Third Bridge Library: Roche to acquire 89bio

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INTERVIEW: Akero Therapeutics – FGF21 Positioning in MASH Landscape & Phase 3 Efruxifermin Programme Analysis

Agenda 

• MASH (metabolic-associated steatohepatitis) treatment landscape evolution, post Rezdiffra (resmetirom) approval, looming GLP-1 entrant and wider candidate acceleration
• Discussion of data generated by Akero Therapeutics' (NASDAQ: AKRO) FGF21 analog EFX (efruxifermin) in pre-cirrhotic F2-F3 MASH patients in the HARMONY trial and compensated cirrhotic F4 patients in the SYMMETRY trial, noting key areas of differentiation 
• Phase 3 programme expectations, including SYNCHRONY histology in F2-F3 patients, SYNCHRONY outcomes in F4 patients and SYNCHRONY Real-World in F4 patients, plus proposed differentiated design of Real-World study
• Competitive positioning of lead FGF21 candidates from 89Bio (NASDAQ: ETNB) and GSK (NYSE: GSK)
• FGF21 analog positioning potential in MASH treatment algorithms and implications of seemingly direct fibrotic effect

Key Insights 

1. Comfortability and robust safety data arsenal may encourage semaglutide uptake in MASH, but operational challenges in dose management and titration could tamper real-world adoption
2. Consistent findings across FGF21s encourages specialist's viewpoint of anti-fibrotic class effect being "an edge", but specialist questions whether anti-fibrotic effect may also be possible in longer studies of Rezdiffra
3. Blood pressure elevations and bone mineral density impacts are "very monitorable" and not an "absolute contraindication" for efruxifermin, specialist says  
4. Non-invasive tests such as vibrationcontrolled transient elastography and enhanced liver fibrosis score are increasingly replacing liver biopsies in clinical practice. Specialist emphasises relevance and advantage of Akero Therapeutics' SYNCHRONY Real-World trial design for clinical translation  
5. C20% vibration-controlled transient elastography score reduction in SYNCHRONY Real-World trial is considered successful, dropping below 10-12 ideally, along with consistent liver chemistries. 52-week endpoint may be closer in outcome to 96-week endpoint, about 30-35% fibrosis improvement, specialist says 

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INTERVIEW: GlaxoSmithKline's Acquisition of Boston Pharmaceuticals' Efimosfermin Alfa – Development Update & MASH Competitive Landscape

Agenda 

• MASH (metabolic dysfunction-associated steatohepatitis) competitive landscape analysis, highlighting GlaxoSmithKline's (GSK’s; LON: GSK) planned acquisition of Boston Pharmaceuticals' efimosfermin alfa asset and evolution of leading market players
• Efimosfermin alfa (BOS-580) deep dive, including FGF21 (fibroblast growth factor 21) mechanistic analysis, phase 2a data assessment and development outlook
• Comparison of efimosfermin alfa with leading FGF21 analogues in development, including Akero Therapeutics' (NASDAQ: AKRO) exfruxifermin and 89Bio's (NASDAQ: ETNB) pegozafermin, noting dosing and potency differences
• Development potential for efimosfermin in alcoholrelated liver disease
• Efimosfermin development timeline and outlook

Key Insights 

1. FGF21 analogues offer potential systemic benefits beyond liver effects, converting white fat to brown fat, increasing thermogenesis and having anti-fibrotic effects, with best potential in F3 and F4 patients
2. Monthly dosing of efimosfermin may improve adherence, but efficacy will ultimately trump convenience in treatment decisions for MASH. Lower immunogenicity of efimosfermin could provide long-term efficacy advantages by reducing antibody formation and loss of drug effectiveness over time. Specialist is concerned about potential relapses, left out of Akero's 96-week release, pointing to the potential of antibody development
3. Specialist thinks FGF21 analogues may be used intermittently rather than lifelong, potentially "resetting the clock" on fibrosis progression for several years. Specialist likens efimosfermin's profile most closely to efruxifermin  
4. First-to-market advantage is significant, but subsequent drugs can compete by demonstrating 10-15% improved efficacy or lower pricing  
5. GSK's plans to study efimosfermin in alcohol-related liver disease could tap into a growing market, as alcohol abuse has accelerated since the pandemic 

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INTERVIEW: Akero Therapeutics – MASHing the Odds

Agenda 

• Liver-directed MASH (metabolic dysfunctionassociated steatohepatitis) therapies, focusing on Akero Therapeutics' (NASDAQ: AKRO) EFX (efruxifermin) and 89bio's (NASDAQ: ETNB) pegozafermin
• Phase 2b EFX SYMMETRY ITT (intention to treat) and 96-week biopsy-excluded subanalyses data 
• Importance of liver scarring improvement and differentiation potential against pegozafermin
• Phase 3 SYNCHRONY programme design evaluation and expectations across fibrosis stages
• Broader MASH competitive landscape dynamics and commercialisation outlook

Key Insights 

1. Non-invasive tests reveal liver heterogeneity better than biopsy, potentially leading to sooner and more accurate F4-staging diagnosis in the future. F4 is more predictably progressive, making EFX's reversal particularly significant
2. Specialist emphasises the need for longer-term safety data, particularly regarding bone density and fracture risk. Cirrhosis patients, especially women, already face bone density issues
3. On staging, despite being best-suited for reversing end-stage disease, differentiated efficacy profile may trigger more use in earlier disease over fat metabolism drugs 
4. Despite unprecedented results, current US political climate doesn't lend to bending of accelerated approval rules, specialist postulates, arguing clinical outcomes will be necessary for regulatory review 
5. Despite impressive results, specialist thinks the 96-week follow-up may be too short to see full reversal effects. A longer period of five years could show greater improvements, given liver disease progression is variable

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INTERVIEW: 89Bio – Pegozafermin Trial Expectations & Possible Future for Liver-targeted MASH Therapies

Agenda 

• MASH (metabolic-associated steatohepatitis) treatment landscape evolution, post Rezdiffra (resmetirom) approval, looming GLP-1 entrant and wider candidate acceleration
• Discussion of data generated by Akero Therapeutics' (NASDAQ: AKRO) FGF21 analog EFX (efruxifermin) in pre-cirrhotic F2-F3 MASH patients in the HARMONY trial and compensated cirrhotic F4 patients in the SYMMETRY trial, noting key areas of differentiation 
• Phase 3 programme expectations, including SYNCHRONY histology in F2-F3 patients, SYNCHRONY outcomes in F4 patients and SYNCHRONY Real-World in F4 patients, plus proposed differentiated design of Real-World study
• Competitive positioning of lead FGF21 candidates from 89Bio (NASDAQ: ETNB) and GSK (NYSE: GSK)
• FGF21 analog positioning potential in MASH treatment algorithms and implications of seemingly direct fibrotic effect

Key Insights 

1. Specialist thinks pegozafermin's dosing schedule advantage is minimal, but prefilled liquid formulation is significantly advantageous to efruxifermin's reconstitution formulation
2. Specialist thinks long-term pegozafermin data may show even more deepening of response than efruxifermin due to PEGylation and long-term binding effect. A1c and broader lipid profiling is important to monitor through phase 3 to help predict long-term outcomes and reliable drug comparisons
3. If pegozafermin's standout in F4 compensated cirrhosis patients continues, this could leverage 89Bio's position in F2 and F3 as it lends to more continuous treatment, particularly since staging is often based on educated guesses 
4. Non-invasive tests, such as Enhanced Liver Fibrosis score and FibroScan, are becoming increasingly important in monitoring MASH treatment progress. Specialist thinks they could replace liver biopsies
5. GLP-1s will probably be relevant for 40-60% of MASH patients, with desire to remove patients within one year and transition to more live-targeted therapies based on biomarker testing

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