Early improvements with long-term impact in Alagille syndrome (ALGS)

Branching out: ICONIC was the first
pivotal study of its kind

The ICONIC study assessed efficacy and safety of treatment with LIVMARLI in
patients ≥1 year old with cholestatic pruritus associated with ALGS^1,2

Cholestatic pruritus responses to LIVMARLI were assessed through approximately 4 years.

A study design chart of the ICONIC study with open label extension.

* Included a 6-week dose escalation period for all participants during the first 6 weeks of the open-label treatment period and for participants who received placebo during the randomized withdrawal design.
^† Twice-per-day dosing was allowed after Week 100. The approved dosage of LIVMARLI is 380 mcg/kg once daily.

84%

(n=26/31) of patients with ALGS experienced clinically meaningful (as defined by ItchRO) improvements in cholestatic pruritus compared with baseline at Week 48 of the ICONIC study due to reductions in sBA.³

Early improvements in cholestatic pruritus^3,4

Significant improvements in cholestatic pruritus from baseline were seen at the very first assessment (Week 3), with the full effect achieved by Week 18 and maintained through 1 year with once-daily LIVMARLI (P<0.0001).^3,4

A graph of the mean change from baseline in the ICONIC study with an open label extension.

Cholestatic pruritus was assessed each day, in the morning and evening, using the ItchRO scale—a validated tool designed to assess the impact of cholestatic pruritus in people with cholestatic liver disease, including ALGS. The ItchRO score is a 0–4 scale, where 0 is none, 1 is mild, 2 is moderate, 3 is severe, and 4 is very severe^3,4
“Clinically meaningful” was defined as ≥1.0 ItchRO(Obs) improvement vs baseline

Efficacy demonstrated in patients who were on background pruritus
therapies, including ursodeoxycholic acid and rifampicin¹

See PFIC data

BL=baseline; ItchRO=Itch Reported Outcome; ItchRO(Obs)=Itch Reported Outcome for Observer; ItchRO(Pt)=Itch Reported Outcome (Patient); sBA=serum bile acid; SE=standard error.

* ItchRO(Obs) was completed by caregivers and was the basis for the key pruritus endpoint. The ItchRO(Pt) was completed independently by participants aged 9 years or older and with caregiver assistance for participants aged 5 to 8 years.^3,4
^† Change from baseline, P<0.0001.^3,4
^‡ Included an initial 6-week dose escalation for participants previously receiving placebo.^3,4

At 7 years, the MERGE study showed

88%

of evaluable patients (14/16) maintained a persistent response with more than 85% of measurements showing a reduction ≥1 point in ItchRO(Obs) score.⁵

Results in fatigue

This analysis assessed the impact of treatment response to LIVMARLI on patients with ALGS health-related quality of life (HRQoL) and used data from the pivotal trial, ICONIC. The Pediatric Quality of Life Inventory (PedsQL) Multidimensional Fatigue Scale was measured using a caregiver proxy report at baseline and Weeks 18, 22, and 48 that was collected prospectively during the study and analyzed retrospectively. As these scales were not specifically developed for patients with ALGS, a subset of individual items from the HRQoL scales deemed most relevant was independently selected by clinical experts for assessment with treatment response.⁶

During the first year of treatment, 74% (n/N=20/27) of patients treated with LIVMARLI were considered responders.⁶

Responders were defined as patients who had a 1-point ItchRO(Obs) improvement from baseline to Week 48⁶
The mean (standard deviation [SD]) change in the Multidimensional Fatigue Scale total score was +25.8 (23.0) for responders vs –3.1 (19.8) for nonresponders⁶
The data were available in 21 patients at baseline and Week 48 and 6 patients had missing data at Week 48⁶

Multidimensional fatigue total score⁶*

A graph of the multidimensional fatigue total score results.

Cholestatic pruritus responders had meaningful improvements in
fatigue while being treated with LIVMARLI.⁶

Limitations⁶

The PedsQL Multidimensional Fatigue Scale has not been optimized for pediatric patients with cholestatic diseases
This analysis was limited by small sample sizes, in some cases due to missing data, meaning some of the analyses may have been underpowered. This study did not adjust for multiplicity
Sleep-related items may have improved because reductions in pruritus results in fewer disruptions and a better quality of sleep
Given these limitations, results should be interpreted with caution

*A higher value in the multidimensional fatigue total score represents a positive response.

Assessed multiple facets of fatigue⁶

LIVMARLI responders experienced improvements in 5 sleep-related assessments of the PedsQL Multidimensional Fatigue Scale compared with nonresponders, including:

Feeling tired
Sleeping a lot
Difficulty sleeping through the night
Feeling tired upon waking
Taking a lot of naps

Additional parameters assessed in the PedsQL Multidimensional Fatigue Scale included “difficulty keeping his or her attention” and “resting a lot,” but no meaningful results were observed.⁶

Téa struggled with persistent itching and disrupted sleep until she started LIVMARLI

"After about 14 days on LIVMARLI, we noticed a change in her itching."

–Michelle, Téa's mom

Watch the full video

Not all patients taking LIVMARLI and their caregivers will have the same experience.

References:

1. LIVMARLI® (maralixibat). Prescribing Information. Mirum Pharmaceuticals, Inc. 2. Miethke A, Moukarzel A, Porta G, et al. Efficacy and safety of maralixibat in patients with progressive familial intrahepatic cholestasis (MARCH-PFIC): a randomized placebo-controlled phase 3 study. Presented at: North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) Annual Meeting: October 4-7, 2023; San Diego, CA. 3. Gonzales E, Hardikar W, Stormon M, et al. Efficacy and safety of maralixibat treatment in patients with Alagille syndrome and cholestatic pruritus (ICONIC): a randomised phase 2 study. Lancet. 2021;398(10311):1581-1592. doi:10.1016/S0140-6736(21)01256-3 4. Gonzales E, Sturm E, Stormon E, et al. Durability of treatment effect with long-term maralixibat in children with Alagille syndrome: 4-year safety and efficacy. Presented at: American Association for the Study of Liver Diseases Annual Meeting: The Liver Meeting; November 8-12, 2019; Boston, MA. 5. Murray KF, Kamath BM, Gonzales E, et al. Clinical benefits of maralixibat for patients with Alagille syndrome are durable through 7 years of treatment: data from the MERGE study. Poster presented at: North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) Annual Meeting; November 6-9, 2024; Hollywood, Florida. 6. Kamath BM, Goldstein A, Howard R, et al. Maralixibat treatment response in Alagille syndrome is associated with improved health-related quality of life. J Pediatr. 2023;252:68-75.e5. doi:10.1016/j.jpeds.2022.09.001 7. Raman RK, Garner W, Vig P, Tucker E. An integrated analysis of long-term clinical safety in maralixibat-treated participants with Alagille syndrome. Poster presented at: European Association for the Study of the Liver (EASL): International Liver Congress; June 23-26, 2021. 8. Shneider BL, Spino C, Kamath BM, et al; Childhood Liver Disease Research Network. Placebo-controlled randomized trial of an intestinal bile salt transport inhibitor for pruritus in Alagille syndrome. Hepatol Commun. 2018;2(10):1184-1198. doi:10.1002/hep4.1244

Indications

LIVMARLI (maralixibat) oral solution and tablets are indicated for the treatment of cholestatic pruritus in patients who are 3 months of age and older with Alagille syndrome.

LIVMARLI (maralixibat) oral solution and tablets are indicated for the treatment of cholestatic pruritus in patients who are 12 months of age and older with progressive familial intrahepatic cholestasis (PFIC).

Limitations of Use: LIVMARLI is not recommended in a subgroup of PFIC type 2 patients with specific ABCB11 variants resulting in nonfunctional or complete absence of bile salt export pump (BSEP) protein.

Important Safety Information

CONTRAINDICATIONS

LIVMARLI (maralixibat) oral solution and tablets are contraindicated in patients with prior or active hepatic decompensation events (eg, variceal hemorrhage, ascites, or hepatic encephalopathy).

WARNINGS AND PRECAUTIONS

Hepatotoxicity: LIVMARLI treatment is associated with a potential for drug-induced liver injury (DILI). In the PFIC trial, treatment-emergent hepatic decompensation events and elevations of liver tests or worsening of liver tests occurred. Two patients experienced DILI attributable to LIVMARLI. Two additional patients experienced DILI in the open-label extension portion of the trial. Of these 4 patients, 1 patient required liver transplant and another patient died.

In the Alagille syndrome trial, treatment-emergent elevations of liver tests or worsening of liver tests occurred.

Obtain baseline liver tests and monitor during treatment. Liver-related adverse reactions and physical signs of hepatic decompensation should also be monitored. Dose reduction or treatment interruption may be considered if abnormalities occur in the absence of other causes. For persistent or recurrent liver test abnormalities, consider treatment discontinuation. Permanently discontinue LIVMARLI if a patient experiences the following: persistent or recurrent liver test abnormalities, clinical hepatitis, or a hepatic decompensation event.

Gastrointestinal Adverse Reactions: Diarrhea and abdominal pain were reported as the most common adverse reactions. Monitor for dehydration and treat promptly. Consider reducing the dosage or interrupting LIVMARLI treatment if a patient experiences persistent diarrhea or diarrhea with bloody stool, vomiting, dehydration requiring treatment, or fever.

Fat-Soluble Vitamin (FSV) Deficiency: Patients can have FSV deficiency (vitamins A, D, E, and K) at baseline, and LIVMARLI may adversely affect absorption of FSVs. Treatment-emergent bone fracture events have been observed more frequently with patients treated with LIVMARLI compared with patients treated with placebo. If bone fractures or bleeding occurs, consider interrupting LIVMARLI and supplement with FSVs. LIVMARLI can be restarted once FSV deficiency is corrected and maintained at corrected levels.

Risk of Propylene Glycol Toxicity (Pediatric Patients Less Than 5 Years of Age): LIVMARLI oral solution contains propylene glycol. Total daily intake of propylene glycol should be considered for managing the risk of propylene glycol toxicity. Monitor patients for signs of propylene glycol toxicity. Discontinue LIVMARLI if toxicity is suspected.

ADVERSE REACTIONS

Alagille syndrome: The most common adverse reactions are diarrhea, abdominal pain, vomiting, FSV deficiency, liver test abnormalities, and bone fractures.

PFIC: The most common adverse reactions are diarrhea, FSV deficiency, abdominal pain, liver test abnormalities, hematochezia, and bone fractures.

DRUG INTERACTIONS

Administer LIVMARLI at least 4 hours before or 4 hours after administration of bile acid binding resins.

A decrease in the absorption of OATP2B1 substrates (eg, statins) due to OATP2B1 inhibition by LIVMARLI in the GI tract cannot be ruled out. Consider monitoring the drug effects of OATP2B1 substrates as needed.

DOSING INFORMATION

In patients with Alagille syndrome, LIVMARLI is taken once daily, 30 minutes before a meal in the morning. In patients with PFIC, LIVMARLI is taken twice daily, 30 minutes before a meal. Refer to the dosing by weight guidelines in the full Prescribing Information for complete details on dosing for the oral solution and tablet formulations. The provided oral solution dosing dispenser must be used to accurately measure the dose. Any remaining LIVMARLI oral solution should be discarded 100 days after first opening the bottle. LIVMARLI tablets can be used in patients weighing ≥25 kg who can swallow tablets.

Please see full Prescribing Information for LIVMARLI.