Slide 1: Acute Liver Injury Mitigation and Management in Patients with DMD Following Administration of Delandistrogene Moxeparvovec
Acute Liver Injury Mitigation and Management in Patients with Duchenne Muscular Dystrophy Following Administration of Delandistrogene Moxeparvovec: Expert Committee Considerations Perry Shieh, PhD, MD University of California, Los Angeles (UCLA) Presenting on behalf of all authors: Perry Shieh, Crys
Slide 2: Disclosure
Disclosure I have the following conflicts of interest to declare: • Dr. Shieh reports being a consultant for Novartis, Biogen, Roche, Pfizer, Sarepta, argenx, Alexion, UCB, Catalyst, Grifols, and CSL Behring, and is receiving grants/research support from Novartis, Biogen, Solid, Pfizer, Sarepta Ther
Slide 3: Background
Background • Delandistrogene moxeparvovec is an rAAVrh74 vector-based gene transfer therapy for DMD approved in the USA and other select countries1–9 • ALI is an identified risk following AAV-based gene therapies, including delandistrogene moxeparvovec • There have been two fatal cases of ALI in non
Slide 4: Interdisciplinary expert committee objectives
Interdisciplinary expert committee objectives Following the two fatal ALF cases associated with delandistrogene moxeparvovec, three interdisciplinary expert committees were convened • Composed of globally recognized medical specialists, each bringing extensive domain expertise and decades of clinica
Slide 5: Expert committee members
Expert committee members Name Specialty Name Specialty Jawad Ahmad, MD Transplant Hepatology Craig McDonald, MD Neuromuscular, Pediatric rehabilitation Diana Bharucha-Goebel, MD Neuromuscular medicine Crystal Proud, MD Neuromuscular Carsten Bönnemann, MD Neuromuscular Alan Salama, MA, MBBS, PhD, FRC
Slide 6: Representative hepatic biomarker trends following delandistrogene moxeparvovec administration
Representative hepatic biomarker trends following delandistrogene moxeparvovec administration Representative ALIa Treatment-related ALF Cases Following Delandistrogene Moxeparvovec n=65/156b n=2 ALT GGT Total Bilirubin INR • Time of onset in two treatment-related ALF cases was similar to that observ
Slide 7: ALI detection challenges and observations in two patients with ALF
ALI detection challenges and observations in two patients with ALF ELEVIDYS Prescribing Information2 Clinical Trial ALI Definition:1 • GGT >3× ULN or ELEVIDYS Prescribing Information recommends a • GLDH >2.5× ULN or corticosteroid dose modification based on abnormal hepatic laboratory monitoring as
Slide 8: Potential approaches for earlier detection of ALI
Potential approaches for earlier detection of ALI Overarching theme: Hepatic biomarker thresholds should be modified to facilitate timely intervention Earlier Intervention Before or When Approaching Hepatic Biomarker Thresholds Advisors highlighted a need for earlier intervention • Advisors agreed t
Slide 9: Potential approaches for the capturing risk
Potential approaches for the capturing risk Overarching theme: No single risk factor was identified that consistently predicted progression from ALI to ALF Capturing Risk Advisors recommended considering Potential for evaluating steatosis risk: enhancing baseline liver characterization: Lipid pane
Slide 10: Potential approaches for improved ALI prevention
Potential approaches for improved ALI prevention Overarching Theme: Addition of prophylactic sirolimusa to the current corticosteroid regimen was preferred to escalating corticosteroid doses for the prevention of ALI Most advisors favored adding sirolimus to the Prophylactic Immunosuppression curren
Slide 11: Potential approaches for improved management of ALI
Potential approaches for improved management of ALI Overarching Theme: Prompt initiation of IV corticosteroids was suggested if patients do not respond to oral corticosteroids ALI Management Strategies Considered* • Some advisors suggested escalation to IV Keep current oral corticosteroid dose corti
Slide 12: Future steps: Overview of proposed ENDEAVOR cohort 8 in non-ambulatory patients
Future steps: Overview of proposed ENDEAVOR cohort 8 in non-ambulatory patients1 Pending FDA review and approval Overarching Theme: Need for real-world and clinical trial data; most favored the study of prophylactic immunosuppression in high-risk subgroups due to limited mechanistic data and potenti
Slide 13: Other discussion points
Other discussion points Potential Compounding Mechanistic Explanations of ALI • Advisors debated whether ALI and ALF exist on a spectrum; most suggested that a secondary insult may differentiate fatal cases • Advisors proposed the role of T cell-mediated liver injury as the leading hypothesis for AL
Slide 14: Conclusions
Conclusions Advisors endorsed modifying hepatic biomarker thresholds in ALI to facilitate timely intervention Advisors recommended considering enhancing baseline liver characterization (e.g., lipid panels, transient elastography, and ultrasound) to better understand risk factors of developing ALI Fo
Slide 15: Expert committee members
Expert committee members Name Specialty Name Specialty Jawad Ahmad, MD Transplant Hepatology Craig McDonald, MD Neuromuscular, Pediatric rehabilitation Diana Bharucha-Goebel, MD Neuromuscular medicine Crystal Proud, MD Neuromuscular Carsten Bönnemann, MD Neuromuscular Alan Salama, MA, MBBS, PhD, FRC
Slide 16: Acknowledgements and disclosures
Acknowledgements and disclosures Acknowledgments • The expert committee meetings were funded by Sarepta Therapeutics, Inc., Cambridge, MA, USA. ENDEAVOR is sponsored by Sarepta Therapeutics, Inc., Cambridge, MA, USA and funded by Sarepta Therapeutics and F. Hoffman-La Roche Ltd, Basel, Switzerland.