Mirum Pharmaceuticals Presents New Data From Clinical Studies of Maralixibat and Volixibat at AASLD Annual Meeting
Data from maralixibat demonstrate the relationship between reduction in serum bile acids and the intensity of pruritus, improvement in growth, and other measures of quality of life.
Analysis of the natural variability of pruritus in children with Alagille syndrome demonstrates persistent severity.
Volixibat data show highly active dose levels selected for phase 2 studies.
Mirum Pharmaceuticals, Inc. (Nasdaq: MIRM), a biopharmaceutical company focused on the development and commercialization of novel therapies for debilitating liver disease, today announced new reviews of its clinical programs maralixibat and volixibat, presented at the American Association for the Study of Liver Disease Annual Meeting – The Liver Meeting Digital Experience ™.
A summary of the results of each of the poster presentations is presented below. To view the data in full, please visit the AASLD section in the Events page on our corporate website.
“Data generated from a six-year clinical evaluation of maralixibat in Alagille syndrome has provided insight into the severe burden of pruritus and associated markers of cholestasis, helping to elucidate the potential benefit of maralixibat in this setting. treatment, ”said Dr. Pam Vig, Scientific Director of Mirum. “We are also delighted to begin Phase 2 studies of volixibat in adult patients with cholestatic liver disease, which will assess dose levels that have been shown to be effective in increasing bile acid excretion, suggesting the potential to reduce the burden of cholestasis in these settings.
Abstract # 341: Intensity of pruritus is associated with cholestasis biomarkers and quality of life measures after maralixibat treatment in children with Alagille syndrome
Pruritus associated with Alagille syndrome (ALGS) is often extremely debilitating, leading to bleeding, scarring, sleep disturbances, fatigue and reduced quality of life, with a significant impact on the patient and their family. . This review, which used data from the maralixibat phase 2b ICONIC study in pediatric patients with cholestatic pruritus associated with ALGS, assessed the relationship between change in pruritus intensity and change in markers of cholestasis and other clinical parameters. The study evaluated 31 patients, 27 of whom were evaluated for this analysis over a 48-week period. Overall, the positive therapeutic effects of maralixibat in patients with ALGS demonstrate important correlations with several clinically relevant parameters. Pruritus, as measured by the Fully Validated Itch Reported Outcome Observer (ItchRO[Obs]), has been correlated with several parameters including clinician’s correction scale, serum bile acids (sBA) and sBA subspecies, autotaxin, measures of growth and quality of life, including fatigue .
Abstract # 1792: Natural variability of pruritus in Alagille syndrome; an analysis of the ICONIC study using the Itch Reported Outcome Observer (ItchRO[Obs]) tool
Itching is known to be one of the most distressing symptoms associated with ALGS; however, the variability of its severity and frequency has not been fully established. Ratings are based on outcome measures reported by observers or patients. The ItchRO (Obs) and ItchRO (Pt) tools were used to assess the natural variability of pruritus in children with ALGS who were enrolled in the randomized phase 2b ICONIC, placebo-controlled study. Scores were assessed during the 28-day ICONIC screening period, when no medication was administered. The results showed that the assessment of morning and evening pruritus was persistent over time with minimal fluctuations in severity and frequency.
Abstract # 1221: A phase 1 dose-dose study evaluating fecal excretion of bile acid by volixibat, an apical sodium-dependent bile acid transporter inhibitor, and coadministered with loperamide
The primary objective of this Phase 1 clinical study was to investigate the safety and efficacy of a range of dose levels and dosing regimens of volixibat, to help guide dose selection for trials. clinical studies in patients with cholestatic disease, in particular the phase 2 programs planned in adult patients with primary sclerosing cholangitis and intrahepatic cholestasis of pregnancy. The study evaluated the effects of volixibat alone and in combination with loperamide, seeking to understand whether adding loperamide would reduce mild gastrointestinal side effects that are often seen with ASBT inhibitors.
Analysis revealed that volixibat was well tolerated at all dose levels and at all dosing regimens evaluated. As expected for the mechanisms of action of volixibat, fecal bile acid excretion was increased in all treatment groups. Overall, twice-daily administration was associated with greater increases in bile acid excretion compared to once-daily administration. The use of volixibat in healthy adult volunteers has been associated with significant increases in fecal excretion of bile acids and serum 7αC4, which are markers of bile acid synthesis. In addition, the standard dosage of loperamide helped reduce mild and transient gastrointestinal disturbances at the initial dose of volixibat, without drug interaction. The effects on trafficking and bile acid synthesis support further study of volixibat in patients with cholestatic liver disease.
Maralixibat is an investigational new drug administered orally with minimal absorption being evaluated in several rare cholestatic liver diseases. Maralixibat inhibits the apical sodium-dependent bile acid transporter (ASBT), which results in the excretion of more bile acids in the stool, resulting in a systemic drop in bile acid levels, reducing thus potentially the liver damage induced by bile acid and the associated effects and complications. More than 1,600 people have received maralixibat, including more than 120 children who have received maralixibat as an experimental treatment for Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC). In the ICONIC Phase 2b ALGS clinical trial, patients taking maralixibat experienced significant reductions in bile acids and pruritus compared to placebo, as well as a reduction in xanthomas and accelerated long-term growth. In one Phase 2 PFIC study, a genetically defined subset of BSEP-deficient (PFIC2) patients responded to maralixibat. The United States Food and Drug Administration (FDA) has granted Maralixibat Breakthrough Therapy designation for the treatment of pruritus associated with ALGS in patients one year of age and older and for PFIC2. Maralixibat was generally well tolerated throughout the studies. The most common treatment-related adverse events were diarrhea and abdominal pain. Until maralixibat is approved by the FDA and available for prescription, the drug is available for patients with ALGS through Mirum’s Expanded Access Program. For more information, please visit ALGSEAP.com. For more information on the Phase 3 study of maralixibat in pediatric patients with PFIC, visit PFICtrial.com.
Volixibat is a minimally absorbed oral agent designed to selectively inhibit ASBT. Volixibat may offer a novel approach in the treatment of cholestatic disease in adults by blocking bile acid recycling, inhibiting the sodium-dependent apical bile acid transporter (ASBT), thereby reducing bile acids systemically and in the liver. Phase 1 and phase 2 clinical trials of volixibat demonstrated targeted fecal bile acid excretion, a pharmacodynamic marker of ASBT inhibition, in addition to decreased LDL cholesterol and increased 7αC4 which are markers of the synthesis of bile acids. Volixibat has been evaluated in over 400 subjects in several clinical trials. The most frequently reported adverse events were mild to moderate gastrointestinal events observed in the volixibat groups.
About Mirum Pharmaceuticals
Mirum Pharmaceuticals, Inc. is a clinical-stage biopharmaceutical company focused on the development and commercialization of an advanced pipeline of novel therapies for debilitating liver disease. The Company’s lead product candidate, maralixibat, is an investigational oral drug in development for Alagille syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC) and biliary atresia. The company has launched an ongoing NDA submission for maralixibat in the treatment of patients with cholestatic pruritus associated with ALGS and plans to complete the submission in the first quarter of 2021. In addition, the company plans to submit an application for marketing authorization to the European Medicines Agency for maralixibat in the treatment of patients with PFIC2 in the fourth quarter of 2020.
The company is also developing volixibat, also an oral ASBT inhibitor, in primary sclerosing cholangitis and intrahepatic cholestasis of pregnancy. For more information visit MirumPharma.com. Follow Mirum on Twitter, Facebook and LinkedIn.
Statements contained in this press release concerning matters which are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include statements concerning, among other things, results , the conduct and advancement of current and planned studies of Mirum for maralixibat and volixibat, and the regulatory approval path for maralixibat and volixibat. Since these statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied in these forward-looking statements. Words such as “plans”, “will”, “may”, “expects”, “objective”, “potential” and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based on Mirum’s current expectations and involve assumptions which may never materialize or prove to be incorrect. Actual results could differ materially from those anticipated in these forward-looking statements due to various risks and uncertainties, which include, but are not limited to, the risks and uncertainties associated with Mirum’s business in general, the impact of the COVID-pandemic. 19, and the other risks described in documents filed by Mirum with the Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date they were made and are based on management’s assumptions and estimates as of that date. Mirum assumes no obligation to update these statements to reflect events that occur or circumstances that exist after the date they were made, except as required by law.
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Ian Clements, Ph.D.