Advancing the treatment of NASH from a patient perspective

By Hank Mansbach , M.D., Chief Medical Officer at 89bio

For years, biopharmaceutical companies have attempted to uncover treatments for non-alcoholic steatohepatitis (NASH), a serious liver condition with significant comorbidities and the fastest growing cause of liver transplants in the U.S. Approximately 17.5 million people in the U.S. have NASH; however, there are still no FDA-approved treatments for this condition. [1] At 89bio, we know science is key to breaking this cycle.

When we founded 89bio nearly five years ago, our vision was to approach the treatment of NASH from the patient’s perspective. Understanding that NASH is a chronic, complex and often asymptomatic disease – and that most patients with NASH take multiple medications for various metabolic and other health issues – we sought to develop a convenient, well-tolerated therapy, ensuring seamless integration into patients’ lives.[2],[3],[4]

Based on this, we are thrilled with the positive topline results from our Phase 2b ENLIVEN trial, which examined the efficacy and safety of pegozafermin in patients with fibrosis stage F2 - F3 NASH. Pegozafermin is an analog of fibroblast growth factor 21 (FGF21), an endogenous hormone that functions as a master metabolic regulator affecting important drivers of NASH such has hepatic fibrosis (scarring), steatosis (fat deposition), inflammation and lipid metabolism.[5],[6],[7],[8],[9],[10],[11] Pegozafermin is specifically designed to provide long-lasting exposure to FGF21 while maintaining the potency and activity profile of the native hormone. The ENLIVEN data show that pegozafermin is generally safe and effective and we have more evidence than ever that it has the potential to be a best-in-class FGF21 analog and ideal candidate for NASH.

Positive, highly statistically significant histology results

The study met, with high statistical significance, both the primary histology endpoints which have been set forth by the U.S. Food and Drug Administration (FDA) as acceptable for accelerated approval in pre-cirrhotic NASH and supports the advancement of pegozafermin into Phase 3.

After 24 weeks of treatment, the 44mg twice-weekly (Q2W) and the 30mg weekly (QW) dose groups both demonstrated at least one-stage fibrosis improvement without worsening of NASH (27% and 26%, respectively) at 3.5 times the placebo rate (7%) and NASH resolution without worsening of fibrosis (26% and 23%, respectively), between 12 to 14 times the placebo rate (2%). We are encouraged by the significant improvement in fibrosis seen in patients treated with pegozafermin since fibrosis is a key driver of disease progression, often leading to cirrhosis and other negative clinical outcomes.

Improvements were also observed across multiple non-invasive liver tests, markers of cardiovascular health and glycemic control. We were pleased to see progress for patients in addressing both the underlying cause of this progressive liver disease as well as related metabolic comorbidities, which is of critical importance for this patient population.

Pegozafermin is the only FGF21 analog to show positive histology data with every-two-week dosing

Because the two dosing regimens of 44mg Q2W and 30mg QW produced remarkably similar results, we now have great dosing optionality as we consider the possible designs of a Phase 3 program.

The ability to give pegozafermin every other week could be preferred for adoption and compliance of injectable therapies for patients living with this chronic, progressive and generally asymptomatic liver disease, and especially those who may already be on multiple medications for different comorbidities. Based on feedback from patients who used injectable medication, 63% preferred or strongly preferred every-two-week to weekly dosing.

Treatment with pegozafermin demonstrated a favorable safety and tolerability profile

For conditions like NASH that require chronic treatment and are often asymptomatic, poor gastrointestinal tolerability can pose difficulties that impact patients’ quality of life and clinical outcomes.[12] Consistent with the prior studies with pegozafermin, in the ENLIVEN study, treatment continued to demonstrate a favorable safety and tolerability profile. This represents an important step forward for not only the evolution of NASH treatments but the patients who have been waiting far too long for effective therapies.

We built our study using rigorous methods

To meet stringent regulatory requirements, as well as ensure the validity and reproducibility of our data, we were incredibly thorough in both the way we designed our trial and analyzed its data. Three expert pathologists read the liver biopsies independently and separately, and were blinded to patient, treatment cohort and timing of biopsy (pre-treatment or post-treatment) and underwent trial-specific concordance training before and during the trial. These pathologists did not discuss or coordinate their findings. We believe this methodology is the most rigorous and objective way to determine biopsy results.

We also analyzed the data in two different ways to account for missing follow-up biopsy data.?the results were consistent and achieved statistical significance for the 44mg Q2W and 30mg QW dose groups using both a multiple imputation analysis the (primary analysis method), and intention-to-treat analysis where missing biopsies are considered non-responders (the primary approach in Phase 3).

Results increase our confidence in Phase 3

These results clearly support advancement of pegozafermin for the treatment of NASH into Phase 3 development. We are one step closer to our vision of developing a therapy that addresses the liver and cardiometabolic manifestations of this complex disease. But this is just the beginning. Working with experts in the field, we will continue to advance our goals – not stopping until we have better medicines that support the needs of all those living with NASH and other cardiometabolic disorders like severe hypertriglyceridemia.

[1] Jagpreet, J. (n.d.). More about NAFLD. NAFLD Simulator. Retrieved April 14, 2023, from https://www.nafldsimulator.org/more-about-nafld

[2] Loomba R, et al. Cell. 2021;184:25376-256.

[3] Wong RJ, et al. J Clin Gastroenterol. 2021;55(10):891-902.

[4] Chalasani N, et al. Hepatology. 2018;67(1):328-357.

[5] Kharitonenkov A, et al. J Clin Invest. 2005;115(6):1627-1635.

[6] Kharitonenkov A, et al. Endocrinology. 2007;148(2):774-781.

[7] Keinicke H, et al. Endocr Connect. 2020;9(8):755-768.

[8] Bao L, et al. Br J Pharmacol. 2018;175(16):3379-3393.

[9] Xu J, et al. Diabetes. 2009;58(1):250-259.

[10] Stojsavljevic-Shapeki S, et al. J Clin Transl Hepatol. 2021;9(1):51-59.

[11] Gaich G, et al. Cell Metab. 2013;18(3):333-340.

[12] David, K., Kowdley, K. V., Unalp, A., Kanwal, F., Brunt, E. M., Schwimmer, J. B. NASH CRN Research Group. (2009, June). Quality of life in adults with nonalcoholic fatty liver disease: Baseline data from the Nonalcoholic Steatohepatitis Clinical Research Network. Hepatology (Baltimore, Md.). Retrieved April 21, 2023, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2692572/