Slide 1: Efficacy and Safety of Maralixibat in Patients with PFIC (MARCH-PFIC)
Efficacy and Safety of Maralixibat in Patients with Progressive Familial Intrahepatic Cholestasis (MARCH-PFIC): A Randomized Placebo-Controlled Phase 3 Study Alexander Miethke1, Adib Moukarzel2, Gilda Porta3, Joshue Covarrubias Esquer4, Piotr Czubkowski5, Felipe Ordonez6, Manila Candusso7, Amal A Aq
Slide 2: Richard J Thompson
Richard J Thompson • Professor of Molecular Hepatology at King’s College London, and Honorary Consultant Paediatric Hepatologist at King’s College Hospital, London • Specializes in genetic liver disease in both children and adults • Through worldwide collaborations, his lab continues to identify new
Slide 3: Disclosures
Disclosures • R J Thompson is a consultant for Mirum Pharmaceuticals, Inc., Albireo, GenerationBio, and Rectify Therapeutics, and is a shareholder in GenerationBio and Rectify Therapeutics 3
Slide 4: Progressive Familial Intrahepatic Cholestasis (PFIC)
Progressive Familial Intrahepatic Cholestasis (PFIC) • Genetic disorders resulting in disrupted bile composition and chronic cholestasis1 • Debilitating pruritus, impaired growth, reduced QoL, and progressive liver disease with most children undergoing liver transplantation2−5 • PFIC types include d
Slide 5: Maralixibat: IBAT Inhibitor That Interrupts Enterohepatic Circulation
Maralixibat: IBAT Inhibitor That Interrupts Enterohepatic Circulation Redirects bile Clinical effects of acid flow by inhibiting reuptake by IBAT maralixibat in cholestasis: ✓ Improvements in pruritus1-3 Interrupts recirculation ✓ Reduction in peripheral sBA1-3 of bile acids to the liver ✓ Five-year
Slide 6: MARCH-PFIC: Phase 3 Study Design
MARCH-PFIC: Phase 3 Study Design Key Entry Criteria Maralixibat • Diagnosis of PFIC 570 µg/kg BID* MARCH-ON • Age ≥12 months and <18 years R Phase 3 open-label extension at time of baseline 1:1 study • Persistent, moderate to severe Placebo pruritus • sBA ≥3× ULN BL 6 months *Maralixibat 570 µg/kg i
Slide 7: MARCH-PFIC: Study Populations
MARCH-PFIC: Study Populations BSEP cohort: nt-BSEP (n = 31) All-PFIC cohort (n = 64) Full-Study FIC1 (n = 13), MDR3 (n = 9), TJP2 (n = 7), Population and MYO5B (n = 4) (N = 93) (n = 33) Heterozygosis* (n = 2), truncated-BSEP (n = 9), variants Exploratory cohort not found (n = 8), fluctuating sBA (n
Slide 8: MARCH-PFIC: Efficacy Endpoints
MARCH-PFIC: Efficacy Endpoints Secondary Endpoints (BSEP and All-PFIC cohorts): ▪ Mean change in morning ItchRO(Obs) severity score between baseline and average of the last 12 weeks in the All-PFIC cohort ▪ Mean change in total sBA level between baseline and average of Primary Endpoint (BSEP cohort)
Slide 9: Key Demographics and Baseline Characteristics
Key Demographics and Baseline Characteristics BSEP All-PFIC Full-Study Maralixibat Placebo Maralixibat Placebo Maralixibat Placebo Variable (n = 14) (n = 17) (n = 33) (n = 31) (n = 47) (n = 46) Age (years); mean 6.3 4.2 4.9 4.4 4.8 4.7 Sex (male); % 50 35 52 42 43 48 Pruritus (ItchRO[Obs]); mean 2.9
Slide 10: Primary Endpoint: Change in Weekly ItchRO(Obs) Score in BSEP Cohort
Primary Endpoint: Change in Weekly ItchRO(Obs) Score in BSEP Cohort Pruritus Score (ItchRO[Obs]) MMRM Analysis Weekly Average Pruritus Score (ItchRO[Obs]) Over Time Maralixibat Placebo Maralixibat Placebo (n = 14) (n = 17) 0.0 0.0 -0.5 Change from Baseline Change from Baseline -0.5 -1.0 Improvement
Slide 11: Change in Weekly ItchRO(Obs) Score in FIC1, MDR3, TJP2, and MYO5B
Change in Weekly ItchRO(Obs) Score in FIC1, MDR3, TJP2, and MYO5B Pruritus Score (ItchRO[Obs]) MMRM Analysis Weekly Average Pruritus Score (ItchRO[Obs]) Over Time Maralixibat Placebo Maralixibat Placebo (n = 19) (n = 14) FIC1, MDR3, TJP2, and MYO5B FIC1, MDR3, TJP2, and MYO5B BSEP BSEP 0.0 0.0 Chang
Slide 12: Secondary Endpoint: Change in Weekly ItchRO(Obs) Score in All-PFIC Cohort
Secondary Endpoint: Change in Weekly ItchRO(Obs) Score in All-PFIC Cohort Pruritus Score (ItchRO[Obs]) MMRM Analysis Weekly Average Pruritus Score (ItchRO[Obs]) Over Time Maralixibat Placebo Maralixibat Placebo (n = 33) (n = 31) 0.0 0.0 Change from Baseline -0.5 Change from Baseline Improvement -0.5
Slide 13: Secondary Endpoint: Change From Baseline in Serum Bile Acids in BSEP Cohort
Secondary Endpoint: Change From Baseline in Serum Bile Acids in BSEP Cohort Serum Bile Acid MMRM Analysis Average Serum Bile Acids Over Time Maralixibat Placebo Maralixibat Placebo (n = 12) (n = 17) 100 100 11 50 50 Change from Baseline, Change from Baseline, 0 Improvement 0 (μmol/L) (μmol/L) -50 -5
Slide 14: Change From Baseline in Serum Bile Acid in FIC1, MDR3, TJP2, and MYO5B
Change From Baseline in Serum Bile Acid in FIC1, MDR3, TJP2, and MYO5B Serum Bile Acid MMRM Analysis Average Serum Bile Acids Over Time Maralixibat Placebo Maralixibat Placebo (n = 19) (n = 14) FIC1, MDR3, TJP2, and MYO5B FIC1, MDR3, TJP2, and MYO5B 50 100 BSEP BSEP -6 50 Change from Baseline, Chang
Slide 15: Secondary Endpoint: Change From Baseline in Serum Bile Acid in All-PFIC Cohort
Secondary Endpoint: Change From Baseline in Serum Bile Acid in All-PFIC Cohort Serum Bile Acid MMRM Analysis Average Serum Bile Acids Over Time Maralixibat Placebo Maralixibat Placebo 100 (n = 31) (n = 31) 50 Change from Baseline, 50 3 Change from Baseline, 0 0 Improvement (μmol/L) -50 (μmol/L) -50
Slide 16: Secondary Endpoint: Pruritus and sBA Responder Analyses in All-PFIC Cohort
Secondary Endpoint: Pruritus and sBA Responder Analyses in All-PFIC Cohort Pruritus Responders* Serum Bile Acid Responders* ≥1-point reduction OR score of ≤1.0 ≥75% reduction OR serum bile acid <102 µmol/L 100 100 p=0.0023 p<0.0001 Δ: 37.8 (11.3, 59.4)† Δ: 45.1 (21.8, 64.0)† 75 75 Responders (%) Res
Slide 17: Exploratory Endpoint: Change From Baseline in Total Bilirubin in All-PFIC Cohort
Exploratory Endpoint: Change From Baseline in Total Bilirubin in All-PFIC Cohort Serum Total Bilirubin MMRM Analysis Average Serum Total Bilirubin Over Time Maralixibat Placebo Maralixibat Placebo (n = 33) (n = 31) 3 3.0 Change from Baseline, 2 Change from Baseline, 2.0 1 Improvement (mg/dL) 1.0 0 (
Slide 18: Exploratory Endpoint: Change From Baseline in Direct Bilirubin in All-PFIC Cohort
Exploratory Endpoint: Change From Baseline in Direct Bilirubin in All-PFIC Cohort Serum Direct Bilirubin MMRM Analysis Average Serum Direct Bilirubin Over Time Maralixibat Placebo Maralixibat Placebo (n = 33) (n = 31) 3 2 Change from Baseline, 3.0 Change from Baseline, 2.0 1 Improvement (mg/dL) 1.0
Slide 19: Change From Baseline in ALT in All-PFIC Cohort
Change From Baseline in ALT in All-PFIC Cohort Serum ALT MMRM Analysis Average Serum ALT Over Time Maralixibat Placebo Maralixibat Placebo 100 (n = 33) (n = 31) Change from Baseline (U/L) 50 Change from Baseline (U/L) 25 50 0 9.7 -7.0 0 -25 -50 -50 Δ: 16.6 (-13.31, 46.60)* 0 2 4 6 8 10 12 14 16 18 2
Slide 20: Exploratory Endpoint: Change From Baseline in Weight and Height Z-Score
Exploratory Endpoint: Change From Baseline in Weight and Height Z-Score in All-PFIC Cohort Weight Z-score MMRM Analysis Height Z-score MMRM Analysis Maralixibat Placebo Maralixibat Placebo (n = 33) (n = 31) (n = 33) (n = 31) 0.4 0.4 Change from Baseline Change from Baseline 0.35 Improvement 0.2 0.2
Slide 21: Summary of TEAEs in Full-Study Cohort (N = 93)
Summary of TEAEs in Full-Study Cohort (N = 93) Maralixibat Placebo TEAE (n = 47) (n = 46) Any TEAE, n (%) 47 (100%) 43 (93.5%) Severe TEAE, n (%) 3 (6.4%) 3 (6.5%) Serious TEAE, n (%) 5 (10.6%) 3 (6.5%) TEAE leading to discontinuation, n (%) 1 (2.1%) 0 TEAE leading to death, n (%) 0 0 Most common TE
Slide 22: Key Takeaways
Key Takeaways • MARCH is the largest Phase 3 trial conducted in children with PFIC that included PFIC types that had not previously been studied • Primary and secondary endpoints were met • Maralixibat demonstrated significant and rapid improvements in pruritus and serum bile acids, consistent acros
Slide 23: Acknowledgments
Acknowledgments • The authors would like to thank the clinical trial participants, their families, and investigators for their participation in the MARCH-PFIC clinical study 23
Slide 24: Author Disclosures
Author Disclosures • A Miethke is a consultant and has a sponsored research agreement for Mirum Pharmaceuticals, Inc • F Ordonez is a speaker for Alexion Pharmaceuticals and Valentech Pharma • A Aqul is a consultant for Mirum Pharmaceuticals, Inc, Albireo, and Sarepta Therapeutics • E Sokal is the f
Slide 25: Back-Up
AAS L D Nov. 4-8, 2022 The Liver e © Meeting’ »~ Back-Up
Slide 26: MARCH-PFIC: Patient Disposition
MARCH-PFIC: Patient Disposition BSEP Deficiency All-PFIC Full-Study Maralixibat Placebo Maralixibat Placebo Maralixibat Placebo Status or Category (n = 14) (n = 17) (n = 33) (n = 31) (n = 47) (n = 46) Screened for eligibility 125 Screen failure 32 Randomized 14 17 33 31 47 46 Safety population 14 17
Slide 27: Change in Weekly ItchRO(Obs) Score and Serum Bile Acids in Full-Study Cohort (N=93)
Change in Weekly ItchRO(Obs) Score and Serum Bile Acids in Full-Study Cohort (N=93) Average Pruritus Score (ItchRO[Obs]) Over Time Average Serum Bile Acid Over Time Maralixibat Placebo 100 Change from Baseline (μmol/L) 0.0 50 Change from Baseline -0.5 0 -1.0 -50 -1.5 -100 -2.0 -150 -2.5 -200 -3.0 -2
Slide 28: Change in Weekly ItchRO(Obs) Score and Serum Bile Acids in No-Variant-Found
Change in Weekly ItchRO(Obs) Score and Serum Bile Acids in No-Variant-Found Pruritus Score (ItchRO[Obs]) MMRM Analysis Serum Bile Acids MMRM Analysis Maralixibat Placebo Maralixibat Placebo (n = 3) (n = 5) (n = 3) (n = 5) 50 1.0 0.05 0.3 0 Change from baseline Change from baseline 0.0 Improvement -5
Slide 29: Change in Weekly ItchRO(Obs) Score and Serum Bile Acids in FIC1
Change in Weekly ItchRO(Obs) Score and Serum Bile Acids in FIC1 Pruritus Score (ItchRO[Obs]) MMRM Analysis Serum Bile Acids MMRM Analysis Maralixibat Placebo Maralixibat Placebo (n = 7) (n = 6) (n = 7) (n = 6) 100 0.0 -0.3 Change from baseline Change from baseline 40 -0.5 p=0.6379* 0 Improvement p =
Slide 30: Change in Weekly ItchRO(Obs) Score and Serum Bile Acids in MDR3
Change in Weekly ItchRO(Obs) Score and Serum Bile Acids in MDR3 Pruritus Score (ItchRO[Obs]) MMRM Analysis Serum Bile Acids MMRM Analysis Maralixibat Placebo Maralixibat Placebo (n = 4) (n = 5) (n = 4) (n = 5) 100 0.0 -16 0 Change from baseline Change from baseline -0.5 Improvement p = 0.7290* (mol