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Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis, inflammation, hepatocellular injury, and progressive liver fibrosis. Resmetirom (MGL-3196) is a liver-directed, orally active, selective thyroid hormone receptor-β agonist designed to improve NASH by increasing hepatic fat metabolism and reducing lipotoxicity. We aimed to assess the safety and efficacy of resmetirom in patients with NASH. MGL-3196-05 was a 36-week randomised, double-blind, placebo-controlled study at 25 centres in the USA. Adults with biopsy confirmed NASH (fibrosis stages 1–3) and hepatic fat fraction of at least 10% at baseline when assessed by MRI-proton density fat fraction (MRI-PDFF) were eligible. Patients were randomly assigned 2:1 by a computer-based system to receive resmetirom 80 mg or matching placebo, orally once a day. Serial hepatic fat measurements were obtained at weeks 12 and 36, and a second liver biopsy was obtained at week 36. The primary endpoint was relative change in MRI-PDFF assessed hepatic fat compared with placebo at week 12 in patients who had both a baseline and week 12 MRI-PDFF. This trial is registered with ClinicalTrials.gov, number NCT02912260. 348 patients were screened and 84 were randomly assigned to resmetirom and 41 to placebo at 18 sites in the USA. Resmetirom-treated patients (n=78) showed a relative reduction of hepatic fat compared with placebo (n=38) at week 12 (−32·9% resmetirom vs −10·4% placebo; least squares mean difference −22·5%, 95% CI −32·9 to −12·2; p<0·0001) and week 36 (−37·3% resmetirom [n=74] vs −8·5 placebo [n=34]; −28·8%, −42·0 to −15·7; p<0·0001). Adverse events were mostly mild or moderate and were balanced between groups, except for a higher incidence of transient mild diarrhoea and nausea with resmetirom. Resmetirom treatment resulted in significant reduction in hepatic fat after 12 weeks and 36 weeks of treatment in patients with NASH. Further studies of resmetirom will allow assessment of safety and effectiveness of resmetirom in a larger number of patients with NASH with the possibility of documenting associations between histological effects and changes in non-invasive markers and imaging. Madrigal Pharmaceuticals.

Patients with previously untreated pulmonary arterial hypertension who were randomly assigned to combination therapy with ambrisentan and tadalafil had a significantly lower risk of a composite clinical failure outcome at 20 months than did the pooled monotherapy group. Regardless of the initiating trigger, pulmonary arterial hypertension results in the altered synthesis of a variety of vasoactive substances derived from the endothelium. 1 Current therapies for pulmonary arterial hypertension 2 target abnormalities in one of three intracellular pathways with signaling dysfunction: the prostacyclin, nitric oxide, or endothelin pathway. 1 However, no single class of drug is consistently effective in treating all patients, which suggests that no single pathway plays a dominant pathogenic role. 3 , 4 Combination therapy with agents that target several different pathways may potentially increase the overall therapeutic effect on the mechanisms of this disease 5 and provide additional clinical benefits. 6 – . . .

In a randomized trial, 506 patients requiring perioperative hemodynamic support after cardiac surgery were assigned to receive levosimendan or placebo in addition to standard care. There was no significant between-group difference in 30-day mortality. Every year, more than 1 million patients undergo cardiac surgery in the United States and Europe. 1 Acute perioperative left ventricular dysfunction is a major complication affecting up to 20% of such patients 2 , 3 and is associated with increased mortality. 4 Inotropic drugs (catecholamines and phosphodiesterase type 3 [PDE-3] inhibitors) are the cornerstone of postoperative hemodynamic support. 3 , 5 However, no randomized, controlled trials have shown the superiority of any inotropic agent in terms of major clinical outcomes. Furthermore, meta-analyses and observational studies suggest that catecholamines and PDE-3 inhibitors may increase mortality. 6 , 7 Levosimendan (Simdax, Orion) is an inotropic agent that has been . . .

Ponatinib has shown potent activity against chronic myeloid leukaemia that is resistant to available treatment, although it is associated with arterial occlusion. We investigated whether this activity and safety profile would result in superior outcomes compared with imatinib in previously untreated patients with chronic myeloid leukaemia. The Evaluation of Ponatinib versus Imatinib in Chronic Myeloid Leukemia (EPIC) study was a randomised, open-label, phase 3 trial designed to assess the efficacy and safety of ponatinib, compared with imatinib, in newly diagnosed patients with chronic-phase chronic myeloid leukaemia. Patients from 106 centres in 21 countries were randomly assigned (1:1, with stratification by Sokal score at diagnosis) using an interactive voice and web response system to receive oral ponatinib (45 mg) or imatinib (400 mg) once daily until progression, unacceptable toxicity, or other criteria for withdrawal were met. Eligible patients were at least 18 years of age, within 6 months of diagnosis, and Philadelphia chromosome-positive by cytogenetic assessment, with Eastern Cooperative Oncology Group performance status of 0–2, and had not previously been treated with tyrosine kinase inhibitors. The primary endpoint was major molecular response at 12 months. Patients who remained on study and had molecular assessments at specified timepoints were studied at those timepoints. Safety analyses included all treated patients, as per study protocol. This trial is registered with ClinicalTrials.gov, number NCT01650805. Between Aug 14, 2012, and Oct 9, 2013, 307 patients were randomly assigned to receive ponatinib (n=155) or imatinib (n=152). The trial was terminated early, on Oct 17, 2013, following concerns about vascular adverse events observed in patients given ponatinib in other trials. Trial termination limited assessment of the primary endpoint of major molecular response at 12 months, as only 13 patients in the imatinib group and ten patients in the ponatinib group could be assessed at this timepoint; the proportion of patients achieving a major molecular response at 12 months did not differ significantly between the two groups (eight [80%] of ten patients given ponatinib and five [38%] of 13 patients given imatinib; p=0·074). 11 (7%) of 154 patients given ponatinib and three (2%) of 152 patients given imatinib had arterial occlusive events (p=0·052); arterial occlusive events were designated serious in ten (6%) of 154 patients given ponatinib and in one (1%) of 152 patients given imatinib (p=0·010). The data monitoring committee criterion for risk assessment (significant difference in serious grade 3 or 4 ischaemic events between groups) was not met (five [3%] of 154 vs one [1%] of 152; p=0·21). Grade 3 or 4 adverse events observed in more than 5% of patients in the ponatinib group were increased lipase (22 [14%] of 154 vs three [2%] of 152 with imatinib), thrombocytopenia (19 [12%] of 154 vs ten [7%] of 152 with imatinib), rash (ten [6%] of 154 vs two [1%] of 152 with imatinib). In the imatinib group, grade 3 or 4 adverse events observed in more than 5% of patients were neutropenia (12 [8%] of 152 vs five [3%] of 154 with ponatinib) and thrombocytopenia (ten [7%] of 152 vs 19 [12%] of 154 with ponatinib). Serious adverse events that occurred in three or more patients given ponatinib were pancreatitis (n=5), atrial fibrillation (n=3), and thrombocytopenia (n=3). No serious adverse event occurred in three or more patients given imatinib. The efficacy of ponatinib treatment of newly diagnosed chronic-phase chronic myeloid leukaemia compared with imatinib could not be assessed due to trial termination, but preliminary data suggest there might be benefit, although with more arterial occlusive events than with imatinib at the doses studied. Because the EPIC trial was terminated early, efficacy of ponatinib in this setting remains to be established. ARIAD Pharmaceuticals.

Ponatinib was developed to overcome resistance to the tyrosine kinase inhibitors used to treat leukemias that are positive for the Philadelphia chromosome. In a phase 1 study, ponatinib was associated with dramatic antitumor effects, with pancreatitis as a dose-limiting toxicity. The fusion protein product of the Philadelphia chromosome (Ph), BCR-ABL, is a constitutively active tyrosine kinase that gives rise to chronic myeloid leukemia (CML) and a subset of acute lymphoblastic leukemia (Ph-positive ALL). 1 , 2 Three tyrosine kinase inhibitors targeting the BCR-ABL protein (imatinib, nilotinib, and dasatinib) have been approved for the treatment of patients with newly diagnosed chronic-phase CML. 3 – 5 Resistance to tyrosine kinase inhibitors is the major reason for the failure of therapy in patients with Ph-positive disease. Primary or secondary resistance to imatinib occurs in approximately 20 to 30% of patients with newly diagnosed chronic-phase CML. 3 , 6 Second-generation . . .

In this trial, 882 cardiac surgical patients with left ventricular dysfunction were assigned to levosimendan or placebo. There was no between-group difference in the rate of death, renal-replacement therapy, perioperative myocardial infarction, or mechanical cardiac assist device use. Cardiac surgery with the use of cardiopulmonary bypass is a common procedure, with more than 1 million operations performed annually in the United States and Europe. 1 Increasingly, patients who are referred for cardiac surgery are older and have multiple coexisting conditions, as compared with those who were referred for these procedures in the past. 2 These patients benefit from cardiac surgery but are at increased risk for perioperative complications that result in high morbidity and mortality and a high use of health care services. 2 – 4 One such complication, the low cardiac output syndrome, occurs in 3 to 14% of patients who . . .

Resmetirom (MGL‐3196), a selective thyroid hormone receptor‐β agonist, was evaluated in a 36‐week paired liver biopsy study (NCT02912260) in adults with biopsy‐confirmed nonalcoholic steatohepatitis (NASH). The primary endpoint was relative liver fat reduction as assessed by MRI–proton density fat fraction (MRI‐PDFF), and secondary endpoints included histopathology. Subsequently, a 36‐week active treatment open‐label extension (OLE) study was conducted in 31 consenting patients (including 14 former placebo patients) with persistently mild to markedly elevated liver enzymes at the end of the main study. In patients treated with resmetirom (80 or 100 mg orally per day), MRI‐PDFF reduction at OLE week 36 was −11.1% (1.5%) mean reduction (standard error [SE]; P < 0.0001) and −52.3% (4.4%) mean relative reduction, P < 0.0001. Low‐density lipoprotein (LDL) cholesterol (−26.1% [4.5%], P < 0.0001), apolipoprotein B (−23.8% [3.0%], P < 0.0001), and triglycerides (−19.6% [5.4%], P = 0.0012; −46.1 [14.5] mg/dL, P = 0.0031) were reduced from baseline. Markers of fibrosis were reduced, including liver stiffness assessed by transient elastography (−2.1 [0.8] mean kilopascals [SE], P = 0.015) and N‐terminal type III collagen pro‐peptide (PRO‐C3) (−9.8 [2.3] ng/mL, P = 0.0004 (baseline ≥ 10 ng/mL). In the main and OLE studies, PRO‐C3/C3M (matrix metalloproteinase‐degraded C3), a marker of net fibrosis formation, was reduced in resmetirom‐treated patients (−0.76 [−1.27, −0.24], P = 0.0044 and −0.68, P < 0.0001, respectively). Resmetirom was well tolerated, with few, nonserious adverse events. Conclusion: The results of this 36‐week OLE study support the efficacy and safety of resmetirom at daily doses of 80 mg and 100 mg, used in the ongoing phase 3 NASH study, MAESTRO‐NASH (NCT03900429). The OLE study demonstrates a potential for noninvasive assessments to monitor the response to resmetirom from an individual patient with NASH.

Background This open-label, Phase 1b/2 study evaluated the highly selective MET inhibitor tepotinib in systemic anticancer treatment (SACT)-naive Asian patients with advanced hepatocellular carcinoma (aHCC) with MET overexpression. Methods In Phase 2b, tepotinib was orally administered once daily (300, 500 or 1,000 mg) to Asian adults with aHCC. The primary endpoints were dose-limiting toxicities (DLTs) and adverse events (AEs). Phase 2 randomised SACT-naive Asian adults with aHCC with MET overexpression to tepotinib (recommended Phase 2 dose [RP2D]) or sorafenib 400 mg twice daily. The primary endpoint was independently assessed time to progression (TTP). Results In Phase 1b ( n  = 27), no DLTs occurred; the RP2D was 500 mg. In Phase 2 ( n  = 90, 45 patients per arm), the primary endpoint was met: independently assessed TTP was significantly longer with tepotinib versus sorafenib (median 2.9 versus 1.4 months, HR = 0.42, 90% confidence interval: 0.26–0.70, P  = 0.0043). Progression-free survival and objective response also favoured tepotinib. Treatment-related Grade ≥3 AE rates were 28.9% with tepotinib and 45.5% with sorafenib. Conclusions Tepotinib improved TTP versus sorafenib and was generally well tolerated in SACT-naive Asian patients with aHCC with MET overexpression. Trial registration ClinicalTrials.gov NCT01988493.

In the phase 3 PhALLCON trial (NCT03589326), ponatinib demonstrated superior efficacy, patient-reported treatment tolerability, and health-related quality of life (HRQoL) compared to imatinib in adults with newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). To explore the association between clinical response and HRQoL and substantiate the superior effect of ponatinib over imatinib on HRQoL, we analyzed the impact of clinical response and treatment tolerability on changes in HRQoL. HRQoL was assessed using the Functional Assessment of Cancer Therapy–Leukemia (FACT-Leu) questionnaire and the EQ-5D-5 L. Treatment tolerability was assessed using the FACT-GP5 item “bothered by treatment side effects.” Linear mixed-effects regression models were used to examine changes in HRQoL over time, with clinical response status and patient-reported overall treatment tolerability as time-varying predictors, while controlling for significant covariates. This analysis included data from 238 patients (159 ponatinib, 79 imatinib). Achieving clinical response (complete remission or incomplete remission) was associated with significantly better changes from baseline across all FACT-Leu domains and the EQ-visual analogue scale than not achieving clinical response ( p  < 0.05). Treatment-related side effects led to significantly and meaningfully worse changes in HRQoL than “not bothered by treatment,” with higher levels of “bother” associated with greater worsening in HRQoL from baseline. Taken together with the better treatment tolerability and longer response duration of ponatinib compared to imatinib, these findings further substantiate the HRQoL benefit of ponatinib over imatinib in patients with Ph + ALL.

This open-label, extension study assessed long-term safety, tolerability, and efficacy of ambrisentan in a pediatric population (age 8– < 18 years) with pulmonary arterial hypertension (PAH). Following completion of a 6-month, randomized study, participants entered the long-term extension at individualized ambrisentan dosages (2.5/5/7.5 or 10 mg/day). Safety assessments included adverse events (AEs), AEs of special interest, and serious AEs (SAEs); efficacy outcomes included 6-min walking distance (6MWD) and World Health Organization functional class (WHO FC). Thirty-eight of 41 (93%) randomized study participants entered the extension; 21 (55%) completed (reaching age 18 years). Most participants received concomitant phosphodiesterase-5 inhibitors ( n  = 25/38, 66%). Median ambrisentan exposure was 3.5 years. Most participants experienced ≥ 1 AE ( n  = 34/38, 89%), and 21 (55%) experienced SAEs, most commonly worsening PAH ( n  = 3/38, 8%), acute cardiac failure, pneumonia, or anemia ( n  = 2/38; 5% each); none considered ambrisentan-related. Seven participants (18%) died, with recorded reasons (MedDRA preferred term): cardiac failure ( n  = 2), PAH ( n  = 2), COVID-19 ( n  = 1), acute right ventricular failure ( n  = 1), and failure to thrive ( n  = 1); median time to death: 5.2 years. Anemia and hepatotoxicity AEs were generally mild to moderate and did not require ambrisentan dose adjustment. Assessed at study end in 29 participants (76%), mean 6MWD improved by 17% (standard deviation: 34.3%), and all (29/29, 100%) had improved or unchanged WHO FC.     Conclusion : Long-term weight-based ambrisentan dosing, alone or combined with other PAH therapies in children with PAH aged 8– < 18 years, exhibited tolerability and clinical improvements consistent with prior randomized study results.     Trial registration : NCT01342952, April 27, 2011. What is Known: • The endothelin receptor antagonist, ambrisentan, is indicated for treatment of pulmonary arterial hypertension (PAH). Previous studies have shown similar efficacy and tolerability in pediatric patients as in adults. What is New: • This open-label extension study assessed the long-term use of ambrisentan in pediatric patients (8–<18 years) with PAH, most of whom were also receiving recommended background PAH treatment. •  Weight-based dosing of ambrisentan, given alone or in combination with other PAH therapies, was well tolerated with clinical improvements consistent with prior randomized study results .