Safety and Efficacy of Efruxifermin in Combination With a GLP-1 Receptor Agonist in Patients With NASH/MASH and Type 2 Diabetes in a Randomized Phase 2 Study.

BACKGROUND & AIMS: In phase 2 studies, efruxifermin, an Fc-FGF21 analog, significantly reduced steatohepatitis and fibrosis in patients with non-alcoholic steatohepatitis, now called metabolic dysfunction-associated steatohepatitis (MASH), for which there is no approved treatment. Type 2 diabetes (T2D) and obesity are prevalent among patients with MASH and increasingly treated with glucagon-like peptide-1 receptor agonists (GLP-1RAs). This study evaluated the safety and efficacy of efruxifermin in patients with MASH, fibrosis, and T2D taking a GLP-1RA. METHODS: Cohort D was a double-blind, placebo-controlled, phase 2b study in adults with T2D and MASH with fibrosis (F1-F3) on stable GLP-1RA therapy randomized (2:1) to receive efruxifermin 50 mg or placebo, once weekly for 12 weeks. The primary endpoint was safety and tolerability of efruxifermin added to a stable dose of GLP-1RA. Secondary endpoints included changes in hepatic fat fraction (HFF), markers of liver injury and fibrosis, and metabolic parameters. RESULTS: Adults (N = 31) with T2D and MASH fibrosis (F1-F3) on a stable GLP-1RA (semaglutide, 48.4%; dulaglutide, 45.2%; liraglutide, 6.5%) received efruxifermin 50 mg (n = 21) or placebo (n = 10) for 12 weeks. The addition of efruxifermin to a GLP-1RA appeared safe and well-tolerated. The most frequent efruxifermin-related adverse events were mild to moderate gastrointestinal events. One patient receiving efruxifermin discontinued due to nausea, and another withdrew consent. There were no treatment-related serious adverse events. After 12 weeks, efruxifermin reduced HFF by 65% (P < .0001 vs placebo) compared with a 10% reduction for placebo (GLP-1RA alone). Efruxifermin also improved noninvasive markers of liver injury, fibrosis, glucose, and lipid metabolism while maintaining GLP-1RA-mediated weight loss. CONCLUSIONS: The tolerability profile of efruxifermin added to GLP-1RA appeared comparable to that of either drug alone, while also significantly reducing HFF and noninvasive markers of fibrosis in patients with MASH and T2D. Liver health in patients already on a GLP-1RA may be further improved by addition of efruxifermin. CLINICALTRIALS: gov, Number: NCT05039450.

TVB-2640 (FASN Inhibitor) for the Treatment of Nonalcoholic Steatohepatitis: FASCINATE-1, a Randomized, Placebo-Controlled Phase 2a Trial.

BACKGROUND & AIMS: Increased de novo lipogenesis creates excess intrahepatic fat and lipotoxins, propagating liver damage in nonalcoholic steatohepatitis. TVB-2640, a fatty acid synthase inhibitor, was designed to reduce excess liver fat and directly inhibit inflammatory and fibrogenic pathways. We assessed the safety and efficacy of TVB-2640 in patients with nonalcoholic steatohepatitis in the United States. METHODS: 3V2640-CLIN-005 (FASCINATE-1) was a randomized, placebo-controlled, single-blind study at 10 US sites. Adults with ≥8% liver fat, assessed by magnetic resonance imaging proton density fat fraction, and evidence of liver fibrosis by magnetic resonance elastography ≥2.5 kPa or liver biopsy were eligible. Ninety-nine patients were randomized to receive placebo or 25 mg or 50 mg of TVB-2640 (orally, once-daily for 12 weeks). The primary end points of this study were safety and relative change in liver fat after treatment. RESULTS: Liver fat increased in the placebo cohort by 4.5% relative to baseline; in contrast TVB-2640 reduced liver fat by 9.6% in the 25-mg cohort (n = 30; least squares mean: -15.5%; 95% confidence interval, -31.3 to -0.23; P = .053), and 28.1% in the 50-mg cohort (n = 28; least squares mean: -28.0%; 95% confidence interval, -44.5 to -11.6; P = .001). Eleven percent of patients in the placebo group achieved a ≥30% relative reduction of liver fat compared to 23% in the 25-mg group, and 61% in the 50-mg group (P < .001). Secondary analyses showed improvements of metabolic, pro-inflammatory and fibrotic markers. TVB-2640 was well tolerated; adverse events were mostly mild and balanced among the groups. CONCLUSIONS: TVB-2640 significantly reduced liver fat and improved biochemical, inflammatory, and fibrotic biomarkers after 12 weeks, in a dose-dependent manner in patients with nonalcoholic steatohepatitis. ClinicalTrials.gov, Number NCT03938246.

Effect of Continuous Glucose Monitoring on Glycemic Control in Patients With Type 2 Diabetes Treated With Basal Insulin: A Randomized Clinical Trial.

Importance: Continuous glucose monitoring (CGM) has been shown to be beneficial for adults with type 2 diabetes using intensive insulin therapy, but its use in type 2 diabetes treated with basal insulin without prandial insulin has not been well studied. Objective: To determine the effectiveness of CGM in adults with type 2 diabetes treated with basal insulin without prandial insulin in primary care practices. Design, Setting, and Participants: This randomized clinical trial was conducted at 15 centers in the US (enrollment from July 30, 2018, to October 30, 2019; follow-up completed July 7, 2020) and included adults with type 2 diabetes receiving their diabetes care from a primary care clinician and treated with 1 or 2 daily injections of long- or intermediate-acting basal insulin without prandial insulin, with or without noninsulin glucose-lowering medications. Interventions: Random assignment 2:1 to CGM (n = 116) or traditional blood glucose meter (BGM) monitoring (n = 59). Main Outcomes and Measures: The primary outcome was hemoglobin A1c (HbA1c) level at 8 months. Key secondary outcomes were CGM-measured time in target glucose range of 70 to 180 mg/dL, time with glucose level at greater than 250 mg/dL, and mean glucose level at 8 months. Results: Among 175 randomized participants (mean [SD] age, 57 [9] years; 88 women [50%]; 92 racial/ethnic minority individuals [53%]; mean [SD] baseline HbA1c level, 9.1% [0.9%]), 165 (94%) completed the trial. Mean HbA1c level decreased from 9.1% at baseline to 8.0% at 8 months in the CGM group and from 9.0% to 8.4% in the BGM group (adjusted difference, -0.4% [95% CI, -0.8% to -0.1%]; P = .02). In the CGM group, compared with the BGM group, the mean percentage of CGM-measured time in the target glucose range of 70 to 180 mg/dL was 59% vs 43% (adjusted difference, 15% [95% CI, 8% to 23%]; P < .001), the mean percentage of time at greater than 250 mg/dL was 11% vs 27% (adjusted difference, -16% [95% CI, -21% to -11%]; P < .001), and the means of the mean glucose values were 179 mg/dL vs 206 mg/dL (adjusted difference, -26 mg/dL [95% CI, -41 to -12]; P < .001). Severe hypoglycemic events occurred in 1 participant (1%) in the CGM group and in 1 (2%) in the BGM group. Conclusions and Relevance: Among adults with poorly controlled type 2 diabetes treated with basal insulin without prandial insulin, continuous glucose monitoring, as compared with blood glucose meter monitoring, resulted in significantly lower HbA1c levels at 8 months. Trial Registration: ClinicalTrials.gov Identifier: NCT03566693.

Resmetirom for nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled phase 3 trial.

Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. MAESTRO-NAFLD-1 was a 52-week randomized, double-blind, placebo-controlled phase 3 trial evaluating the safety of resmetirom in adults with nonalcoholic fatty liver disease and presumed NASH. Patients were randomized to three double-blind arms (100 mg resmetirom (n = 325), 80 mg resmetirom (n = 327) or placebo (n = 320)) or open-label 100 mg resmetirom (n = 171). The primary end point was incidence of treatment-emergent adverse events (TEAEs) over 52 weeks and key secondary end points were LDL-C, apoB, triglycerides (over 24 weeks), hepatic fat (over 16 and 52 weeks) and liver stiffness (over 52 weeks). Resmetirom was safe and well tolerated. TEAEs occurred in 86.5% (open-label 100 mg resmetirom), 86.1% (100 mg resmetirom), 88.4% (80 mg resmetirom) and 81.8% (placebo) of patients. TEAEs in excess of placebo included diarrhea and nausea at the initiation of treatment. Key secondary end points included least square means difference from placebo at 80 mg, 100 mg resmetirom: LDL-C (-11.1%, -12.6%), apoB (-15.6%, -18.0%), triglycerides (-15.4%, -20.4%), 16-week hepatic fat (-34.9%, -38.6%), (P < 0.0001) and liver stiffness (-1.02, -1.70) and 52-week hepatic fat (-28.8, -33.9). These findings demonstrate resmetirom was safe and well tolerated in adults with presumed NASH, supporting a role for further clinical development. (ClinicalTrials.gov identifier NCT04197479 ).

Safety and efficacy of once-weekly efruxifermin versus placebo in non-alcoholic steatohepatitis (HARMONY): a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial.

BACKGROUND: Fibroblast growth factor 21 (FGF21) regulates metabolism and protects cells against stress. Efruxifermin is a bivalent Fc-FGF21 analogue that replicates FGF21 agonism of fibroblast growth factor receptor 1c, 2c, or 3c. The aim of this phase 2b study was to assess its efficacy and safety in patients with non-alcoholic steatohepatitis (NASH) and moderate (F2) or severe (F3) fibrosis. METHODS: HARMONY is a multicentre, randomised, double-blind, placebo-controlled, 96-week, phase 2b trial that was initiated at 41 clinics in the USA. Adults with biopsy-confirmed NASH, defined by a non-alcoholic fatty liver disease activity score (NAS) of 4 or higher and scores of 1 or higher in each of steatosis, ballooning, and lobular inflammation, with histological stage F2 or F3 fibrosis, were randomly assigned (1:1:1), via an interactive response system, to receive placebo or efruxifermin (28 mg or 50 mg), subcutaneously once weekly. Patients, investigators, pathologists, site staff, and the sponsor were masked to group assignments during the study. The primary endpoint was the proportion of patients with improvement in fibrosis of at least 1 stage and no worsening of NASH, based on analyses of baseline and week 24 biopsies (liver biopsy analysis set [LBAS]). A sensitivity analysis evaluated the endpoint in the full analysis set (FAS), for which patients with missing biopsies were considered non-responders. This trial is registered with ClinicalTrials.gov, NCT04767529, and is ongoing. FINDINGS: Between March 22, 2021, and Feb 7, 2022, 747 patients were assessed for eligibility and 128 patients (mean age 54·7 years [SD 10·4]; 79 [62%] female and 49 male [38%]; 118 [92%] white; and 56 [41%] Hispanic or Latino) were enrolled and randomly assigned to receive placebo (n=43), efruxifermin 28 mg (n=42; two randomised patients were not dosed because of an administrative error), or efruxifermin 50 mg (n=43). In the LBAS (n=113), eight (20%) of 41 patients in the placebo group had an improvement in fibrosis of at least 1 stage and no worsening of NASH by week 24 versus 15 (39%) of 38 patients in the efruxifermin 28 mg group (risk ratio [RR] 2·3 [95% CI 1·1-4·8]; p=0·025) and 14 (41%) of 34 patients in the efruxifermin 50 mg group (2·2 [1·0-5·0]; p=0·036). Based on the FAS (n=128), eight (19%) of 43 patients in the placebo group met this endpoint versus 15 (36%) of 42 in the efruxifermin 28 mg group (RR 2·2 [95% CI 1·0-4·8]; p=0·033) and 14 (33%) of 43 in the efruxifermin 50 mg group (1·9 [0·8-4·3]; p=0·123). The most frequent efruxifermin-related adverse events were diarrhoea (16 [40%] of 40 patients in the efruxifermin 28 mg group and 17 [40%] of 43 patients in efruxifermin 50 mg group vs eight [19%] of 43 patients in the placebo group; all events except one were grade 1-2) and nausea (11 [28%] patients in the efruxifermin 28 mg group and 18 [42%] patients in the efruxifermin 50 mg group vs ten [23%] patients in the placebo group; all grade 1-2). Five patients (two in the 28 mg group and three in the 50 mg group) discontinued due to adverse events. Serious adverse events occurred in four patients in the 50 mg group; one was defined as drug related (ulcerative esophagitis in a participant with a history of gastro-oesophageal reflux disease). No deaths occurred. INTERPRETATION: Efruxifermin improved liver fibrosis and resolved NASH over 24 weeks in patients with F2 or F3 fibrosis, with acceptable tolerability, supporting further assessment in phase 3 trials. FUNDING: Akero Therapeutics.

The Effect of Discontinuing Continuous Glucose Monitoring in Adults With Type 2 Diabetes Treated With Basal Insulin.

OBJECTIVE: To explore the effect of discontinuing continuous glucose monitoring (CGM) after 8 months of CGM use in adults with type 2 diabetes treated with basal without bolus insulin. RESEARCH DESIGN AND METHODS: This multicenter trial had an initial randomization to either real-time CGM or blood glucose monitoring (BGM) for 8 months followed by 6 months in which the BGM group continued to use BGM (n = 57) and the CGM group was randomly reassigned either to continue CGM (n = 53) or discontinue CGM with resumption of BGM for glucose monitoring (n = 53). RESULTS: In the group that discontinued CGM, mean time in range (TIR) 70-180 mg/dL, which improved from 38% before initiating CGM to 62% after 8 months of CGM, decreased after discontinuing CGM to 50% at 14 months (mean change from 8 to 14 months -12% [95% CI -21% to -3%], P = 0.01). In the group that continued CGM use, little change was found in TIR from 8 to 14 months (baseline 44%, 8 months 56%, 14 months 57%, mean change from 8 to 14 months 1% [95% CI -11% to 12%], P = 0.89). Comparing the two groups at 14 months, the adjusted treatment group difference in mean TIR was -6% (95% CI -16% to 4%, P = 0.20). CONCLUSIONS: In adults with type 2 diabetes treated with basal insulin who had been using real-time CGM for 8 months, discontinuing CGM resulted in a loss of about one-half of the initial gain in TIR that had been achieved during CGM use.