Explore the vast range of titles available.

Preclinical and clinical data suggest that fibroblast growth factor 21 (FGF21) is anti-fibrotic, improves metabolic status and has potential to treat non-alcoholic steatohepatitis (NASH). We assessed the safety and efficacy of efruxifermin, a long-acting Fc-FGF21 fusion protein, for the treatment of NASH. BALANCED was a randomized, placebo-controlled study in patients with NASH conducted at 27 centers in the United States (ClinicalTrials.gov NCT03976401 ). Eighty patients, stratified by hepatic fat fraction (HFF) and fibrosis stage, were randomized using a centrally administered minimization algorithm 1:1:1:1 to receive placebo ( n  = 21) or efruxifermin 28 mg ( n  = 19), efruxifermin 50 mg ( n  = 20) or efruxifermin 70 mg ( n  = 20) via weekly subcutaneous injection for 16 weeks. The primary endpoint—absolute change from baseline in HFF measured as magnetic resonance imaging–proton density fat fraction at week 12—was met. For the full analysis set, the least squares mean absolute changes (one-sided 97.5% confidence interval) from baseline in HFF were −12.3% (−infinity (−inf), −10.3), −13.4% (−inf, −11.4) and −14.1% (−inf, −12.1) in the 28-, 50- and 70-mg groups, respectively, versus 0.3% (−inf, 1.6) in the placebo group, with statistically significant differences between efruxifermin groups and placebo ( P  < 0.0001 each). Overall, 70 of 79 patients who received the study drug (89%) experienced at least one treatment-emergent adverse event (TEAE), with the majority grade 1–2 (64 (81%)), five (6%) grade 3 and one grade 4. The most commonly reported drug-related TEAEs were grade 1–2 gastrointestinal (36 (46%)). Treatment with efruxifermin significantly reduced HFF in patients with F1–F3 stage NASH, with an acceptable safety profile. Results from BALANCED, a phase 2a, multicenter, randomized controlled trial testing efruxifermin (a long-acting Fc-FGF21 fusion protein) over 16 weeks, demonstrated significant reductions in the hepatic fat fraction in patients with F1–F3 stage non-alcoholic steatohepatitis.

The integrase inhibitor elvitegravir (EVG) has been co-formulated with the CYP3A4 inhibitor cobicistat (COBI), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) in a single tablet given once daily. We compared the efficacy and safety of EVG/COBI/FTC/TDF with standard of care—co-formulated efavirenz (EFV)/FTC/TDF—as initial treatment for HIV infection. In this phase 3 trial, treatment-naive patients from outpatient clinics in North America were randomly assigned by computer-generated allocation sequence with a block size of four in a 1:1 ratio to receive EVG/COBI/FTC/TDF or EFV/FTC/TDF, once daily, plus matching placebo. Patients and study staff involved in giving study treatment, assessing outcomes, and collecting and analysing data were masked to treatment allocation. Eligibility criteria included screening HIV RNA concentration of 5000 copies per mL or more, and susceptibility to efavirenz, emtricitabine, and tenofovir. The primary endpoint was HIV RNA concentration of fewer than 50 copies per mL at week 48. The study is registered with ClinicalTrials.gov, number NCT01095796. 700 patients were randomly assigned and treated (348 with EVG/COBI/FTC/TDF, 352 with EFV/FTC/TDF). EVG/COBI/FTC/TDF was non-inferior to EFV/FTC/TDF; 305/348 (87·6%) versus 296/352 (84·1%) of patients had HIV RNA concentrations of fewer than 50 copies per mL at week 48 (difference 3·6%, 95% CI −1·6% to 8·8%). Proportions of patients discontinuing drugs for adverse events did not differ substantially (13/348 in the EVG/COBI/FTC/TDF group vs 18/352 in the EFV/FTC/TDF group). Nausea was more common with EVG/COBI/FTC/TDF than with EFV/FTC/TDF (72/348 vs 48/352) and dizziness (23/348 vs 86/352), abnormal dreams (53/348 vs 95/352), insomnia (30/348 vs 49/352), and rash (22/348 vs 43/352) were less common. Serum creatinine concentration increased more by week 48 in the EVG/COBI/FTC/TDF group than in the EFV/FTC/TDF group (median 13 μmol/L, IQR 5 to 20 vs 1 μmol/L, −6 to 8; p<0·001). If regulatory approval is given, EVG/COBI/FTC/TDF would be the only single-tablet, once-daily, integrase-inhibitor-based regimen for initial treatment of HIV infection. Gilead Sciences.

The HIV integrase strand transfer inhibitor elvitegravir (EVG) has been co-formulated with the CYP3A4 inhibitor cobicistat (COBI), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) into a once-daily, single tablet. We compared EVG/COBI/FTC/TDF with a ritonavir-boosted (RTV) protease inhibitor regimen of atazanavir (ATV)/RTV+FTC/TDF as initial therapy for HIV-1 infection. This phase 3, non-inferiority study enrolled treatment-naive patients with an HIV-1 RNA concentration of 5000 copies per mL or more and susceptibility to atazanavir, emtricitabine, and tenofovir. Patients were randomly assigned (1:1) to receive EVG/COBI/FTC/TDF or ATV/RTV+FTC/TDF plus matching placebos, administered once daily. Randomisation was by a computer-generated random sequence, accessed via an interactive telephone and web response system. Patients, and investigators and study staff who gave treatments, assessed outcomes, or analysed data were masked to the assignment. The primary endpoint was HIV RNA concentration of 50 copies per mL or less after 48 weeks (according to the US FDA snapshot algorithm), with a 12% non-inferiority margin. This trial is registered with ClinicalTrials.gov, number NCT01106586. 1017 patients were screened, 715 were enrolled, and 708 were treated (353 with EVG/COBI/FTC/TDF and 355 with ATV/RTV+FTC/TDF). EVG/COBI/FTC/TDF was non-inferior to ATV/RTV+FTC/TDF for the primary outcome (316 patients [89·5%] vs 308 patients [86·8%], adjusted difference 3·0%, 95% CI −1·9% to 7·8%). Both regimens had favourable safety and tolerability; 13 (3·7%) versus 18 (5·1%) patients discontinued treatment because of adverse events. Fewer patients receiving EVG/COBI/FTC/TDF had abnormal results in liver function tests than did those receiving ATV/RTV+FTC/TDF and had smaller median increases in fasting triglyceride concentration (90 μmol/L vs 260 μmol/L, p=0·006). Small median increases in serum creatinine concentration with accompanying decreases in estimated glomerular filtration rate occurred in both study groups by week 2; they generally stabilised by week 8 and did not change up to week 48 (median change 11 μmol/L vs 7 μmol/L). If regulatory approval is given, EVG/COBI/FTC/TDF would be the first integrase-inhibitor-based regimen given once daily and the only one formulated as a single tablet for initial HIV treatment. Gilead Sciences.

Efruxifermin is a bivalent fibroblast growth factor 21 analogue in development for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). This trial aimed to prospectively assess the safety and efficacy of efruxifermin administration for 96 weeks in individuals with MASH and moderate (stage 2; F2) or severe (stage 3; F3) fibrosis. HARMONY is a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial conducted at 41 academic and community centres in the USA. Adults (aged 18–75 years) with biopsy-confirmed MASH (defined as non-alcoholic fatty liver disease activity score of 4 or higher and a score of 1 or higher for 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 subcutaneous efruxifermin (28 mg or 50 mg) once per week or placebo. Participants, investigators, pathologists, site staff, and the sponsor were masked to group assignments. The primary endpoint was an improvement in liver fibrosis (decrease ≥1 stage) without worsening of MASH at week 24, which has been previously reported. End-of-treatment endpoints at week 96 included a final evaluation of the primary endpoint, as well as MASH resolution without fibrosis worsening. The trial is registered with ClinicalTrials.gov, NCT04767529, and is complete. Between March 22, 2021, and Feb 7, 2022, 128 participants were randomly assigned and 126 received at least one dose of efruxifermin or placebo and were included in the modified intention-to-treat analysis. 79 (62%) of 128 participants were female and 49 (38%) were male. The proportion of participants in the modified intention-to-treat population with ≥1-stage fibrosis improvement without MASH worsening at week 96 was eight (19%) of 43 in the placebo group, 12 (30%) of 40 in the 28 mg group (difference vs placebo: 12 percentage points [95% CI –6 to 31]; p=0·19), and 21 (49%) of 43 in the 50 mg group (difference: 31 percentage points [12 to 49]; p=0·0030). Of 88 participants with week-96 biopsies, ≥1-stage fibrosis improvement without MASH worsening was observed in eight (24%) of 34 participants in the placebo group, 12 (46%) of 26 in the 28 mg group (difference vs placebo: 22 percentage points [95% CI –1 to 45]; p=0·070), and 21 (75%) of 28 in the 50 mg group (difference: 52 percentage points, [31 to 73]; p<0·0001). 38 (95%) of 40 participants in the 28 mg group, 43 (100%) of 43 in the 50 mg group, and 42 (98%) of 43 in the placebo group reported an adverse event. Mild to moderate gastrointestinal adverse events were more common with efruxifermin than placebo. There were no reports of drug-induced liver injury or deaths across the groups. Efruxifermin resulted in greater improvements in fibrosis than placebo after 96 weeks, warranting further investigation in phase 3 trials. Akero Therapeutics.

To the Editor: In the SYMMETRY trial involving patients with metabolic dysfunction–associated steatohepatitis (MASH) with biopsy-confirmed compensated cirrhosis, Noureddin et al. (June 26 issue) 1 conclude that efruxifermin does not significantly reduce liver fibrosis at 36 weeks. However, this conclusion overlooks a critical confounder: certain patients may have used medications for concomitant hypertension, type 2 diabetes, or both. Many such drugs, including some specific sulfonylureas, statins, and antihypertensive agents, are metabolized by the liver and may induce hepatic stress or have toxic effects that could worsen fibrosis or mask therapeutic effects. 2,3 Medication regimens were not systematically recorded in the trial, and drug . . .

In phase 2 trials involving patients with stage 2 or 3 fibrosis caused by metabolic dysfunction-associated steatohepatitis (MASH), efruxifermin, a bivalent fibroblast growth factor 21 (FGF21) analogue, reduced fibrosis and resolved MASH. Data are needed on the efficacy and safety of efruxifermin in patients with compensated cirrhosis (stage 4 fibrosis) caused by MASH. In this phase 2b, randomized, placebo-controlled, double-blind trial, we assigned patients with MASH who had biopsy-confirmed compensated cirrhosis (stage 4 fibrosis) to receive subcutaneous efruxifermin (at a dose of 28 mg or 50 mg once weekly) or placebo. The primary outcome was a reduction of at least one stage of fibrosis without worsening of MASH at week 36. Secondary outcomes included the same criterion at week 96. A total of 181 patients underwent randomization and received at least one dose of efruxifermin or placebo. Of these patients, liver biopsy was performed in 154 patients at 36 weeks and in 134 patients at 96 weeks. At 36 weeks, a reduction in fibrosis without worsening of MASH occurred in 8 of 61 patients (13%) in the placebo group, in 10 of 57 patients (18%) in the 28-mg efruxifermin group (difference from placebo after adjustment for stratification factors, 3 percentage points; 95% confidence interval [CI], -11 to 17; P = 0.62), and in 12 of 63 patients (19%) in the 50-mg efruxifermin group (difference from placebo, 4 percentage points; 95% CI, -10 to 18; P = 0.52). At week 96, a reduction in fibrosis without worsening of MASH occurred in 7 of 61 patients (11%) in the placebo group, in 12 of 57 patients (21%) in the 28-mg efruxifermin group (difference from placebo, 10 percentage points; 95% CI, -4 to 24), and in 18 of 63 patients (29%) in the 50-mg efruxifermin group (difference from placebo, 16 percentage points; 95% CI, 2 to 30). Gastrointestinal adverse events were more common with efruxifermin; most events were mild or moderate. In patients with compensated cirrhosis caused by MASH, efruxifermin did not significantly reduce fibrosis at 36 weeks. (Funded by Akero Therapeutics; SYMMETRY ClinicalTrials.gov number, NCT05039450.).