Combination & Sequential Therapy Focus Day
Monday, September 29
8:30 am Morning Refreshments & Check In
Evaluating Mechanisms of Action to Explore the Emerging Potential in Combination & Sequential Treatments for More Efficacious MASH Therapies
9:15 am Sustainable Treatments to Reverse MASH & Obesity-Linked Comorbidities
Synopsis
- Quelling hepatic injury through strategic inflammatory modulation to dampen the damaging inflammatory cascade within the liver to benefit the long-term trajectory of the disease
- Understanding the biology of targeting chemokine receptors (e.g., CCR2/CCR5 inhibition) to limit the recruitment of inflammatory cells to the liver to introduce a new method of treating MASH
- Investigating the potential of inhibiting apoptosis pathways (e.g., ASK1 inhibition) to preserve hepatocytes to reduce liver damage driven by inflammation
9:45 am Myeloid Cells Orchestrate Fibrosis in MASH: A Call to Refocus Therapeutic Targeting Beyond Adaptive Immunity
Synopsis
- Investigating immune-mediated mechanisms driving fibrosis in MASH, with emphasis on the interplay between innate and adaptive immune cells
- Identifying myeloid cells as essential architects of the fibrotic niche, promoting bystander T-cell accumulation and activating myofibroblasts
- Supporting reorienting anti-fibrotic strategies toward targeting innate immune and stromal components, based on integrated analyses from human and preclinical models
10.15 am MITO-1041: A Unique Liver-Directed siRNA Approach to Treat Mitochondrial Dysregulation in MASH
Synopsis
- Mitochondrial dysregulation is a key driver for the initiation and progression of MASH
- MCJ is a key regulator of mitochondrial metabolism and knockdown improves steatosis, inflammation and fibrosis in MASH preclinical models
- MITO-1041 is a GalNAc MCJ siRNA which shows promise as a safe and effective therapy that can be used alone or in combination for treating patients with MASH
10:45 am Morning Break & Networking
11:30 am Leveraging FGF21 Signaling to Target Fibrosis & Metabolic Pathways for More Effective Treatment Development
Synopsis
- Using FGF21 therapy as a potent modulator of fibrosis progression and regression across cirrhotic and non-cirrhotic patients
- Evaluating the effect of FGF21 analogs on hepatic steatosis and inflammation reduction to improve the underlying drivers of fibrosis
- Examining additive effects when combined with incretin therapies to provide a holistic approach to therapy
12:00 pm EPHB2 Deficiency Suppresses Liver Fibrosis in Metabolic Dysfunction-Associated Steatohepatitis
Synopsis
- Hepatic EPHB2 expression is elevated in human and murine MASH
- Global EPHB2 deletion, including its deficiency in hepatic stellate cells, attenuates fibrosis in MASH
- Targeting EPHB2 with a novel small molecule inhibitor mitigates MASH fibrosis
12:30 pm Roundtable Discussion: Synthesizing Novel Mechanisms to Chart the Future of MASH Therapeutic Strategies for Continued Innovation
Synopsis
- Synthesizing learnings from the diverse mechanisms of action presentations for a holistic understanding of MASH pathophysiology to enable the identification of convergent pathways and novel, synergistic drug targets
- Debating the most promising emerging mechanisms to provide a platform for critical evaluation and prioritization of research efforts for guiding strategic investment, and accelerating the development of high-impact MASH therapies
- Identifying opportunities for multi-targeted or combination approaches based on mechanistic insights to foster innovative thinking beyond single-target therapies for designing more effective MASH treatments
1:15 pm Lunch
Revolutionizing MASH Therapy Development by Harnessing Biomarkers & Innovative Trial Designs to Accelerate Progress Towards Effective Combination & Sequential Therapies
2:15 pm Fibrosis Biomarkers in Alpha-1 Antitrypsin Deficiency Associated Liver Disease (AATD-LD)
Synopsis
- Suggesting a link between alterations of individual proteins and pathways in Pi*ZZ subjects and increased hepatocyte stress/damage, apoptosis, inflammation, fibrogenesis and liver fibrosis
- Assessing the key molecular features associated with fibrosis progression and regression are conserved in AATD-LD as in other fibrotic liver disease such as MASH and PSC
2:45 pm Optimizing MASH Combination Therapy Trials Through Novel Composite Endpoints to Enhance Sensitivity & Demonstrate Long-Term Clinical Benefit
Synopsis
- Employing composite endpoints to capture multiple dimensions of MASH resolution (steatosis, inflammation, fibrosis) to provide a more holistic measure of treatment efficacy in combination therapy trials
- Applying time-to-event analyses to composite endpoints to demonstrate the long-term benefits of MASH combination therapies for clinically relevant outcomes
- Incorporating patient-reported outcomes (PROs) into composite endpoints to ensure that the patient experience is adequately captured in MASH clinical trials to progress to a more patient-centred approach to drug development
3.15 pm Panel Discussion: Designing Therapies with Novel Mechanisms & Predictive Biomarkers to Holistically Improve Treatment for Better Patient Outcomes
Synopsis
- Integrating the design of therapies involving novel mechanisms with new, predictive biomarkers to provide a more precise and efficient approach to drug discovery and development for earlier identification of responders and non-responders
- Leveraging cutting-edge understanding of MASH pathogenesis to design innovative therapies to target the root causes of the disease for more effective treatments that can holistically improve patient outcomes
- Developing and validating novel predictive biomarkers alongside new therapeutic candidates for early and accurate identification of patient response for more streamlined clinical trials and impactful MASH therapies
3:45 pm Roundtable Discussion: Combining MASH Therapies to Investigate Combination & Sequential Approaches to Effectively Treat the Differing Stages of MASH
Synopsis
- Discussing combination therapy rationale to offer a strategic advantage by simultaneously targeting the multiple pathogenic pathways of MASH, addressing steatosis, inflammation, and fibrosis to optimize synergistic effects and improve treatment outcomes compared to monotherapies
- Highlighting sequential therapy to achieve initial therapeutic goals like steatosis reduction before addressing other disease aspects, and minimize potential toxicity to optimize the risk-benefit profile of MASH treatment
- Emphasizing precision medicine in MASH to gain a deeper understanding of the genetic and molecular heterogeneity of MASH to tailored combination and sequential approaches that can maximize individual patient response