ATP8B1

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.

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.

New research shows how important protein keeps our cell membranes in balance. Researchers have studied the structure, function and mechanisms of the protein ATP8B1, which flips lipid molecules in our cell membranes and plays a key role in bile biosynthesis. Importantly, ATP8B1 has also emerged as a genetic marker of Alzheimer's resilience. These results give new possibilities for therapeutic interventions in conditions related to bile homeostasis disorders and neurodegenerative diseases. Lipids are the main constituents of our cell membranes, which are formed as lipid bilayers. The distribution of lipids is far from uniform; it is asymmetric, with different lipid compositions in the outside and inside layers. This asymmetry is essential for a variety of cellular functions, from maintaining membrane homeostasis to enabling cell signaling and numerous other physiological processes at or across membranes. P4-ATPases, also known as flippases, are key players in creating and maintaining this lipid asymmetry. These enzymes actively transport lipids from the outside (exoplasmic) leaflet to the inside (cytosolic) leaflet coupled to ATP hydrolysis and ensure the proper distributions of lipids. The ATP8B1-CDC50A flippase complex in particular, has been the subject of the current study, leading to several new, groundbreaking discoveries. The function of ATP8B1 lipid flippase is critical for the regulation of bile production, a vital substance in our digestive system, but the direct link within bile producing liver cells remains unknown. Additionally, recent studies have spotlighted the relevance of genetic variants in the regulatory segment of the ATP8B1 gene as a strong genetic marker for Alzheimer's resilience. Interestingly, mutations that impair function of the closely related ATP8B4 lipid flippase are oppositely important risk factors of Alzheimer's. It is therefore of strong interest to understand how ATP8B1 is linked to these processes and pathologies. In the new study, the research team employed state-of-the-art cryo-electron microscopy techniques to capture nine different states associated with the lipid transport and determine structures at 2.4 to 3.1 Å resolution for these states. These structural insights, combined with functional and computational studies, reveal the inner workings of the human flippase ATP8B1-CDC50A complex and its fine regulation by specific regulatory lipids known as phosphoinositides, or PIPs. These findings open doors to a deeper understanding of how lipid flippases operate and the intricate roles they play in cellular processes and are regulated. Importantly, the study also resolves earlier discrepancies about the ATP8B1 transport substrates. Noteworthy, both up- or down-regulation of ATP8B1-CDC50 function could potentially be of interest in drug discovery, and the study also reveals critical information to such applications.