treatment option for those afflicted with the disease’s rarest subtypes. The FDA’s decision is backed by data from the Phase III MARCH trial, which according to Mirum’s announcement is the “largest randomized clinical trial conducted in PFIC.” MARCH enrolled 93 patients across the several different genetic subtypes of PFIC, including those with unidentified mutational status. Results showed that Livmarli was able to significantly improve pruritus symptoms in treated patients, as well as concentrations of serum bile acids and bilirubin. Patients in the livmarli arm also showed significantly better growth versus placebo. Mirum’s sNDA for PFIC, which the FDA accepted in February 2023, also included data from the phase II INDIGO study, which focused on patients with the PFIC2 genetic subtype. Responders, as determined by serum bile acid levels, had better transplant-free survival. Designed to be orally available, Livmarli is a selective inhibitor of the ileal bile acid transporter. The drug’s mechanism of action is not yet completely understood, but according to its label Livmarli reduces the overall reabsorption of bile acids from the terminal ileum. The FDA first approved Livmarli in September 2021 for the treatment of cholestatic pruritus associated with Alagille syndrome. Mirum’s main competitor in the PFIC arena is Ipsen, which acquired the AstraZeneca spin-off Albireo in January 2023 for $952 million. The deal introduced Bylvay (odevixibat) into the Ipsen fold. Bylvay, also an ileal bile acid transporter inhibitor, was first approved in July 2021 and became the first drug authorized to treat PFIC patients. Unlike Livmarli, Bylvay can be given to children as young as three months of age but is also administered at a much lower dose of 40 mcg/kg. Livmarli’s recommended dosing is 380 mcg/kg. In June 2023, the FDA expanded Bylvay’s label, allowing it to be used as a treatment for patients with chronic pruritus related to Alagille syndrome. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

Mirum Pharmaceuticals’s LIVMARLI (maralixibat) oral solution is now available in the US for cholestatic pruritus in patients with PFIC. Credit: Mirum Pharmaceuticals / Business Wire. The US Food and Drug Administration (FDA) has approved Mirum Pharmaceuticals ’s LIVMARLI (maralixibat) oral solution to treat cholestatic pruritus. The medication is intended for patients aged five years and above with progressive familial intrahepatic cholestasis (PFIC). A once-daily, orally administered ileal bile acid transporter inhibitor, LIVMARLI is the sole FDA-approved treatment for PFIC. The approval is based on findings from the Phase III MARCH clinical trial in 93 PFIC patients. The randomised trial enrolled people with PFIC genetic types PFIC1, PFIC2, PFIC3, PFIC4 and PFIC6, along with people with unidentified mutational status. See Also: Terns scores FDA orphan designation for CML therapy FDA issues CRL to Mapi Pharma for GA Depot to treat RMS The FDA, the European Commission and Health Canada have also granted approval for LIVMARLI for the treatment of cholestatic pruritus in patients with Alagille syndrome in their respective regions. In addition to its current approvals, Mirum has filed a supplemental new drug application to the FDA. The aim is to introduce a higher concentration formulation of LIVMARLI, which was utilised in the Phase III MARCH study. This could expand the treatment’s label for younger PFIC patients later in 2024. A rare genetic disorder, PFIC results in progressive liver disease that can go on to cause liver failure. Mirum Pharmaceuticals CEO Chris Peetz stated: “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. “Thank you to the patients, families and clinicians whose study participation made this approval possible.” In September 2023, the company concluded the acquisition of the bile acid product portfolio of Travere Therapeutics . Mirum gained the rights and assets related to Cholbam (cholic acid) and Chenodal (chenodiol). Travere secured $210m from Mirum, with the potential to receive $235m in sales-based milestone payments.