Weinberg, Ethan M

Refractory ascites often requires therapeutic paracentesis, which is associated with potential risks and diminished quality of life. Terlipressin is a vasopressin analog that is indicated for i.v. bolus injection for hepatorenal syndrome, with the potential to reduce large-volume ascites and its complications. Continuous infusion of terlipressin is associated with fewer adverse effects than bolus dosing. The efficacy and safety of continuous infusion of a novel liquid formulation of terlipressin acetate (BIV201) were evaluated in this open-label phase 2 study. Patients with cirrhosis and refractory ascites were randomly assigned (2:1) to receive two 28-day cycles of continuous infusion BIV201 plus standard of care (SOC) separated by a ≤56-day washout (n=10), or SOC alone (n=5). Data analysis was limited by the small sample size and confounded by a potential interaction with gabapentinoids in the BIV201+SOC group. Nonetheless, there were differences in favor of BIV201+SOC versus SOC in the coprimary efficacy endpoints and several quality of life assessments. The beneficial effects of BIV201 on liver complications (mean: 90% CI; BIV201-completers=2.87: 1.51; 5.46 vs. SOC=2.38: 1.20; 4.73) and the change in cumulative ascites (mean: 90% CI; BIV201-completers=−10.76: −26.51; 5.00 vs. SOC=−4.99: −21.95; 11.97) were more pronounced versus SOC in the 5 BIV201+SOC patients who completed both treatment cycles. There were also greater improvements in exploratory quality of life assessments and the percent change in therapeutic paracenteses with BIV201+SOC (−27.94±41.80) versus SOC (−16.67±45.64). Despite the high rate of hyponatremia in the BIV201+SOC group (4/10 patients), the safety profile suggested that continuous BIV201 infusion was well tolerated. These findings support further development of BIV201 in confirmatory trials.

Hepatorenal syndrome-acute kidney injury (HRS-AKI) is associated with significant morbidity and mortality. While liver transplantation is the definitive treatment, continuous terlipressin infusion for HRS-AKI may provide benefit and, as such, was assessed in a population composed of candidates for liver transplant (LT). Fifty hospitalized LT-eligible patients with HRS-AKI received a single bolus followed by continuous terlipressin infusion. Acute-on-chronic liver failure grade 3, serum creatinine (SCr)>5.0 mg/dL, or Model for End-Stage Liver Disease (MELD) ≥35 were exclusions. Fifty hospitalized patients who received midodrine and octreotide or norepinephrine for HRS-AKI served as a historical comparator cohort. Complete response (CR) was defined as a ≥30% decrease in SCr with end-of-treatment (EOT) SCr≤1.5, partial response as a ≥30% decrease in SCr with EOT SCr>1.5, and nonresponse as a <30% decrease in SCr. CR rate was significantly higher in the terlipressin cohort compared to the historical cohort (64% vs. 16%, p<0.001). Survival, while numerically higher in those who received terlipressin, was statistically similar (D30: 94% vs. 82%, p=0.12; D90: 78% vs. 68%, p=0.37). Renal replacement therapy (RRT) was more common among terlipressin NR than CR and PR (70% vs. 3% vs. 13%, p < 0.001). EOT MELD and SCr were significantly lower within terlipressin cohort (MELD: 19 vs. 25, SCr: 1.4 vs. 2.1 mg/dL, p<0.001). Sixteen of 40 terlipressin-treated patients received LT-alone (terlipressin CR in 10/16). One patient on terlipressin had a hypoxic respiratory failure that responded to diuretics; one possibly had drug-related rash. With continuous terlipressin infusion, a CR rate of 64% was observed with a favorable safety profile. Terlipressin use was associated with lower EOT MELD and SCr than the historical midodrine and octreotide/norepinephrine cohort; LT-alone was accomplished in a high proportion of complete terlipressin responders.

Hepatorenal syndrome-acute kidney injury (HRS-AKI), a serious complication of decompensated cirrhosis, has limited therapeutic options and significant morbidity and mortality. Terlipressin improves renal function in some patients with HRS-1, while liver transplantation (LT) is a curative treatment for advanced chronic liver disease. Renal failure post-LT requiring renal replacement therapy (RRT) is a major risk factor for graft and patient survival. A post hoc analysis with a 12-month follow-up of LT recipients from a placebo-controlled trial of terlipressin (CONFIRM; NCT02770716) was conducted to evaluate the need for RRT and overall survival. Patients with HRS-1 were treated with terlipressin plus albumin or placebo plus albumin for up to 14 days. RRT was defined as any type of procedure that replaced kidney function. Outcomes compared between groups included the incidence of HRS-1 reversal, the need for RRT (pretransplant and posttransplant), and overall survival. Of the 300 patients in CONFIRM (terlipressin n = 199; placebo, n = 101), 70 (23%) underwent LT alone (terlipressin, n = 43; placebo, n = 27) and 5 had simultaneous liver-kidney transplant (terlipressin, n = 3, placebo, n = 2). The rate of HRS reversal was significantly higher in the terlipressin group compared with the placebo group (37%, n = 16 vs. 15%, n = 4; p = 0.033). The pretransplant need for RRT was significantly lower among those who received terlipressin (p = 0.007). The posttransplant need for RRT, at 12 months, was significantly lower among those patients who received terlipressin and were alive at Day 365, compared to placebo (p = 0.009). Pretransplant treatment with terlipressin plus albumin in patients with HRS-1 decreased the need for RRT pretransplant and posttransplant.

Abstract To repurpose therapeutics for fibrolamellar carcinoma (FLC), we developed and validated patient-derived xenografts (PDX) from surgical resections. Most agents used clinically and inhibitors of oncogenes overexpressed in FLC showed little efficacy on PDX. A high-throughput functional drug screen found primary and metastatic FLC were vulnerable to clinically available inhibitors of TOPO1 and HDAC and to napabucasin. Napabucasin's efficacy was mediated through reactive oxygen species and inhibition of translation initiation, and specific inhibition of eIF4A was effective. The sensitivity of each PDX line inversely correlated with expression of the antiapoptotic protein Bcl-xL, and inhibition of Bcl-xL synergized with other drugs. Screening directly on cells dissociated from patient resections validated these results. This demonstrates that a direct functional screen on patient tumors provides therapeutically informative data within a clinically useful time frame. Identifying these novel therapeutic targets and combination therapies is an urgent need, as effective therapeutics for FLC are currently unavailable. Significance: Therapeutics informed by genomics have not yielded effective therapies for FLC. A functional screen identified TOPO1, HDAC inhibitors, and napabucasin as efficacious and synergistic with inhibition of Bcl-xL. Validation on cells dissociated directly from patient tumors demonstrates the ability for functional precision medicine in a solid tumor. This article is highlighted in the In This Issue feature, p. 2355