The Strategic Potential of 89bio’s Pegozafermin in the NASH and SHTG Markets

The biopharmaceutical landscape for Non-Alcoholic Steatohepatitis (NASH) and Severe Hypertriglyceridemia (SHTG) is witnessing a paradigm shift, driven by innovative therapies targeting metabolic dysfunction. At the forefront of this transformation is 89bio’s Pegozafermin, a glycoPEGylated analog of fibroblast growth factor 21 (FGF21). With its dual therapeutic potential in NASH and SHTG, Pegozafermin is positioned to redefine treatment standards through a unique mechanism of action, robust clinical data, and a favorable regulatory trajectory. This analysis evaluates its pipeline differentiation and market readiness against key competitors like Olezarsen (Ionis Pharmaceuticals) and Resmetirom (Madrigal Pharmaceuticals).

Pipeline Differentiation: Mechanism and Efficacy

Pegozafermin’s mechanism as an FGF21 agonist sets it apart. FGF21 is a metabolic regulator that enhances insulin sensitivity, reduces hepatic steatosis, and lowers triglyceride levels [1]. In a phase 2 trial for SHTG, Pegozafermin achieved a 57.3% reduction in triglycerides compared to a 11.9% reduction in the placebo group, meeting its primary endpoint [2]. This outperforms Olezarsen, an antisense oligonucleotide targeting apolipoprotein C-III (apoC-III), which demonstrated a 72% reduction in triglycerides in phase 3 trials but lacks antifibrotic activity [3].

For NASH, Pegozafermin’s multi-targeted approach addresses both steatosis and fibrosis. A network meta-analysis revealed that Pegozafermin showed a mean fibrosis improvement of -4.85 compared to placebo, outperforming Resmetirom’s -3.86 for steatosis reduction [4]. Resmetirom, Madrigal’s FDA-approved therapy for MASH, focuses primarily on steatosis and inflammation but has limited antifibrotic data. Pegozafermin’s ability to regress fibrosis—demonstrated in phase 2 histology data—positions it as a more comprehensive solution for advanced NASH patients [5].

Market Readiness: Regulatory and Commercial Pathways

89bio’s regulatory strategy is accelerating Pegozafermin’s path to market. The drug has received FDA Breakthrough Therapy Designation for NASH with fibrosis, a critical milestone that expedites development timelines [6]. The ENTRUST trial for SHTG (NCT05852431) is expected to report topline data in Q1 2026, while the ENLIGHTEN program for MASH (including cirrhotic patients) will deliver histology results in 2027–2028 [7]. These timelines align with the projected $13.83 billion NASH market valuation by 2029, driven by unmet needs in fibrosis management [8].

Competitively, Pegozafermin’s once-weekly subcutaneous administration offers a dosing advantage over daily oral therapies like Resmetirom. Its safety profile, with no serious adverse events reported in phase 2 trials, further strengthens its commercial appeal [9]. In contrast, Olezarsen’s RNAi mechanism, while effective for triglyceride reduction, faces challenges in long-term safety and patient adherence due to monthly injections.

Strategic Positioning in a Crowded Market

The NASH/SHTG pipeline is crowded, with over 20 therapies in development. However, Pegozafermin’s dual indication (NASH and SHTG) and antifibrotic differentiation create a unique value proposition. For instance, while Resmetirom dominates early-stage NASH with its steatosis resolution rates (30% in phase 3 trials), it lacks robust data in advanced fibrosis [10]. Pegozafermin’s ENLIGHTEN-Cirrhosis trial specifically targets compensated cirrhosis (F4), a patient population with limited treatment options [11].

Moreover, Pegozafermin’s glycoPEGylation technology extends its half-life, reducing dosing frequency and improving patient compliance compared to short-acting FGF21 analogs like efruxifermin [12]. This technological edge, combined with 89bio’s aggressive R&D investment (a $42.4 million non-recurring payment in Q2 2025 underscores commitment to trials [13]), signals strong execution capability.

Conclusion: A High-Potential Investment

89bio’s Pegozafermin represents a compelling investment opportunity in the NASH/SHTG space. Its differentiated mechanism, superior fibrosis outcomes, and regulatory momentum position it to capture market share from both established players (e.g., Resmetirom) and emerging therapies (e.g., Olezarsen). With key Phase III readouts in 2026 and a growing emphasis on antifibrotic therapies, Pegozafermin could emerge as a cornerstone treatment for metabolic liver disease. Investors should closely monitor the ENTRUST and ENLIGHTEN trials, as positive results could catalyze a valuation leap for 89bio in the high-growth NASH/SHTG market.

Source:
[1] Hypertriglyceridemia Clinical Trials and Studies [https://www.einpresswire.com/article/785336621/hypertriglyceridemia-clinical-trials-and-studies-ema-pdma-fda-approvals-mechanism-of-action-roa-nda]
[2] The FGF21 analog pegozafermin in severe hypertriglyceridemia [https://pmc.ncbi.nlm.nih.gov/articles/PMC10353930/]
[3] Ionis reports outcomes from Phase III trials of olezarsen [https://www.clinicaltrialsarena.com/news/ionis-olezarsen-trials/]
[4] Comparative efficacy and safety of pharmacologic therapies [https://www.researchgate.net/publication/390696739_Comparative_efficacy_and_safety_of_pharmacologic_therapies_for_metabolic_dysfunction-associated_steatotic_liver_disease_over_24_weeks_in_reducing_liver_steatosis_and_fibrosis_A_network_meta-analysis]
[5] 89bio Announces FDA Breakthrough Therapy Designation [https://www.89bio.com/news/89bio-announces-u-s-fda-has-granted-breakthrough-therapy-designation-for-pegozafermin-in-nonalcoholic-steatohepatitis-nash/]
[6] 89bio Reports First Quarter 2025 Financial Results [https://ir.89bio.com/news-releases/news-release-details/89bio-reports-first-quarter-2025-financial-results-and-corporate/]
[7] Pegozafermin Clinical Development [https://89bio.com/pipeline/]
[8] Non-Alcoholic Steatohepatitis Treatment Market Report 2025 [https://www.researchandmarkets.com/reports/5785592/non-alcoholic-steatohepatitis-treatment-market?srsltid=AfmBOooScDC79L8gIWQ7l_536WKM4yct6_ppVzCRljx7GkeG34mZ4-cx]
[9] The FGF21 analog pegozafermin in severe hypertriglyceridemia [https://pmc.ncbi.nlm.nih.gov/articles/PMC10353930/]
[10] Resmetirom’s phase 3 MAESTRO-NASH trial data [https://www.clinicaltrialsarena.com/projects/rezdiffra-treatment-nash-us/]
[11] 89bio Initiates Phase 3 ENLIGHTEN-Cirrhosis Trial [https://ir.89bio.com/news-releases/news-release-details/89bio-initiates-phase-3-enlighten-cirrhosis-trial-pegozafermin/]
[12] Pegozafermin - Drug Targets, Indications, Patents [https://synapse.patsnap.com/drug/fce8e68c6a5847479ec8f935d896b61d]
[13] 89bio Reports Second Quarter 2025 Financial Results [https://news.futunn.com/en/post/60288468/press-release-89bio-reports-second-quarter-2025-financial-results-and]