Maralixibat for Itching in Liver Disease
Recruiting in Palo Alto (17 mi)
+34 other locations
Age: Any Age
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
Sponsor: Mirum Pharmaceuticals, Inc.
Must be taking: Antipruritics, Ursodeoxycholic acid
Must not be taking: IBAT inhibitors
Disqualifiers: ALGS, ICP, PBC, PFIC, PSC, others
Pivotal Trial (Near Approval)
Prior Safety Data
Breakthrough Therapy
Approved in 3 Jurisdictions
Trial Summary
What is the purpose of this trial?The purpose of this study is to determine whether the investigational treatment (maralixibat) is safe and effective in pediatric and adult participants who have cholestatic liver disease with pruritus that has been refractory to other therapies, and who have no other treatment options.
Will I have to stop taking my current medications?
The trial does not require you to stop taking your current medications if you are on antipruritics or ursodeoxycholic acid, as long as you have been on a stable dose for at least 30 days before the screening and continue this dosing during the study.
What data supports the effectiveness of the drug Maralixibat for itching in liver disease?
Research shows that Maralixibat can significantly reduce itching in children with Alagille syndrome, a liver disease, with some patients experiencing complete relief and stopping other itch medications. In clinical trials, Maralixibat was found to be safe and led to a noticeable decrease in itching compared to a placebo.
12345Is Maralixibat safe for humans?
Maralixibat has been studied in various clinical trials and is generally considered safe for humans, though some participants experienced side effects like gastrointestinal issues. Serious adverse events were similar between those taking maralixibat and those taking a placebo.
12345What makes the drug Maralixibat unique for treating itching in liver disease?
Maralixibat is unique because it targets the bile acid transport system, which is different from other treatments that may not address this specific mechanism. This approach can help reduce itching by decreasing the accumulation of bile acids in the body, which is a common issue in liver disease.
678910Eligibility Criteria
This trial is for children and adults with cholestatic liver disease who suffer from severe itching that hasn't improved with other treatments. Participants must have no remaining treatment options available to them.Inclusion Criteria
I can read and understand questionnaires.
I have been on a stable dose of medication for itching or ursodeoxycholic acid for the last 30 days.
Informed consent and assent (as applicable)
+4 more
Exclusion Criteria
Unstable and/or serious medical disease that is likely to impair the ability to participate in all aspects of the study, confound efficacy and/or safety assessments, or result in substantially shortened life expectancy (e.g., any active malignancy including hematological malignancy, end-stage heart failure, active infection, acute and chronic diarrhea). Exceptionally, previous history of malignancy, adequately treated/in remission, that in opinion of investigator and medical monitor does not impact participant safety and participation in the study, may be allowed
Known intolerance/hypersensitivity to maralixibat or its excipients
I have had skin itching or atopic dermatitis in the last year.
+6 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive maralixibat or placebo for up to 20 weeks, followed by maralixibat for an additional 20 weeks
40 weeks
Weekly visits for the first 20 weeks, then bi-weekly visits
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The study is testing the safety and effectiveness of a drug called Maralixibat compared to a placebo in reducing itchiness associated with cholestatic liver disease.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: MaralixibatExperimental Treatment1 Intervention
Participants will receive maralixibat oral solution 300 μg/kg orally once daily for 1 week and then twice daily for 39 weeks.
Group II: PlaceboPlacebo Group1 Intervention
Participants will receive placebo matched to maralixibat oral solution orally once daily for 1 week and then twice daily for 19 weeks. After 20 weeks, participants will receive maralixibat oral solution 300 μg/kg orally once daily for 1 week and then twice daily for 19 weeks.
Maralixibat is already approved in United States, European Union, Canada for the following indications:
🇺🇸 Approved in United States as Livmarli for:
- Treatment of cholestatic pruritus in patients with Alagille syndrome (ALGS) 1 year of age and older
- Treatment of cholestatic pruritus in patients with Alagille syndrome (ALGS) 3 months of age and older
🇪🇺 Approved in European Union as Livmarli for:
- Treatment of cholestatic pruritus in patients with Alagille syndrome
🇨🇦 Approved in Canada as Livmarli for:
- Treatment of cholestatic pruritus in adults with Alagille syndrome
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
New York University (NYU)New York, NY
Children's Hospital Los Angeles (CHLA)Los Angeles, CA
Ochsner Clinic FoundationNew Orleans, LA
Stanford Children's Health in Palo AltoPalo Alto, CA
More Trial Locations
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Who Is Running the Clinical Trial?
Mirum Pharmaceuticals, Inc.Lead Sponsor
References
Resolution of Pruritus in a Child With Alagille Syndrome Treated With Maralixibat for Seven Years: Durable Response and Discontinuation of Other Medications. [2023]Intractable pruritus is one of the most prominent and debilitating features of Alagille syndrome. Maralixibat is the first US Food and Drug Administration-approved drug for the treatment of cholestatic pruritus in children with Alagille syndrome aged 3 months and older. Clinical trials of maralixibat have reported follow-up to 4 years and reported a ≥1-pt reduction using the Itch-Reported Outcome (Observer) (ItchRO[Obs]) instrument (0-4 scale), as this decrease was previously defined as a clinically meaningful improvement in pruritus; participants in clinical trials were expected to be maintained on stable doses of antipruritic agents. We report on a patient with 3 notable features: (1) complete resolution of her pruritus; (2) durability of this response for over 7 years; and (3) ability to discontinue all other antipruritic medications.
Placebo-Controlled Randomized Trial of an Intestinal Bile Salt Transport Inhibitor for Pruritus in Alagille Syndrome. [2023]Medically refractory, severe, cholestasis-induced pruritus in Alagille syndrome may be improved by surgical interruption of the enterohepatic circulation. This multicenter trial (NCT02057692) tested the hypothesis that the intestinal bile acid transport inhibitor maralixibat would similarly reduce pruritus in Alagille syndrome. Thirty-seven children with Alagille syndrome were randomly assigned to double-blinded administration of placebo, 70, 140, or 280 µg/kg/day of maralixibat for 13 weeks. Pruritus was assessed by caregiver (itch-reported outcome instrument [ItchRO]) and clinician report (range, 0-4 [severe]). Liver chemistries and serum bile acids were measured. The primary outcome was the change from baseline to week 13 in ItchRO relative to placebo. In the a priori first analysis of the primary efficacy endpoint, the mean adjusted difference between participants receiving 140 or 280 µg/kg/day and placebo was -0.47 (95% confidence interval [CI], -1.14, 0.20; P = 0.16). Statistically significant decreases were observed with doses of 70 and 140 µg/kg/day (mean adjusted difference, -0.89; 95% CI, -1.70, -0.08; P = 0.032; and mean adjusted difference, -0.91; 95% CI, -1.62, -0.19; P = 0.014) but not 280 µg/kg/day (mean adjusted difference, -0.04; 95% CI, -0.94, 0.86; P = 0.44) or all doses combined (mean adjusted difference, -0.61; 95% CI, -1.24, 0.20; P = 0.055). A 1-point reduction in pruritus was more common in maralixibat-treated versus placebo-treated participants (caregiver ItchRO, 65% versus 25%; P = 0.06; clinician score, 76% versus 25%; P = 0.01). There were no significant changes in liver chemistries or bile acids relative to placebo. Adverse and serious adverse events were similar between maralixibat and placebo. Conclusion: Although the prespecified primary analyses of ItchRO were not all statistically significant, the data suggest that maralixibat is safe and may reduce pruritus in Alagille syndrome.
A Randomized, Controlled, Phase 2 Study of Maralixibat in the Treatment of Itching Associated With Primary Biliary Cholangitis. [2021]Primary biliary cholangitis (PBC) is typically associated with elevated serum bile acid levels and pruritus, but pruritus is often refractory to treatment with existing therapies. This phase 2 study assessed the efficacy and safety of maralixibat, a selective, ileal, apical, sodium-dependent, bile acid transporter inhibitor, in adults with PBC and pruritus. Adults with PBC and pruritus who had received ursodeoxycholic acid (UDCA) for ≥6 months or were intolerant to UDCA were randomized 2:1 to maralixibat (10 or 20 mg/day) or placebo for 13 weeks in combination with UDCA (when tolerated). The primary outcome was change in Adult Itch Reported Outcome (ItchRO™) average weekly sum score (0, no itching; 70, maximum itching) from baseline to week 13/early termination (ET). The study enrolled 66 patients (maralixibat [both doses combined], n = 42; placebo, n = 24). Mean ItchRO™ weekly sum scores decreased from baseline to week 13/ET with maralixibat (-26.5; 95% confidence interval [CI], -31.8, -21.2) and placebo (-23.4; 95% CI, -30.3, -16.4). The difference between groups was not significant (P = 0.48). In the maralixibat and placebo groups, adverse events (AEs) were reported in 97.6% and 70.8% of patients, respectively. Gastrointestinal disorders were the most frequently reported AEs (maralixibat, 78.6%; placebo, 50.0%). Conclusion: Reductions in pruritus did not differ significantly between maralixibat and placebo. However, a large placebo effect may have confounded assessment of pruritus. Lessons learned from this rigorously designed and executed trial are indispensable for understanding how to approach trials assessing pruritus as the primary endpoint and the therapeutic window of bile acid uptake inhibition as a therapeutic strategy in PBC.
Maralixibat: First Approval. [2022]Maralixibat (Livmarli™) is an orally-administered, small-molecule ileal bile acid transporter (IBAT) inhibitor being developed by Mirum Pharmaceuticals for the treatment of rare cholestatic liver diseases including Alagille syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC) and biliary atresia. Maralixibat received its first approval on 29 September 2021, in the USA, for use in the treatment of cholestatic pruritus in patients with ALGS 1 year of age and older. Maralixibat is also under regulatory review for ALGS in Europe, and clinical development for cholestatic liver disorders including ALGS in patients under 1 year of age, PFIC and biliary atresia is continuing in several other countries. This article summarises the milestones in the development of maralixibat leading to this first approval for ALGS.
Impact of long-term administration of maralixibat on children with cholestasis secondary to Alagille syndrome. [2023]There is growing interest in, but limited data about, intestinal bile acid transport inhibitors as treatment for cholestatic liver disease. The current analyses combine two similar randomized placebo-controlled trials with subsequent extension phases investigating the impact of maralixibat in children with severe cholestasis secondary to Alagille Syndrome (n = 57). The primary outcomes were measures of pruritus (ItchRO[Obs]) and clinician scratch scale (CSS), both increasing in severity from 0 to 4) and quality of life (QoL) (Parent PedsQL and Multidimensional Fatigue Scale module [MFS] scaled 0-100 with increased QoL) at week 48 of the extension phase relative to the baseline of the placebo-controlled trials (week 13). Secondary assessments included other clinical and biochemical parameters assessed in participants at week 72 or end of treatment (after week 48). At week 48, statistically and clinically significant least square mean (95% CI) improvements in pruritus and QoL were observed (ItchRO[Obs] -1.59 [-1.81, -1.36], CSS -1.36 [-1.67, -1.05], PedsQL +10.17 [4.48, 15.86], and multidimension fatigue [MFS] +13.97 [7.85, 20.08]). At week 48, serum bile acids, platelet count, and cholesterol decreased, whereas alanine aminotransferase (ALT) increased and total bilirubin (TB) and albumin were stable. Changes were durable at week 72 and end of treatment. There were no deaths; 2 participants underwent liver transplantation. Study drug was discontinued in 9 participants after treatment-emergent adverse events, 6 of which were events of increased ALT or TB. Conclusion: Maralixibat administration was associated with marked improvement in pruritus and QoL. Interpretation of these findings is complicated by the complex natural history of severe cholestasis in Alagille syndrome.
Use of levamisole in parasitic infections. [2018]Levamisole is a drug of choice for treatment of ascariasis. With recommended dosages, it is virtually free of side effects. Single doses of 50 to 150mg will eliminate all parasites in 90 to 100% of ascariasis patients irrespective of worm burden. Activity against hookworms has been demonstrated for levamisole but the most effective treatment regimen has not been determined. Further drug trials are needed for better assessment of efficacy. Levamisole has little or no curative action on infections with whipworms and pinworms. It may have some activity against strongyloides but confirmatory studies are needed. It has been shown that levamisole has significant activity against microfilariae of Wuchereria bancrofti and Brugia malayi. It is not, however, as effective as diethylcarbamazine ('Hetrazan'), and side reactions are greater. In tolerated doses, levamisole does not have significant action on adult forms or microfilariae of Onchoceea volvulus. The drug applied topically, however, may find a place in treatment of ocular onchocerciasis. Limited trials with levamisole for toxoplasmosis and chronic cutaneous leishmaniasis have given promising results, and further studies are indicated.
[Use of levamisole in W. bancrofti filariasis]. [2016]16 african patients with diagnosed W. bancroft's filariasis admitted to Pedro Kourí Tropical Medicine Institute were subjected to a therapeutic management with levamisole: 300 mg as starting dosage, and 150 mg/day for seven days. 11 patients had been previously treated with several courses of diethylcarbamazine (DEC), but a low microfilaremia persisted in them. In the other 5 patients the only medication used was levamisole. A rapid fall in microfilaria concentrations was found from the first day of treatment on in all patients. Eventually, 14 patients (87,5%) were negative and two patients (12,5%) persisted having low microfilaremia and their concentrations lowered by 89 ad 93% respectively.
Semiannual Treatment of Albendazole Alone is Efficacious for Treatment of Lymphatic Filariasis: A Randomized Open-label Trial in Cote d'Ivoire. [2022]Ivermectin (IVM) plus albendazole (ALB), or IA, is widely used in mass drug administration (MDA) programs that aim to eliminate lymphatic filariasis (LF) in Africa. However, IVM can cause severe adverse events in persons with heavy Loa loa infections that are common in Central Africa. ALB is safe in loiasis, but more information is needed on its efficacy for LF. This study compared the efficacy and safety of 3 years of semiannual treatment with ALB to annual IA in persons with bancroftian filariasis.
Vitamin A status of Indonesian children infected with Ascaris lumbricoides after dosing with vitamin A supplements and albendazole. [2018]In developing countries, both marginal vitamin A status and intestinal helminths are common among children. Indonesian children (n = 309, 0.6-6.6 y), known to be infected with Ascaris lumbricoides, were randomized into six different treatment groups (A-F). The treatments included 210 mumol vitamin A supplement and a dose of 400 mg albendazole (5-propylthio-1H-benzimidazol-2-yl carbamic acid methyl ester) administered orally either at the same health visit (Groups B and F) or at different contact times during a 1-mo period (groups A, C, D and E). Vitamin A status was assessed both before and 3-4 wk after the treatments by the modified relative dose response (MRDR) test. Vitamin A supplementation was most important in improving the vitamin A status (P
Levamisole and mebendazole in the treatment of bancroftian infection. [2013]Levamisole and mebendazole, broad spectrum anthelminthic compounds were tested against microfilaria of Wuchereria bancrofti, and the results were compared with similarly treated diethylcarbamazine and untreated group. Levamisole at a dosage of 3 mg/kg daily for 8 days showed marked reduction in both microfilaria rate and microfilaria density and immediately thereafter mf-rate steadily increased almost up to pre-treatment level, the mf-density however showed only marginal increase. Mebendazole at dosage of 6 mg/kg daily for 10 days following 8 days treatment of levamisole also showed marginal increase of mf-rate but no increase of mf-density. Treatment with DEC at a dosage of 6 mg/kg daily for 12 days showed comparatively better results both in respect of reduction in mf-rate and mf-density. The reactions - severity and duration were more among levamisole treated groups as compared to DEC treated group. Thus with the dosages tried, DEC could be considered as a better drug than levamisole and mebendazole. Both the latter compounds had no or very limited effect on the adult worms of W. bancrofti.