Timing Is Everything: Improving NASH Histology in Clinical Trials Should Not Be Rushed
Authors: Vlad Ratziu
Journal: Hepatology (2020)

Potential conflict of interest: Dr. Ratziu consults for Genfit, Intercept, Galmed, Boehringer Ingelheim, AstraZeneca, Bristol‐Myers Squibb, and Madrigal. He received grants from Gilead. See Article on Page 1198 The farnesoid X receptor (FXR)–fibroblast growth factor 19 (FGF19) axis has provided promising therapeutic targets for nonalcoholic steatohepatitis (NASH), with obeticholic acid (OCA), the first‐in‐class FXR agonist, showing fibrosis improvement in two human trials.(1,2) FXR regulates bile acid, lipid, and glucose metabolism by controlling a broad transcriptional repertoire in the intestine and liver. FGF19, the most prominent FXR target gene in the intestine, is released into portal circulation and binds to the FGF receptor 4 (FGFR4) on the surface of hepatocytes. Activated FGFR4 leads to transcriptional suppression of cytochrome 7A1, which encodes the pacemaker enzyme to convert cholesterol into bile acids. The same pathway of extracellular signal‐regulated kinase (ERK)/ribosomal S6 kinase/glycogen synthase kinase 3b phosphorylation induced on binding of FGF19 to FGFR4 on hepatocytes is responsible for beneficial metabolic effects elicited by FGF19, such as glycogen synthesis and reduction of sterol regulatory element–binding protein‐1c with subsequent reduction in lipogenesis.(3) However, full activation of FGF19 also stimulates signal transducer and activator of transcription 3 (STAT 3)‐dependent hepatocyte proliferation, increasing risk and poor prognosis of colon cancer and hepatocellular carcinoma (HCC). A synthetic FGF19 engineered by NGM induces the beneficial "metabolic" arm of signaling through ERK without stimulating the proliferative branch of STAT 3–mediated FGFR4 pro‐oncogenic signaling.(4) Two studies with this FGF19 construct (aldafermin [NGM282]) have been conducted in human NASH. In the first phase 2 study, daily dosing at 3 or 6 mg of aldafermin over 12 weeks resulted in steatosis reductions, with 72%‐79% of patients achieving ≥5% absolute reduction in liver fat.(5) This reduction correlated with reduction in serum C4, a pharmacodynamic marker of FGF19 target engagement. Importantly, treatment‐induced liver fat reduction correlated with a sharp decline in aminotransferases; one‐third of patients experienced normalized alanine aminotransferase (ALT) levels, suggesting a metabolic reprogramming(6) or an improvement in hepatic inflammation and liver cell injury. However, without follow‐up biopsies, it remains unknown whether the aldafermin‐induced liver fat and ALT response translates into a histological benefit on steatohepatitis. The follow‐up study by Harrison and colleagues in this issue of Hepatology is intriguing. Because of the high rate of withdrawal caused by adverse events in the 6‐mg group,(5) the authors tested a 1‐mg dose and the 3‐mg dose in a 12‐week, open‐label trial. Although detailed data are not provided, gastrointestinal side effects, the major tolerability issue with NGM282, were manageable and less frequent. The trial was not placebo controlled, and it is unclear whether the allocation between the 1‐ and 3‐mg arms was random. However, this was compensated by a control biopsy performed after 12 weeks of treatment, a bold move considering the reluctance of investigators and patients alike to schedule closely repeated biopsies. Some patients achieved histological improvement beyond steatosis reduction with both doses of aldafermin after 12 weeks. Six of 24 patients (25%) in the 1‐mg arm and 8 of 19 patients (42%) in the 3‐mg arm had a ≥1 stage improvement in fibrosis without NASH worsening. Prima facie, 42% seems higher than the 13% placebo response rate observed in a more robust and longer phase 3 trial(2) but is similar to a 43% response rate from another small study, unfortunately unconfirmed in a phase 3 trial.(7) This study was limited by small sample size and lack of a placebo control group. It is unclear if the changes in liver histology could have been impacted by sampling variability or spontaneous improvement over a 12‐week period. Overall, lobular inflammation and ballooning were lower at the end of treatment, indicating that NASH activity can start improving early in therapy. Unfortunately, no data are presented showing the proportion of patients with improvements in these parameters in both arms. Because the rate of steatohepatitis resolution was low (approximately 10%‐12%, comparable with placebo in larger data sets(2)), the improvement in disease activity was probably insufficient for ballooning and inflammation scores to have declined to zero. Alternatively, some subsets of inflammatory cells may be necessary to promote steatohepatitis resolution. Routine histological assessment does not phenotype different cellular populations; therefore, the transient presence of proresolution inflammatory cells might be miscategorized as ongoing steatohepatitis. Early control biopsies, a key feature of the Harrison et al. study, raise more important questions than answers. Because early aspects of histological recovery and tissue regeneration in human NASH are unknown, the changes are difficult to interpret. Moreover, an early assessment (week 12) of a slow process, such as fibrosis reversal, may not capture a drug's full antifibrotic potency. If a drug reduces fibrosis because of steatohepatitis resolution instead of a direct antifibrotic effect, longer therapy duration may be desirable. Finally, considering that NASH is a slowly evolving disease for which long‐term (if not lifelong) therapy is probably necessary, there is no clinical necessity to evaluate efficacy at such an early time point. Data on fibrosis biomarkers show a remarkable distinction between responders and nonresponders. Although prediction of response is legitimate, an early predictor of a later, maximum, histological response is needed; here, the longer‐term efficacy is unknown because only short‐term biopsies are available. Although data (Fig. 1) are encouraging, which part of the response (on nonalcoholic fatty liver disease activity score or on fibrosis stage) accounts for most of the biomarker changes is still undetermined.FIG. 1: (A) A simplified schematic view of FXR and FGF19 signaling throughout the gut‐liver axis. Intestinal FXR activation induces FGF19 release. FGF19 enters the portal circulation and binds to FGFR4 to induce signal transduction pathways within the hepatocyte. Beyond FGF19 secretion, activation of intestinal FXR has additional impact on intestinal barrier integrity and the composition of the intestinal microbiome. Activation of hepatocyte‐borne FXR by an FXR agonist enhances FGFR4‐mediated signal transduction, further amplifying the pathways. The FGFR4‐mediated activation of the STAT 3 pathway drives hepatocyte proliferation and is implicated in the development of HCC. In parallel, FGF19‐induced FGFR4 activation turns on the Ras/Mek/ERK axis, thereby controlling bile acid metabolism by reducing Cyp7A1 expression. This "metabolic branch" of FGFR4 activation converges with insulin signaling, yielding overall beneficial metabolic effects. NGM282 is reported to activate only the metabolic branch, leaving the proliferative branch of FGFR4 activation unaffected. (B) FGF19/FGFR4 signaling is only a subpart of FXR activation in the liver. FGFR4 is reported to be expressed in hepatocytes (HCs) and cholangiocytes (CCs) in the liver and, independent of wild‐type or engineered FGF19, this cytokine can only exert its effects primarily in these cell types. FXR, however, is more broadly expressed in HCs, CCs, Kupffer cells (KCs), and endothelial cells (ECs). HCs, KCs, and ECs are all reported to contribute to the antifibrotic activity of FXR agonists and FGF19 proteins. (C) The natural FGF19/FGFR4 pathway as a subpart as well as the FXR pathway in toto follow the ingestion of meals and the associated bile acid release. Therefore, they follow a circadian activation pattern. (i) The FGF19 pattern is induced by naturally released bile acids during the digestion process. (ii) A short‐lived synthetic FXR agonist, depending on its pharmacokinetic profile, can beneficially be superimposed onto the endogenous rhythm. (iii) Disrupting this circadian pattern by unphysiological activation of FXR by a long‐lasting agonist or of FGFR4 through administered FGF19 leads to deleterious overstimulation of the proliferative arm, which is reported to increase the risk of HCC. NGM282 was engineered to be void of this proliferative liability. RSK, ribosomal S6 kinase.Aldafermin is clearly a potent antisteatotic agent, and the early and profound reduction in ALT suggests it may mitigate liver injury. The histological data presented here are not conclusive. If subsequently confirmed in longer trials, they will inform that histological improvement can occur early. Clinically, it is unclear how important it is to achieve an early reduction in fibrosis. In a hypothetical scenario of combination therapies, the balance between a strong antifibrotic potency and an imperfect tolerability of an injectable drug might augur an early but limited utilization as an induction therapy. However, will FGF19‐based compounds have the same antifibrotic potential as FXR agonists? Conceptually, FGF19 can only play part of the antifibrotic repertoire of FXR agonists because FGF19 relies primarily on FGFR4 activation, which is restricted to hepatocytes and cholangiocytes, whereas the antifibrotic effects of OCA may also be conveyed through FXR activation in hepatic endothelial and Kupffer cells.(8,9) There are benefits and limitations of aldafermin versus OCA or second‐generation FXR agonists as best‐in‐class NASH drug candidates. Both compounds share the same increase in low‐density lipoprotein cholesterol, neither seem to improve glycemic control, the optimal dose minimizing gastrointestinal side effects of aldafermin needs to be determined, and aldafermin does not induce pruritus. Additionally, although FGF19 is the most prominent FXR target gene in the intestine, intestinal FXR activation has a dramatic positive impact on the gut microbiome and intestinal barrier integrity, providing possible benefits for treating NASH. Longer‐term studies need to confirm that the engineered version of FGF19 lacks untoward proliferative effects, particularly because its subcutaneous delivery is not superimposed to the natural FGF19 diurnal cycle. Bile acids and thus FGF19 serum levels undergo major circadian changes, and disruption of the diurnal synchronization of bile acids and FXR/FGF19 signaling in jet‐lagged or FXR−/− mice dramatically increases HCC incidence.(10) Subcutaneous daily injections of NGM282 do not follow the natural circadian rhythm of FGF19 levels, which tend to peak 2‐3 times a day in a postprandial fashion (Fig. 1B). Furthermore, although not yet reported, the serum and liver levels of recombinant NGM282 following 3‐ or 6‐mg doses are likely much higher than those of endogenous FGF19. It remains to be seen if an engineered version of FGF19 that retains only minimal proliferative capacity and can down‐regulate the bile acid pool will compensate for the profile of unnatural exposure over time. Whether any of the disease‐modifying effects of FXR agonists cannot be mimicked by subcutaneously injected NGM282 remains to be determined. In the crowded field of FXR agonists, aldafermin may benefit from potential superior histological efficacy, which can only be shown in longer‐term studies. Although the pace of drug development in NASH is speeding up, festina lente is, again, a timeless reminder that some things should not be rushed.