Ronald Palacios Castrillo, MD, PhD.
Pharmacotherapy in patients with non-alcoholic steatohepatitis (NASH) has been a disappointing endeavor, with even late-stage clinical trials yielding a handful of failures compared to successes.
The complex pathobiologic features of NASH, the slow and variable natural history of the disease, and the rigorous nature of histologic endpoint assessment have contributed to the difficulty in achieving efficacy with pharmacotherapy that is significantly different than that seen with placebo.
In this context, it makes sense that studies that have demonstrated modest solid histological efficacy have been announced. Therapeutic approaches have been divided between those broadly targeting weight loss and those targeting more specific aspects of the lipotoxicity-fibroinflammatory cascade.
Fibroblast growth factor 21 (FGF21) has pleiotropic metabolic effects, partially mediated by adiponectin, which improve insulin sensitivity and reduce inflammation, improve vascular function, and improve liver, adipose tissue and acts directly on many tissues, including the pancreas.
These effects regulate lipogenesis, ketogenesis, and energy expenditure (1). Several FGF21 analogs, such as pegozfermin, a long-acting glycosylated analog of FGF21, are being developed for the treatment of NASH, and metabolic effects in humans vary between the compounds (2).
Efficacy is difficult to assess histologically, and the Food and Drug Administration (FDA) recognizes histological endpoints only as surrogates for clinical outcomes (for example, death and liver-related events), Which must be evaluated for a drug to get approval from the FDA.
In a phase 2b trial, Loomba et al.(3) evaluated treatment with pegozafermin at a dose of 15 mg or 30 mg weekly or at a dose of 44 mg every 2 weeks compared to placebo for 24 weeks. A reduction in the level of fibrosis, one of the two primary endpoints, was observed in patients receiving pegozfermin, with a difference in treatment effect compared to placebo of 14 percentage points (with pegozfermin at a dose of 15 mg per week), 19 percentage points (at a dose of 30 mg weekly) and 20 percentage points (at a dose of 44 mg every 2 weeks).
The results also supported pegosefermin for the second primary endpoint of NASH resolution. The margin of efficacy compared to placebo is important, because placebo response in NASH trials, depending on the endpoint, ranges from 2%, as reported by Loomba et al, to 40%, 4 a range that is not complete. Limits the relevance of evaluation. -Response percentage.
Given the mechanism of action of pegozfermin, a more pronounced effect on the resolution of NASH might be expected. The reduction showed greater signal effectiveness when researchers used a less stringent histologic endpoint (a two-point reduction in the activity score for non-alcoholic fatty liver disease, an assessment that does not require the complete absence of hepatocyte enlargement). . There was an increase in disease activity and no decline in fibrosis, with a treatment effect of 39% with pegozafermin at a weekly dose of 30 mg compared to placebo.
If a therapeutic agent is tentatively approved for the treatment of NASH, it will be necessary to evaluate the efficacy of the therapy using non-invasive testing, as liver biopsy is not practical on a large scale and should be performed less frequently in practice. is done. Continued validation based on clinical trials and larger cohorts will provide important information about the accuracy of various non-invasive tests in this context.
Changes in alanine aminotransferase (ALT) levels and magnetic resonance imaging proton density fat fraction (MRI-PDF) results have been the most consistent biomarkers for predicting resolution of NASH and, to a lesser extent, reduction in fibrosis, although cost and relatively low availability. This will limit the use of MRI-PDFF as a non-invasive test in widespread clinical practice.
In this trial, 60% of patients in the 30 mg weekly group had at least a 30% reduction in liver fat volume (as assessed by MRI-PDF) and a decline in liver fat levels. There was histological improvement in ALT of more than 17 U per liter, compared with only 9% of patients receiving placebo, a response that may provide an indication of efficacy. Furthermore, the proportion of patients whose ALT levels improved in a dose-dependent manner is encouraging.
Unless non-invasive testing can be distinguished from histologic findings (a very limited reference standard), the success of non-invasive testing as a predictor of treatment response or nonfunction will be limited.
The results of the trial reported by Loomba et al are as promising as they are promising. Should be interpreted with caution. Durability of response to treatment has been a significant limitation of other FGF21 analogs. Although covalent conjugation with polyethylene glycol (for example, the FGF21 analog to pegosafermin) improves the pharmacokinetic profile and reduces the immunogenicity of glycosylated proteins, immunogenicity is reduced rather than enhanced. 7
In the Phase 1b-2a trial prior to the current trial, antidrug antibodies against pegozermin developed in 65% of patients at 12 weeks, and the frequency and titer increased with dose and duration of treatment; These findings raise the possibility that antidrug antibodies may have contributed to the apparent lack of dose dependence in resolution of NASH in the present trial.
NASH is a chronic disease with pathobiological features rooted in energy metabolism, making the time horizon of NASH therapy more similar to that of type 2 diabetes (measured in years) than that of hepatitis C (measured in weeks).
Therefore, although the 24-week open-label extension employed in this trial will provide information regarding the durability of response to pegozafermin, even a 48-week follow-up is needed to evaluate the durability of response to this or any other treatment. The duration may also be very short. On FGF21. Treatment.
The results of testing by Loomba et al. They are an exciting advance in NASH therapeutics. We anxiously await determination of whether the rapid pace of response can be sustained to the end of the marathon.
- Geng L, Lam KSL, Xu A. The therapeutic potential of FGF21 in metabolic diseases: from bench to clinic. Nat Rev Endocrinol 2020;16:654-667.
- Shao W, Jin T. Hepatic hormone FGF21 and its analogs in clinical trials. Chronic Dis Transl Med 2022;8:19-25.
- Loomba R, Sanyal AJ, Caudley KV, et al. Randomized, controlled trial of the FGF21 analog pegozfermin in NASH. N Engl J Med 2023;389:998-1008.
- Sanyal AJ, Abdelmalek MF, Suzuki A, Cummings OW, Chojkir M, EPE-A Study Group. No significant effect of ethyl-eicosapentaenoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial. Gastroenterology 2014;147(2):377-84.e1.
- Huang DQ, Sharpton SR, Amangurbanova M, et al. Clinical utility of combined MRI-PDFF and ALT response in predicting histological response in non-alcoholic fatty liver disease. Clin Gastroenterol Hepatol 2022 Sep 6, (Epub ahead of print).
- Loomba R, Sanyal AJ, Nakajima A, et al. Pegbelferrin in patients with nonalcoholic steatohepatitis and stage 3 fibrosis (FALCON 1): a randomized phase 2b study. Clin Gastroenterol Hepatol 2023 Sep 6 (Epub ahead of print).
- Veronese FM, Mero A. Impact of PEGylation on biological therapies. Biodrugs 2008;22:315-329.
- Loomba R, Lovitz EJ, Frias JP, et al. Safety, Pharmacokinetics, and Pharmacodynamics of Pagozafermin in Patients with Non-Alcoholic Steatohepatitis: A Randomized, Double-Blind, Placebo-Controlled, Phase 1B/2A Multiple-Ascending-Dose Study. Lancet Gastroenterol Hepatol 2023;8:120-132.