Mirum Pharmaceuticals, Inc. · NASDAQ:MIRM
Mirum Pharmaceuticals — Technical Presentation (November 2021)
26 slides from Mirum Pharmaceuticals's technical presentation, Nov 15, 2021
Slide 1: Application of real-world evidence analytics: 6-year event-free survival analysis in Alagille syndrome
Application of real-world evidence analytics: A 6-year event-free survival analysis in Alagille syndrome of the GALA clinical research database and maralixibat treated patients Bettina E. Hansen, PhD1 and Binita M. Kamath, MBBChir2 on behalf of the GALA study group 1Toronto General Hospital Universi
Slide 2: Bettina E. Hansen, PhD
Bettina E. Hansen, PhD • Associate Professor of Biostatistics at the Toronto Centre for Liver Disease, Toronto General Hospital & IHPME, University of Toronto, Canada • She holds the Francis Family Chair in International Biostatistics Research for Autoimmune Liver Disease. • Dr. Hansen leads large-s
Slide 3: Disclosures
Disclosures Bettina E. Hansen, PhD I disclose the following financial relationship(s) with a commercial interest: • Mirum: Grant/Research Support, Consulting • Intercept: Grant/Research Support, Consulting, Advisory Committee • CymaBay: Grant/Research Support, Consulting • Calliditas: Grant/Research
Slide 4: Alagille syndrome: Background
Alagille syndrome: Background • Alagille syndrome (ALGS) is a rare, autosomal dominant developmental disorder characterized by bile duct paucity and extrahepatic clinical manifestations • Key clinical features of ALGS are cholestasis, xanthomas and severe debilitating pruritus • Complications of cho
Slide 5: Substantial risk for liver transplant in patients with ALGS
Substantial risk for liver transplant in patients with ALGS GALA1 (Global) ChiLDReN (North America network)2 Native liver survival (NLS) in patients with ALGS Transplant-free survival (TFS) in patients with ALGS (N=293) presenting with neonatal cholestasis (N=911) 100 100 80 57% NLS 80 at 10 years 6
Slide 6: Maralixibat is an IBAT inhibitor that interrupts bile acid recirculation and improves pruritus
Maralixibat is an Ileal Bile Acid Transporter (IBAT) inhibitor that interrupts bile acid recirculation and significantly improves pruritus1,2 Placebo-controlled Interrupts recirculation of bile withdrawal acids to the liver1 0 Maralixibat vs placebo Maralixibat-placebo-maralixibat (core) Mean (SE) c
Slide 7: Primary objective
Primary objective • To compare time to first clinical event between a maralixibat (MRX) cohort of 84 patients treated for up to 6 years and an external control cohort from the GALA database – Events defined as: liver transplantation; biliary diversion surgery; decompensation event (ascites requiring
Slide 8: Challenges in clinical research for rare diseases
Challenges in clinical research for rare diseases • Long-term, randomized controlled trials with definitive clinical outcomes are difficult, if not impossible, to conduct in rare diseases • Use of Real-World Data as a control arm is a potential alternative to assess long-term outcomes. Challenges to
Slide 9: GALA: the only global clinical research database of children and young adults with ALGS
GALA: the only global clinical research database of children and young adults with ALGS Currently, >1,600 patients with ALGS from 35 countries
Slide 10: Pre-specified statistical method I: Harmonize design
Pre-specified statistical method I: Harmonize design Fit for purpose • Outcome, confounders RWD • Quality of lab-values, patient and disease blinded for outcome GALA factors, missingness Selection Firewall on Selection • Align inclusion/exclusion criteria Index time • Overlay sites / regions / calen
Slide 11: Pre-specified statistical method II: Analysis of time to event
Pre-specified statistical method II: Analysis of time to event Treatment arm Analysis of endpoint • Check for informative • Kaplan-Meier & Cox regression methods un-blinded for outcome censoring • Crude effect Composite endpoint • Weighted Firewall off • Characterize type of events • Adjusted for co
Slide 12: Pre-specified selection criteria for GALA external control cohort
Pre-specified selection criteria to ensure GALA external control cohort was aligned with maralixibat entry criteria Key Inclusion Criteria Key Exclusion Criteria • Age at inclusion: ≥1 year and <18 years • ALT >15 x ULN • Diagnosed after 1990 • Clinical event, defined as BD surgery, liver • Cholesta
Slide 13: Selection of index time: best fit
Selection of index time: best fit Treatment MRX Index time Follow-up Event / end of follow-up MRX Screening period Index time Follow-up Event / end of follow-up GALA ◊ ◊ ◊ ◊ ◊ ◊ 1 yr 18 yr Age ◊ Eligible visit MRX, maralixibat. ◊ Eligible visit and selection of index time
Slide 14: Demographic characteristics are well balanced between maralixibat and GALA groups
Demographic characteristics are well balanced between the maralixibat and GALA groups MRX Cohort GALA Control Baseline characteristic p-value N=84 N=469 Male 49 (58.3) 274 (58.4) Sex, n (%) 0.988 Female 35 (41.7) 195 (41.6) Age at BL, years Median (Q1, Q3) 5.6 (2.7, 9.9) 4.3 (2.2, 9.6) 0.078 Year of
Slide 15: Disease characteristics are well-balanced between maralixibat and GALA groups
Disease characteristics are well-balanced between the maralixibat and GALA groups MRX Cohort GALA Control Baseline characteristic p-value N=84 N=469 Median (Q1,Q3) 3.15 (1.00, 8.15) 1.99 (0.60, 11.52) 0.392 Total bilirubin, mg/dL <2 mg/dL 37 (44.0) 235 (50.1) 0.306 ≥2 mg/dL 47 (56.0) 234 (49.9) Medi
Slide 16: Maralixibat shows significant improvement in Event Free Survival
Maralixibat shows significant improvement in Event Free Survival EFS: biliary diversion surgery, decompensation event, liver transplantation, or death 100 80 MRX Cohort Event-free survival (%) 60 GALA Control 40 20 Primary analysis* – adjusted: HR=0.305 (95% CI: 0.189–0.491), p<0.0001 Unadjusted*: H
Slide 17: Consistent results when adjusting for baseline covariates
Consistent results when adjusting for baseline covariates Estimated HR (95% CI) of EFS in MRX Cohort vs. GALA Control Hazard ratio HR 95% CI p-value Primary comparison SAP specified 0.305 (0.189, 0.491) <.0001 Unadjusted 0.380 (0.238, 0.604) <.0001 Adjusted 1 0.301 (0.188, 0.484) <.0001 Adjusted 2 0
Slide 18: Selection of index time: first visit
Selection of index time: first visit Treatment MRX Index time Follow-up Event / end of follow-up MRX Screening period 1st Follow-up Index time Event / end of follow-up GALA ◊ ◊ ◊ ◊ ◊ ◊ 1 yr 18 yr Age ◊ Eligible visit MRX, maralixibat. ◊ Eligible visit and selection of index time
Slide 19: Selection of index time: random visit
Selection of index time: random visit Treatment MRX Index time Follow-up Event / end of follow-up MRX Screening period Random Follow-up Index time Event / end of follow-up GALA ◊ ◊ ◊ ◊ ◊ ◊ 1 yr 18 yr Age ◊ Eligible visit MRX, maralixibat. ◊ Eligible visit and selection of index time
Slide 20: Selection of index time: date of birth
Selection of index time: date of birth Age = 0 index time Follow-up Event / end of follow-up MRX ◊ Screening period Age = 0 Follow-up index time Event / end of follow-up GALA ◊ ◊ ◊ ◊ ◊ ◊ ◊ 0 yr 1 yr 18 yr Age ◊ Eligible visit MRX, maralixibat. ◊ Choice of selection of index time
Slide 21: Consistent results across index times and Liver Transplant Free Survival
Consistent results across index times and Liver Transplant Free Survival Estimated HR (95% CI) of EFS in MRX Cohort vs. GALA Control Hazard ratio HR 95% CI p-value Sensitivity analyses First eligible visit 0.618 (0.369, 1.036) 0.0680 Date of birth 0.504 (0.320, 0.795) 0.0032 Last eligible visit 0.24
Slide 22: Consistent results across sub-group analyses
Consistent results across sub-group analyses Estimated HR (95% CI) of EFS in MRX Cohort vs. GALA Control Hazard ratio HR 95% CI p-value Subgroup analyses By region North America 0.249 (0.114, 0.542) 0.0005 By region Europe 0.360 (0.187, 0.693) 0.0022 By region Australia 0.140 (0.024, 0.832) 0.0306 B
Slide 23: Maralixibat shows significant improvement in EFS: pruning first 12 months
Maralixibat shows significant improvement in EFS Pruning for events occurring in the first 12 months 100 MRX Cohort 80 Event-free ssurvival (%) 60 40 GALA Control 20 HR=0.503 (95% CI: 0.273–0.930), p=0.0280 0 MRX Cohort 79 79 67 60 56 41 16 0 GALA Control 205 205 108 77 48 30 23 17 0 2 4 6 Follow-up
Slide 24: Consistent results observed across several sensitivity analyses
Consistent results observed across several sensitivity analyses Estimated HR (95% CI) of EFS in MRX Cohort vs. GALA Control Hazard ratio HR 95% CI p-value Primary comparison SAP specified 0.305 (0.189, 0.491) <.0001 Unadjusted 0.380 (0.238, 0.604) <.0001 Adjusted 1 0.301 (0.188, 0.484) <.0001 Adjust
Slide 25: Key takeaway: real-world analytics are difficult but possible
Key takeaway: real-world analytics are difficult but possible • This 6-year analysis demonstrates a 70% reduction for clinical outcomes with maralixibat treatment vs natural history in patients with ALGS • This real-world evidence analysis provides a potential method to evaluate long-term outcomes i
Slide 26: Thank You
Thank You For methodology-related questions: Please contact Bettina E. Hansen: bettina.hansen@utoronto.ca For GALA-related questions: Please contact Binita M. Kamath: binita.kamath@sickkids.ca
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