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

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). 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. 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. 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 diseas

Randomized Placebo-Controlled Trial of Emricasan in Non-alcoholic Steatohepatitis (NASH) Cirrhosis with Severe Portal Hypertension.

BACKGROUND AND AIM Emricasan, an oral pan-caspase inhibitor, decreased portal pressure in experimental cirrhosis and in patients with cirrhosis and portal pressure (assessed by the hepatic venous pressure gradient [HVPG]) ≥12 mmHg. We aimed to confirm these results in a randomized, placebo-controlled, double blind study. METHODS Multicenter study including 263 patients with cirrhosis due to non-alcoholic steatohepatitis (NASH) and baseline HVPG ≥12 mmHg randomized 1:1:1:1 to emricasan 5 (n=65), 25 (n=65), 50 (n=66) mg or placebo (n=67) orally twice daily for up to 48 weeks. Primary endpoint was change in HVPG (ΔHVPG) at week 24. Secondary endpoints were changes in biomarkers (aminotransferases, caspases, cytokeratins) and development of liver-related outcomes. RESULTS There were no significant differences in ΔHVPG for any emricasan dose vs. placebo (-0.21, -0.45, -0.58 mmHg, respectively) adjusted by baseline HVPG, compensation status, and non-selective beta-blocker use. Compensated subjects (n=201 [76%]) tended to have a greater decrease in HVPG (emricasan all vs. placebo, p=0.06), the decrease being greater in those with higher baseline HVPG (p=0.018), with a significant interaction between baseline HVPG (continuous, p=0.024; dichotomous at 16 mmHg [median], p=0.013) and treatment. Biomarkers decreased significantly with emricasan at week 24 but returned to baseline levels by week 48. New or worsening decompensating events (∼10% over median exposure of 337 days), progression in MELD and Child Pugh scores, and treatment-emergent adverse events were similar among treatment groups. CONCLUSIONS Despite reduction in biomarkers indicating target engagement, emricasan was not associated with improvement in HVPG or clinical outcomes in patients with NASH cirrhosis and severe portal hypertension. Compensated subjects with higher baseline HVPG had evidence of a small treatment effect. Emricasan treatment appeared safe and well-tolerated