Aldafermin in patients with non-alcoholic steatohepatitis (ALPINE 2/3): a randomised, double-blind, placebo-controlled, phase 2b trial.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis, inflammation, and injury, and is associated with an increased risk of liver transplantation and death. NASH affects more than 16 million people in the USA, and there is no approved therapy. The aim of this study was to evaluate the safety and efficacy of aldafermin, an engineered analogue of the gut hormone fibroblast growth factor 19 (FGF19). METHODS: In this randomised, double-blind, placebo-controlled, phase 2b study (ALPINE 2/3) in patients with biopsy-confirmed NASH and stage 2 or 3 fibrosis, we randomly assigned patients stratified by fibrosis stage in a 1:1:1:1 ratio to receive placebo, aldafermin 0·3 mg, 1·0 mg, or 3·0 mg once daily for 24 weeks at 30 study sites in the USA. Patients, investigators, the funder, and all other staff, were masked to treatment assignment throughout the study. The primary endpoint was an improvement in liver fibrosis of at least one stage with no worsening of NASH at week 24. Analyses were done by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT03912532, and has been completed. FINDINGS: Between May 16, 2019, and Sept 4, 2020, 786 patients were screened, of whom 171 were randomly assigned to a treatment group and included in the intention-to-treat population: 43 in the 0·3 mg aldafermin group, 42 in the 1·0 mg group, 43 in the 3·0 mg group, and 43 in the placebo group. In total, 145 (85%) of patients completed treatment. At week 24, among patients with biopsies at both baseline and week 24, was seven (19%) of 36 patients in the placebo group, 11 (31%) of 36 in the 0·3 mg aldafermin group (difference 90% CI 12% [-9 to 33]; p=0·11), five (15%) of 34 patients in the 1·0 mg group (difference -5% [-24 to 13]; p=0·80), and 11 (30%) of 37 patients in the 3·0 mg group (difference 10% [-9 to 30]; p=0·12) had an improvement in liver fibrosis of at least one stage with no worsening of NASH, without meeting the prespecified significance for dose response (p=0·55). Adverse events were mostly mild or moderate in severity. Diarrhoea occurred in six (14%) of 43 patients in the placebo group, three (7%) of 43 patients in the 0·3 mg aldafermin group, five (12%) of 41 patients in the 1·0 mg group, and ten (23%) of 43 patients in the 3·0 mg group. Incidences of serious adverse events and discontinuations owing to adverse events were similar between groups. INTERPRETATION: Aldafermin was generally well tolerated but did not produce a significant dose response on fibrosis improvement of at least one stage with no worsening of NASH, despite positive effects on a number of secondary endpoints. The findings of this trial may have implications for the design of future NASH trials. FUNDING: NGM Biopharmaceuticals.

Safety, Tolerability, and Biologic Activity of AXA1125 and AXA1957 in Subjects With Nonalcoholic Fatty Liver Disease.

INTRODUCTION: AXA1125 and AXA1957 are novel, orally administered endogenous metabolic modulator compositions, specifically designed to simultaneously support multiple metabolic and fibroinflammatory pathways associated with nonalcoholic fatty liver disease (NAFLD). This study assessed safety, tolerability, and biologic activity of AXA1125 and AXA1957 in NAFLD. METHODS: In this multicenter, 16-week, placebo-controlled, single-blind, randomized clinical study in subjects with NAFLD stratified by type 2 diabetes, AXA1125 24 g, AXA1957 13.5 g or 20.3 g, or placebo was administered twice daily. Key metabolism (MRI-proton density fat fraction [MRI-PDFF] and homeostasis model assessment of insulin resistance [HOMA-IR]) and fibroinflammation markers (alanine aminotransferase [ALT], corrected T1 [cT1], keratin-18 [K-18] M65, and N-terminal type III collagen propeptide [Pro-C3]) were evaluated. Safety outcomes included adverse events and standard laboratory assessments. RESULTS: Baseline characteristics of the 102 enrolled subjects, including 40 with type 2 diabetes, were consistent with presumed nonalcoholic steatohepatitis. AXA1125 showed consistently greater biologic activity than AXA1957 or placebo. Week 16 changes from baseline with AXA1125 vs placebo: MRI-PDFF -22.9% vs -5.7%, HOMA-IR -4.4 vs +0.7, ALT -21.9% vs -7.2%, K-18 M65 -13.6% vs +20.1%, cT1 -69.6 vs +18.3 ms (P < 0.05), and Pro-C3 -13.6% vs -3.6%. Week 16 changes from baseline with AXA1957 20.3 g: MRI-PDFF -8.1%, HOMA-IR +8.4, ALT -20.7%, K-18 M65 6.6%, cT1 -34.7 ms, and Pro-C3 -15.6%. A greater proportion of subjects treated with AXA1125 achieved clinically relevant thresholds: ≥30% MRI-PDFF, ≥17-IU/L ALT, and ≥80-ms cT1 reductions at week 16. Study products were safe and well tolerated with stable lipid and weight profiles. DISCUSSION: Both compositions showed multitargeted activity on relevant NAFLD pathways. AXA1125 demonstrated the greatest activity over 16 weeks, warranting continued clinical investigation in nonalcoholic steatohepatitis subjects.

A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis.

BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is characterized by hepatocyte steatosis, ballooning, and lobular inflammation which may lead to fibrosis. Lipotoxicity activates caspases, which cause apoptosis and inflammatory cytokine (IL-1ß and IL-18) production. Emricasan is a pan-caspase inhibitor that decreases serum aminotransferases and caspase activation in patients with NASH. This study postulated that 72 weeks of emricasan treatment would improve liver fibrosis without worsening of NASH. METHODS: In this double-blind, placebo-controlled study 318 patients were randomized 1:1:1 to twice-daily treatment with emricasan (5 mg or 50 mg) or matching placebo for 72 weeks. Patients had definite NASH and NASH CRN fibrosis stage F1-F3, as determined by a central reader, on a liver biopsy obtained within 6 months of randomization. RESULTS: Emricasan treatment did not achieve the primary objective of fibrosis improvement without worsening of NASH (emricasan 5 mg: 11.2%; emricasan 50 mg: 12.3%; placebo: 19.0%; odds ratios vs. placebo 0.530 and 0.588, with p = 0.972 and 0.972, respectively) or the secondary objective of NASH resolution without worsening of fibrosis (emricasan 5 mg: 3.7%; emricasan 50 mg: 6.6%; placebo: 10.5%; odds ratios vs. placebo 0.334 and 0.613, with p = 0.070 and 0.335, respectively). In the small subset of patients with consistent normalization of serum alanine aminotransferase over 72 weeks, emricasan may have improved histologic outcomes. CONCLUSIONS: Emricasan treatment did not improve liver histology in patients with NASH fibrosis despite target engagement and may have worsened fibrosis and ballooning. Caspase inhibition lowered serum alanine aminotransferase in the short-term but may have directed cells to alternative mechanisms of cell death, resulting in more liver fibrosis and hepatocyte ballooning. CLINICAL TRIAL NUMBER: Clinical Trials.gov #NCT02686762. LAY SUMMARY: Non-alcoholic steatohepatitis (NASH) is characterized by fat accumulation in liver cells, which leads to inflammation and fibrosis. Emricasan was previously shown to inhibit some of the liver enzymes which lead to liver inflammation and fibrosis. In this study, emricasan did not improve liver inflammation or fibrosis in patients with NASH and pre-existing liver fibrosis.

A Phase 2, Randomized, Placebo-Controlled Study Evaluating Matrix Metalloproteinase-9 Inhibitor, Andecaliximab, in Patients With Moderately to Severely Active Crohn's Disease.

BACKGROUND AND AIMS: Matrix metalloproteinase-9 [MMP9] is implicated in the pathogenesis of Crohn's disease and may serve as a potential biomarker. A phase 2 trial was conducted to examine the efficacy and safety of the anti-MMP9 antibody andecaliximab [GS-5745] in patients with moderately to severely active Crohn's disease. METHODS: Patients were randomized 1:2:2:2 to receive subcutaneous injections of placebo weekly [QW], andecaliximab 150 mg every 2 weeks [Q2W], andecaliximab 150 mg QW, or andecaliximab 300 mg QW.The co-primary study efficacy endpoints were evaluation of a clinical response, defined as liquid or very soft stool frequency and abdominal pain composite [from Patient-Reported Outcome 2] score ≤ 8 at week 8, and an endoscopic response, defined as a ≥ 50% reduction from baseline in the Simple Endoscopic Score for Crohn's Disease, following 8 weeks of treatment. RESULTS: A total of 187 participants were randomized to treatment; 53 participants were randomized to each andecaliximab treatment group and 28 participants were randomized to placebo. Proportions of patients receiving andecaliximab were not different from proportions of patients receiving placebo based on clinical and endoscopic response and Crohn's disease activity index-defined remission at week 8. Rates of adverse events were comparable among the andecaliximab and placebo groups. CONCLUSIONS: Eight weeks of induction treatment with 150 mg andecaliximab Q2W, 150 mg andecaliximab QW, or 300 mg andecaliximab QW in patients with Crohn's disease did not induce a clinically meaningful symptomatic or endoscopic response. Andecaliximab was well tolerated. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02405442.

Certolizumab pegol for active Crohn's disease: a placebo-controlled, randomized trial.

BACKGROUND & AIMS: Certolizumab pegol (CZP) is a pegylated-conjugated Fab' against tumor necrosis factor (TNF). Additional data are needed regarding the efficacy of induction therapy with CZP in active Crohn's disease (CD). METHODS: A placebo-controlled trial evaluated the efficacy of CZP therapy in 439 adults with moderate to severe CD naive to anti-TNF therapy. Patients were randomized to receive CZP (400 mg subcutaneously) or placebo at weeks 0, 2, and 4. The primary end point was clinical remission at week 6. RESULTS: Clinical remission rates at week 6 in the CZP and placebo groups were 32% and 25% (P = .174), respectively. Remission rates at weeks 2 and 4 in the CZP and placebo groups were 23% and 16% (P = .033) and 27% and 19% (P = .063), respectively. Clinical response rates at weeks 2, 4, and 6 in the CZP and placebo groups were 33% and 20% (P = .001), 35% and 26% (P = .024), and 41% and 34% (P = .179), respectively. There were significantly greater rates of clinical remission at week 6 for CZP in patients with increased concentrations of C-reactive protein (≥5 mg/L) at entry. Serious adverse events developed in 5% and 4% of patients in the CZP and placebo groups, respectively. CONCLUSIONS: The primary end point did not reach statistical significance. Significant differences between CZP and placebo were observed in patients who had increased concentrations of C-reactive protein when the study began. Future clinical trials should emphasize the treatment of patients who have objective evidence of inflammation in addition to symptoms of active disease.

Role of growth factors in oesophageal mucosal healing: A work in progress.

Reflux of gastroduodenal contents into the oesophagus results in dynamic cycles of injury followed by cell proliferation and repair. These processes are receiving increased attention due to the high incidence of gastro-oesophageal reflux disease and the rising incidence of adenocarcinoma of the oesophagus. Repeated cycles of injury and repair may lead to abnormal differentiation followed by abnormal growth. This article summarizes the research performed by our group in the field of oesophageal injury and repair. We initially developed an in vivo perfused rabbit oesophagus model that served to study the effects of various components of the gastroduodenal juice on several parameters of oesophageal injury. We have shown that pepsin causes severe morphological oesophagitis at an acidic pH but is ineffective at an alkaline pH. We have also demonstrated that trypsin causes severe morphological oesophagitis at an alkaline pH but not at an acidic pH. Bile salts were found to disrupt the oesophageal barrier at both pH levels. We have also studied the effects of epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I) on oesophageal regeneration. We used an ex vivo oesophageal explant model for these experiments. Both EGF and IGF-I cause a dose-dependent increase in oesophageal DNA synthesis, cell proliferation and mucosal growth. These effects are synergistic and can be inhibited by specific tyrphostins. We are currently studying the role of growth factors as therapeutic agents and the role of growth factors in the development of Barrett's oesophagus and adenocarcinoma.