Characterization of the Cynomolgus Macaque Model of Marburg Virus Disease and Assessment of Timing for Therapeutic Treatment Testing.

Marburg virus (MARV) causes severe disease and high mortality in humans. The objective of this study was to characterize disease manifestations and pathogenesis in cynomolgus macaques exposed to MARV. The results of this natural history study may be used to identify features of MARV disease useful in defining the ideal treatment initiation time for subsequent evaluations of investigational therapeutics using this model. Twelve cynomolgus macaques were exposed to a target dose of 1000 plaque-forming units MARV by the intramuscular route, and six control animals were mock-exposed. The primary endpoint of this study was survival to Day 28 post-inoculation (PI). Anesthesia events were minimized with the use of central venous catheters for periodic blood collection, and temperature and activity were continuously monitored by telemetry. All mock-exposed animals remained healthy for the duration of the study. All 12 MARV-exposed animals (100%) became infected, developed illness, and succumbed on Days 8-10 PI. On Day 4 PI, 11 of the 12 MARV-exposed animals had statistically significant temperature elevations over baseline. Clinically observable signs of MARV disease first appeared on Day 5 PI, when 6 of the 12 animals exhibited reduced responsiveness. Ultimately, systemic inflammation, coagulopathy, and direct cytopathic effects of MARV all contributed to multiorgan dysfunction, organ failure, and death or euthanasia of all MARV-exposed animals. Manifestations of MARV disease, including fever, systemic viremia, lymphocytolysis, coagulopathy, and hepatocellular damage, could be used as triggers for initiation of treatment in future therapeutic efficacy studies.

Bictegravir/emtricitabine/tenofovir alafenamide in older individuals with HIV: Results of a 96-week, phase 3b, open-label, switch trial in virologically suppressed people ≥65 years of age.

OBJECTIVES: Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) is an effective treatment for HIV-1 infection; however, clinical trial data in older people living with HIV (PLWH) are lacking. The primary 24-week and secondary 48-week analyses of study GS-US-380-4449 (NCT03405935), which assessed the efficacy and safety of switching to B/F/TAF in older PLWH, have been published. Here we report the results of the final 96-week analyses from the study. METHODS: In this 96-week, phase 3b, open-label, single-arm trial, virologically suppressed PLWH aged ≥65 years switched from elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide or a tenofovir disoproxil fumarate-based regimen to B/F/TAF. Viral suppression, resistance, immune response, safety, tolerability and adherence were evaluated through week 96. RESULTS: Of 90 participants screened, 86 were enrolled and switched to B/F/TAF. No participants had HIV-1 RNA ≥50 copies/ml (by FDA Snapshot algorithm) at weeks 72 or 96; virologic suppression rates were 94.2% (81/86; 95% CI 87.0-98.1) and 74.4% (64/86; 95% CI 63.9-83.2), respectively. No treatment-emergent resistance was observed, and CD4 counts remained stable. There were no study drug-related serious adverse events. Three participants experienced drug-related treatment-emergent adverse events that led to premature drug discontinuation. There were no clinically relevant changes from baseline to week 96 in fasting lipid parameters, and the median change in body weight at week 96 was 0.0 kg (IQR -2.3, 2.0). Median self-reported adherence was 100% (IQR 100-100%). CONCLUSIONS: Switching to B/F/TAF is an effective long-term option for virologically suppressed adults ≥65 years of age, with favourable safety and tolerability profiles in this population.

High efficacy of switching to bictegravir/emtricitabine/tenofovir alafenamide in people with suppressed HIV and preexisting M184V/I.

OBJECTIVE: We investigated the prevalence of preexisting M184V/I and associated risk factors among clinical trial participants with suppressed HIV and evaluated the impact of M184V/I on virologic response after switching to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF). DESIGN: Participant data were pooled from six clinical trials investigating the safety and efficacy of switching to B/F/TAF in virologically suppressed people with HIV. METHODS: Preexisting drug resistance was assessed by historical genotypes and/or baseline proviral DNA genotyping. Virologic outcomes were determined by last available on-treatment HIV-1 RNA. Stepwise selection identified potential risk factors for M184V/I in a multivariate logistic regression model. RESULTS: Altogether, 2034 participants switched treatment regimens to B/F/TAF and had follow-up HIV-1 RNA data, and 1825 of these participants had baseline genotypic data available. Preexisting M184V/I was identified in 182 (10%), mostly by baseline proviral DNA genotype ( n  = 167). Most substitutions were M184V ( n  = 161) or M184V/I mixtures ( n  = 10). Other resistance substitutions were often detected in addition to M184V/I ( n  = 147). At last on-treatment visit, 98% (179/182) with preexisting M184V/I and 99% (2012/2034) of all B/F/TAF-treated participants had HIV-1 RNA less than 50 copies/ml, with no treatment-emergent resistance to B/F/TAF. Among adult participants, factors associated with preexisting M184V/I included other resistance, black race, Hispanic/Latinx ethnicity, lower baseline CD4 + cell count, advanced HIV disease, longer duration of antiretroviral therapy, and greater number of prior third agents. CONCLUSION: M184V/I was detected in 10% of virologically suppressed clinical trial participants at study baseline. Switching to B/F/TAF demonstrated durable efficacy in maintaining viral suppression, including in those with preexisting M184V/I.

Switching to Bictegravir/Emtricitabine/Tenofovir Alafenamide in Black Americans With HIV-1: A Randomized Phase 3b, Multicenter, Open-Label Study.

BACKGROUND: With the highest rates of HIV/AIDS in the United States, Black Americans are still underrepresented in HIV medical research. SETTING: BRAAVE (NCT03631732) is a randomized, phase 3b, multicenter, open-label US study. METHODS: Adults identifying as Black or African American and virologically suppressed on 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus third agent were randomized (2:1) to switch to open-label bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) once daily or stay on baseline regimen (SBR) for 24 weeks, after which SBR had delayed switch to B/F/TAF. Resistance to non-NRTIs, protease inhibitors, and/or NRTIs was permitted; integrase strand transfer inhibitor resistance was exclusionary. Primary endpoint was proportion of participants with HIV-1 RNA ≥50 copies/mL at week 24 (snapshot algorithm; noninferiority margin of 6%). RESULTS: Of 558 screened, 495 were randomized/treated (B/F/TAF n = 330; SBR n = 165). Overall, 32% were ciswomen, 2% transwomen, and 10% had an M184V/I mutation. At week 24, 0.6% on B/F/TAF vs 1.8% on SBR had HIV-1 RNA ≥50 copies/mL (difference -1.2%; 95% confidence interval -4.8% to 0.9%), demonstrating noninferiority of B/F/TAF vs SBR. Proportions with HIV-1 RNA <50 copies/mL at week 24 were 96% B/F/TAF and 95% SBR and remained high at week 48. No participant had treatment-emergent resistance to study drug. Treatments were well tolerated. Study drug-related adverse events, mostly grade 1, occurred in 10% of participants on B/F/TAF through week 48 and led to discontinuation in 9 participants through week 48. CONCLUSIONS: For Black Americans with HIV, switching to B/F/TAF was noninferior to continuing a variety of regimens, including those with pre-existing NRTI mutations.

Bictegravir/Emtricitabine/Tenofovir Alafenamide in Virologically Suppressed People with HIV Aged ≥ 65 Years: Week 48 Results of a Phase 3b, Open-Label Trial.

INTRODUCTION: We report the 48-week results of an ongoing study to assess the efficacy and safety of switching older people with HIV to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF). METHODS: This was a 96-week, phase 3b, open-label, single-arm study (GS-US-380-4449; NCT03405935). Virologically suppressed individuals aged ≥ 65 years receiving elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide or a tenofovir disoproxil fumarate-based regimen were switched to B/F/TAF. Primary endpoint was the percentage of participants with HIV-1 RNA < 50 copies/ml at week 24. RESULTS: Eighty-six participants (median age 69 [range 65-80] years; 87% male; 95% white) were enrolled and treated in five European countries. Rates of virologic suppression were 97.7% at week 24 and 90.7% at week 48; none had HIV-1 RNA ≥ 50 copies/ml, and 100% had virologic suppression by missing = excluded analysis at both time points. No treatment-emergent resistance was observed. There were no grade 3-4 study drug-related adverse events (AEs) or study drug-related serious AEs or deaths. Three AEs led to premature discontinuation; one (moderate abdominal discomfort) was attributed to the study drug by the investigator. At week 48, median changes from baseline in weight and estimated glomerular filtration rate were + 0.1 kg (interquartile range [IQR] - 1.0, 2.3) and - 6.0 ml/min (IQR - 10.2, 0.0), respectively. There were no clinically relevant changes from baseline to week 48 in fasting lipid parameters. Treatment satisfaction improved, and health-related quality of life was maintained from baseline through week 48. Median adherence to the study drug was 98.6% (IQR 96.0, 100). CONCLUSIONS: Switching to B/F/TAF was effective and well tolerated through 48 weeks in virologically suppressed adults aged ≥ 65 years. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03405935.

Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial.

Importance: Remdesivir demonstrated clinical benefit in a placebo-controlled trial in patients with severe coronavirus disease 2019 (COVID-19), but its effect in patients with moderate disease is unknown. Objective: To determine the efficacy of 5 or 10 days of remdesivir treatment compared with standard care on clinical status on day 11 after initiation of treatment. Design, Setting, and Participants: Randomized, open-label trial of hospitalized patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and moderate COVID-19 pneumonia (pulmonary infiltrates and room-air oxygen saturation >94%) enrolled from March 15 through April 18, 2020, at 105 hospitals in the United States, Europe, and Asia. The date of final follow-up was May 20, 2020. Interventions: Patients were randomized in a 1:1:1 ratio to receive a 10-day course of remdesivir (n = 197), a 5-day course of remdesivir (n = 199), or standard care (n = 200). Remdesivir was dosed intravenously at 200 mg on day 1 followed by 100 mg/d. Main Outcomes and Measures: The primary end point was clinical status on day 11 on a 7-point ordinal scale ranging from death (category 1) to discharged (category 7). Differences between remdesivir treatment groups and standard care were calculated using proportional odds models and expressed as odds ratios. An odds ratio greater than 1 indicates difference in clinical status distribution toward category 7 for the remdesivir group vs the standard care group. Results: Among 596 patients who were randomized, 584 began the study and received remdesivir or continued standard care (median age, 57 [interquartile range, 46-66] years; 227 [39%] women; 56% had cardiovascular disease, 42% hypertension, and 40% diabetes), and 533 (91%) completed the trial. Median length of treatment was 5 days for patients in the 5-day remdesivir group and 6 days for patients in the 10-day remdesivir group. On day 11, patients in the 5-day remdesivir group had statistically significantly higher odds of a better clinical status distribution than those receiving standard care (odds ratio, 1.65; 95% CI, 1.09-2.48; P = .02). The clinical status distribution on day 11 between the 10-day remdesivir and standard care groups was not significantly different (P = .18 by Wilcoxon rank sum test). By day 28, 9 patients had died: 2 (1%) in the 5-day remdesivir group, 3 (2%) in the 10-day remdesivir group, and 4 (2%) in the standard care group. Nausea (10% vs 3%), hypokalemia (6% vs 2%), and headache (5% vs 3%) were more frequent among remdesivir-treated patients compared with standard care. Conclusions and Relevance: Among patients with moderate COVID-19, those randomized to a 10-day course of remdesivir did not have a statistically significant difference in clinical status compared with standard care at 11 days after initiation of treatment. Patients randomized to a 5-day course of remdesivir had a statistically significant difference in clinical status compared with standard care, but the difference was of uncertain clinical importance. Trial Registration: ClinicalTrials.gov Identifier: NCT04292730.

Remdesivir (GS-5734) Is Efficacious in Cynomolgus Macaques Infected With Marburg Virus.

Marburg virus (MARV) is a filovirus with documented human case-fatality rates of up to 90%. Here, we evaluated the therapeutic efficacy of remdesivir (GS-5734) in nonhuman primates experimentally infected with MARV. Beginning 4 or 5 days post inoculation, cynomolgus macaques were treated once daily for 12 days with vehicle, 5 mg/kg remdesivir, or a 10-mg/kg loading dose followed by 5 mg/kg remdesivir. All vehicle-control animals died, whereas 83% of animals receiving a 10-mg/kg loading dose of remdesivir survived, as did 50% of animals receiving a 5-mg/kg remdesivir regimen. Remdesivir-treated animals exhibited improved clinical scores, lower plasma viral RNA, and improved markers of kidney function, liver function, and coagulopathy versus vehicle-control animals. The small molecule remdesivir showed therapeutic efficacy in this Marburg virus disease model with treatment initiation 5 days post inoculation, supporting further assessment of remdesivir for the treatment of Marburg virus disease in humans.

Remdesivir for 5 or 10 Days in Patients with Severe Covid-19.

BACKGROUND: Remdesivir is an RNA polymerase inhibitor with potent antiviral activity in vitro and efficacy in animal models of coronavirus disease 2019 (Covid-19). METHODS: We conducted a randomized, open-label, phase 3 trial involving hospitalized patients with confirmed SARS-CoV-2 infection, oxygen saturation of 94% or less while they were breathing ambient air, and radiologic evidence of pneumonia. Patients were randomly assigned in a 1:1 ratio to receive intravenous remdesivir for either 5 days or 10 days. All patients received 200 mg of remdesivir on day 1 and 100 mg once daily on subsequent days. The primary end point was clinical status on day 14, assessed on a 7-point ordinal scale. RESULTS: In total, 397 patients underwent randomization and began treatment (200 patients for 5 days and 197 for 10 days). The median duration of treatment was 5 days (interquartile range, 5 to 5) in the 5-day group and 9 days (interquartile range, 5 to 10) in the 10-day group. At baseline, patients randomly assigned to the 10-day group had significantly worse clinical status than those assigned to the 5-day group (P = 0.02). By day 14, a clinical improvement of 2 points or more on the ordinal scale occurred in 64% of patients in the 5-day group and in 54% in the 10-day group. After adjustment for baseline clinical status, patients in the 10-day group had a distribution in clinical status at day 14 that was similar to that among patients in the 5-day group (P = 0.14). The most common adverse events were nausea (9% of patients), worsening respiratory failure (8%), elevated alanine aminotransferase level (7%), and constipation (7%). CONCLUSIONS: In patients with severe Covid-19 not requiring mechanical ventilation, our trial did not show a significant difference between a 5-day course and a 10-day course of remdesivir. With no placebo control, however, the magnitude of benefit cannot be determined. (Funded by Gilead Sciences; GS-US-540-5773 ClinicalTrials.gov number, NCT04292899.).

Initial combination therapy of ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) in the modified intention-to-treat population of the AMBITION study: post hoc analysis.

OBJECTIVES: To evaluate initial combination therapy with ambrisentan plus tadalafil (COMB) compared with monotherapy of either agent (MONO), and the utility of baseline characteristics and risk stratification in predicting outcomes, in patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) and the systemic sclerosis (SSc)-pulmonary arterial hypertension (PAH) subpopulation. METHODS: This post hoc analysis of the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) study included patients with CTD-PAH from the modified intention-to-treat population. Time to clinical failure (TtCF) was assessed by baseline characteristics, treatment assignment and risk group (low, intermediate and high) at baseline and week 16. TtCF was compared between groups using Kaplan-Meier curves and Cox proportional hazards regression modelling. RESULTS: The analysis included 216 patients (COMB, n=117; MONO, n=99). The risk of clinical failure was lower with COMB versus MONO (risk reduction: CTD-PAH 51.7%, SSc-PAH 53.7%), particularly in patients with haemodynamic parameters characteristic of typical PAH without features of left heart disease and/or restrictive lung disease at baseline. The risk of clinical failure was lower with COMB versus MONO in the baseline low-risk group (HR not calculated due to no events in COMB), baseline intermediate-risk group (HR 0.519, 95% CI 0.297 to 0.905) and in the week 16 low-risk group (HR 0.069, 95% CI 0.009 to 0.548). CONCLUSIONS: The benefit of COMB over MONO was demonstrated in patients with CTD-PAH, particularly in those with typical PAH haemodynamic characteristics at baseline. COMB is appropriate for patients categorised as low risk and intermediate risk at baseline and low risk at follow-up. TRIAL REGISTRATION NUMBER: NCT01178073.

Characterization of Ebola Virus Disease (EVD) in Rhesus Monkeys for Development of EVD Therapeutics.

Recent Ebola virus (EBOV) outbreaks in West Africa and the Democratic Republic of the Congo have highlighted the urgent need for approval of medical countermeasures for treatment and prevention of EBOV disease (EVD). Until recently, when successes were achieved in characterizing the efficacy of multiple experimental EVD therapeutics in humans, the only feasible way to obtain data regarding potential clinical benefits of candidate therapeutics was by conducting well-controlled animal studies. Nonclinical studies are likely to continue to be important tools for screening and development of new candidates with improved pharmacological properties. Here, we describe a natural history study to characterize the time course and order of progression of the disease manifestations of EVD in rhesus monkeys. In 12 rhesus monkeys exposed by the intramuscular route to 1000 plaque-forming units of EBOV, multiple endpoints were monitored for 28 days following exposure. The disease progressed rapidly with mortality events occurring 7-10 days after exposure. Key disease manifestations observed consistently across the infected animals included, but were not limited to, viremia, fever, systemic inflammation, coagulopathy, lymphocytolysis, renal tubular necrosis with mineralization, and hepatocellular degeneration and necrosis.

Patients with pulmonary arterial hypertension with and without cardiovascular risk factors: Results from the AMBITION trial.

BACKGROUND: The purpose of this study was to compare patients with pulmonary arterial hypertension enrolled in the AMBITION trial with (excluded from the primary analysis set [ex-primary analysis set]) and without (primary analysis set) multiple risk factors for left ventricular diastolic dysfunction. METHODS: Treatment-naive patients with pulmonary arterial hypertension were randomized to once-daily ambrisentan and tadalafil combination therapy, ambrisentan monotherapy, or tadalafil monotherapy. The primary end point was time from randomization to first adjudicated clinical failure event. RESULTS: Primary analysis set patients (n = 500), compared with ex-primary analysis set patients (n = 105), were younger (mean, 54.4 vs 62.1 years) with greater baseline 6-minute walk distance (median, 363.7 vs 330.5 meters) and fewer comorbidities (e.g., hypertension and diabetes). Treatment effects of initial combination therapy vs pooled monotherapy were directionally the same for both populations, albeit of a lower magnitude for ex-primary analysis set patients. Initial combination therapy reduced the risk of clinical failure compared with pooled monotherapy in primary analysis set patients (hazard ratio, 0.50; 95% confidence interval, 0.35-0.72), whereas the effect was less clear in ex-primary analysis set patients (hazard ratio, 0.70; 95% confidence interval, 0.35-1.37). Overall, primary analysis set patients had fewer clinical failure events (25% vs 33%), higher rates of satisfactory clinical response (34% vs 24%), and lower rates of permanent study drug withdrawal due to adverse events (16% vs 31%) than ex-primary analysis set patients. CONCLUSIONS: Efficacy of initial combination therapy vs pooled monotherapy was directionally similar for primary analysis set and ex-primary analysis set patients. However, ex-primary analysis set patients (with multiple risk factors for left ventricular diastolic dysfunction) experienced higher rates of clinical failure events and the response to combination therapy vs monotherapy was attenuated. Tolerability was better in primary analysis set than ex-primary analysis set patients.

Clinical outcomes stratified by baseline functional class after initial combination therapy for pulmonary arterial hypertension.

BACKGROUND: Initial combination therapy with ambrisentan and tadalafil reduced the risk of clinical failure events for treatment-naïve participants with pulmonary arterial hypertension (PAH) as compared to monotherapy. Previous studies in PAH have demonstrated greater treatment benefits in more symptomatic participants. METHODS: AMBITION was an event-driven, double-blind study in which participants were randomized 2:1:1 to once-daily initial combination therapy with ambrisentan 10 mg plus tadalafil 40 mg, ambrisentan 10 mg plus placebo, or tadalafil 40 mg plus placebo. In this pre-specified subgroup analysis, we compared the efficacy data between those with functional class (FC) II vs. FC III symptoms at baseline. RESULTS: This analysis included 500 participants in the previously defined primary analysis set (n = 155 FC II, n = 345 FC III). Comparing combination therapy to pooled monotherapy, the risk of clinical failure events was reduced by 79% (hazard ratio, 0.21 [95% confidence interval: 0.071, 0.63]) for FC II patients and 42% (hazard ratio, 0.58 [95% confidence interval: 0.39, 0.86]) for FC III patients. In a post-hoc analysis, the risk of first hospitalization for worsening PAH was also reduced by combination therapy, particularly for FC II patients (0 combination vs. 11 [14%] pooled monotherapy). Adverse events were frequent but comparable between the subgroups. CONCLUSIONS: Treatment benefit from initial combination therapy appeared at least as great for FC II as for FC III participants. Hospitalizations for worsening PAH were not observed in FC II participants assigned to combination. The present data support an initial combination strategy for newly diagnosed patients even when symptoms are less severe. Funded by Gilead Sciences, Inc. and GlaxoSmithKline; AMBITION ClinicalTrials.gov number, NCT01178073.

Initial combination therapy with ambrisentan + tadalafil on pulmonary arterial hypertension‒related hospitalization in the AMBITION trial.

BACKGROUND: In the randomized, double-blind, event-driven AMBITION study, initial combination therapy with ambrisentan and tadalafil was associated with a 50% reduction in risk of clinical failure (first occurrence of all-cause death, hospitalization for worsening pulmonary arterial hypertension [PAH], disease progression, or unsatisfactory long-term clinical response) vs pooled monotherapy. These results were primarily driven by a reduction in PAH-related hospitalization in the combination therapy group, although a significant effect was not observed in a post-hoc analysis of all-cause hospitalization. METHODS: The effect of initial combination therapy with ambrisentan and tadalafil in AMBITION was further explored to study PAH-related hospitalization, which was not reported in the primary publication. RESULTS: Initial combination therapy was associated with a 63% reduction in risk of PAH-related hospitalization when compared with pooled monotherapy (hazard ratio [HR] 0.372, 95% confidence interval [CI] 0.217 to 0.639, p = 0.0002). For every 9 patients treated with combination therapy vs monotherapy, 1 PAH-related hospitalization could be prevented over a 1-year period. Serious adverse events leading to hospitalization, not necessarily PAH-related, occurred in 87 of 253 (34%) and 89 of 247 (36%) of patients on combination therapy and pooled monotherapy, respectively (post-hoc summary). CONCLUSIONS: Initial combination therapy with ambrisentan and tadalafil was found to reduce the risk of PAH-related hospitalization by 63% compared with pooled monotherapy.

Risk-stratified outcomes with initial combination therapy in pulmonary arterial hypertension: Application of the REVEAL risk score.

BACKGROUND: The multinational AMBITION study demonstrated a 50% risk reduction in time to first clinical failure event (TtCF, a composite of death, hospitalization for worsening pulmonary arterial hypertension [PAH], disease progression, or unsatisfactory long-term clinical response) in treatment-naive Functional Class II and III PAH patients initiated on combination therapy (ambrisentan and tadalafil) vs monotherapy. A post-hoc analysis of AMBITION data by risk stratification, as determined by baseline REVEAL risk score, was undertaken to better assess the impact of combination therapy. METHODS: Patients were randomized 2:1:1 to initial combination therapy with ambrisentan 10 mg plus tadalafil 40 mg vs either drug plus placebo, respectively. Baseline REVEAL risk scores in the 605 patients were grouped by low, intermediate, or high risk. Adjudicated outcomes (TtCF and post-hoc composite end-point of time to first PAH hospitalization or death) were assessed by risk group and treatment assignment. RESULTS: At baseline, risk groups were similarly represented across treatment assignments as low (16%), intermediate (46%), and high (38%) risk. Greater risk was associated with worse outcome. At each level of risk, patients on combination therapy had significantly fewer TtCF or PAH hospitalization/death events relative to those on monotherapy, and discontinuations due to adverse events were not higher on combination therapy. CONCLUSIONS: This post-hoc analysis comparing outcomes by REVEAL risk group has shown that, at all levels of risk, patients enrolled in AMBITION receiving initial combination therapy have superior outcomes and, even in those assessed as low risk, initial combination therapy was clinically beneficial.

Hepatic safety of ambrisentan alone and in combination with tadalafil: a post-hoc analysis of the AMBITION trial.

Treatment with endothelin receptor antagonists (ERA) can result in adverse hepatic effects in patients with pulmonary arterial hypertension (PAH). We evaluated the hepatic safety of ambrisentan (ABS), an ERA, used as monotherapy, or with tadalafil (TAD), a phosphodiesterase-5 (PDE5) inhibitor as initial combination therapy (ABS + TAD) in the AMBITION trial. This was a retrospective analysis set in academic and private outpatient clinics and research centers. This analysis included 596 patients with PAH who were randomized to ABS or TAD as monotherapy or ABS + TAD as initial combination therapy and received at least one dose of study drug, and who had baseline and follow-up hepatic function data. Treatment options following a clinical failure event included blinded combination therapy (BCT). The proportion of patients with elevations in alanine or aspartate aminotransferases (ALT/AST) > 3 × upper limit of normal (ULN), and those with total bilirubin (TBili) > 2× ULN and ALT or AST > 3 × ULN (referred to as potential Hy's law), were determined before BCT as well as including time on BCT. Elevations in ALT/AST > 3 × ULN during the study were in the range of 3.4-3.7%, with an annualized incidence of 2.1-2.93%. The majority of patients with elevations in ALT/AST had elevations > 3 to ≤ 5 × ULN. Three patients (0.5%) had ALT/AST > 3 × ULN plus TBili > 2 × ULN. All three patients had probable alternative causes (cardiogenic shock, liver metastases, lymphoma) for the elevations. Our analysis of the AMBITION trial demonstrated that ABS and ABS + TAD were not associated with drug-induced liver injury.

Clinical and hemodynamic improvements after adding ambrisentan to background PDE5i therapy in patients with pulmonary arterial hypertension exhibiting a suboptimal therapeutic response (ATHENA-1).

OBJECTIVE: Pulmonary arterial hypertension (PAH) is a condition which may lead to right ventricular failure and premature death. While recent data supports the initial combination of ambrisentan (a selective ERA) and tadalafil (a PDE5i) in functional class II or III patients, there is no published data describing the safety and efficacy of ambrisentan when added to patients currently receiving a PDE5i and exhibiting a suboptimal response. The ATHENA-1 study describes the safety and efficacy of the addition of ambrisentan in this patient population. METHODS: PAH patients with a suboptimal response to current PDE5i monotherapy were assigned ambrisentan in an open-label fashion and evaluated for up to 48 weeks. Cardiopulmonary hemodynamics (change in PVR as primary endpoint) were evaluated at week 24 and functional parameters and biomarkers were measured through week 48. Time to clinical worsening (TTCW) and survival are also described. RESULTS: Thirty-three subjects were included in the analysis. At week 24, statistically significant improvements in PVR (-32%), mPAP (-11%), and CI (+25%) were observed. Hemodynamic improvements at week 24 were further supported by improvements in the secondary endpoints: 6-min walk distance (+18 m), NT-proBNP (-31%), and maintenance or improvement in WHO FC in 97% of patients. Adverse events were consistent with known effects of ambrisentan. CONCLUSION: The hemodynamic, functional, and biomarker improvements observed in the ATHENA-1 study suggests that the sequential addition of ambrisentan to patients not having a satisfactory response to established PDE5i monotherapy is a reasonable option.

Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial.

BACKGROUND: Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH), in particular systemic sclerosis (SSc), had an attenuated response compared with idiopathic PAH in most trials. Thus, there is uncertainty regarding the benefit of PAH-targeted therapy in some forms of CTD-PAH. OBJECTIVE: To explore the safety and efficacy of initial combination therapy with ambrisentan and tadalafil versus ambrisentan or tadalafil monotherapy in patients with CTD-PAH and SSc-PAH enrolled in the AMBITION trial. METHODS: This was a post hoc analysis of patients with CTD-PAH and SSc-PAH from AMBITION, an event-driven, double-blind trial in patients with WHO functional class II/III PAH. Treatment-naive patients were randomised 2:1:1 to once-daily initial combination therapy with ambrisentan plus tadalafil or monotherapy with ambrisentan or tadalafil, respectively. The primary endpoint was time to the first clinical failure event (first occurrence of death, hospitalisation for worsening PAH, disease progression or unsatisfactory long-term clinical response). RESULTS: In the primary analysis set (N=500), 187 patients had CTD-PAH, of whom 118 had SSc-PAH. Initial combination therapy reduced the risk of clinical failure versus pooled monotherapy in each subgroup: CTD-PAH (HR 0.43 (95% CI 0.24 to 0.77)) and SSc-PAH (0.44 (0.22 to 0.89)). The most common AE was peripheral oedema, which was reported more frequently with initial combination therapy than monotherapy in the two PAH subgroups. The relative frequency of adverse events between those on combination therapy versus monotherapy was similar across subgroups. CONCLUSIONS: This post hoc subgroup analysis provides evidence that CTD-PAH and SSc-PAH patients benefit from initial ambrisentan and tadalafil combination therapy. TRIAL REGISTRATION NUMBER: NCT01178073, post results.

Initial combination therapy with ambrisentan and tadalafil and mortality in patients with pulmonary arterial hypertension: a secondary analysis of the results from the randomised, controlled AMBITION study.

BACKGROUND: In treatment-naive patients with pulmonary arterial hypertension, initial combination therapy with ambrisentan and tadalafil reduces the risk of clinical failure events compared with monotherapy. We did this secondary analysis to further investigate the effect of combination therapy on survival. METHODS: We analysed survival data from the modified intention-to-treat population of the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial. AMBITION was a multicentre, randomised, double-blind study, in which treatment-naive patients with pulmonary arterial hypertension were randomly assigned in a 2:1:1 ratio and received combination therapy with ambrisentan and tadalafil, ambrisentan and placebo, or tadalafil and placebo. We did a prespecified analysis of all mortality events from randomisation to the end of the study, including patients who discontinued their assigned treatment. In a post-hoc analysis, we analysed survival at 7 days after the termination of each individual patient's randomised treatment. We used Cox proportional hazard regression, Kaplan-Meier survival estimates, and the stratified log-rank test to compare the survival of patients receiving initial combination therapy or initial monotherapy. FINDINGS: The study population consisted of 605 patients with pulmonary arterial hypertension who were randomly assigned and received combination therapy (n=302) or monotherapy (n=303; 152 patients assigned to ambrisentan monotherapy and 151 patients to tadalafil monotherapy). At the end of the study, 29 (10%) of 302 patients in the combination therapy group had died compared with 41 (14%) of 303 patients in the monotherapy group (hazard ratio 0·67, 95% CI 0·42-1·08; stratified log-rank p=0·10). At 7 days after the end of randomised treatment, fewer patients had died in the combination therapy group (3 [1%] of 302 patients) compared with the monotherapy group (13 [4%] of 303 patients; hazard ratio 0·21, 95% CI 0·06-0·73). INTERPRETATION: These data indicate that initial combination therapy might be associated with a survival advantage compared with initial monotherapy in patients with newly diagnosed pulmonary arterial hypertension. This hypothesis needs to be addressed in future studies. FUNDING: Gilead, GlaxoSmithKline.

Ambrisentan response in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) - A subgroup analysis of the ARIES-E clinical trial.

OBJECTIVE: Pulmonary arterial hypertension (PAH) is a condition which may lead to right ventricular failure and early mortality and is an important complication in patients with connective tissue disease (CTD). Previously, the endothelin A selective receptor antagonist, ambrisentan, demonstrated efficacy and safety in treating patients with PAH due to WHO Group I etiologies. These analyses describe the 3-year efficacy and safety of ambrisentan in patients specifically with CTD associated PAH (CTD-PAH). METHODS: Patients with CTD-PAH participating in the ARIES-1 and -2 clinical trials and their long-term extension were evaluated. Efficacy evaluations including 6-min walk distance (6MWD), clinical worsening, and survival were collected at routine study visits. Additional analyses of 6MWD categorical (30 m) breakpoints were conducted to determine any relationship between 6MWD and a prognostic threshold for survival. RESULTS: 124 patients with CTD-PAH were evaluated. 62.6%, 57.3%, and 58.2% of CTD-PAH patients treated with ambrisentan exhibited increases in 6MWD at 1-, 2-, and 3- years respectively. At 3 years, 64% of patients were free from clinical worsening and 76% of patients were still alive (Kaplan-Meier estimates). Identified factors holding prognostic relevance for survival include: baseline functional class, CTD-PAH subgroup, patient sex, improvement in 6MWD ≥30 m over the first 12 weeks of treatment, the most recent 6MWD, and a 6MWD absolute threshold of 222 m. CONCLUSION: These first analyses of the 3-year treatment of CTD-PAH patients with ambrisentan revealed fewer clinical worsening events and improved survival compared to historical controls. Key exercise parameters were also identified which appear important in guiding treatment.

Novel Approach Targeting the Complex Pathophysiology of Hypertrophic Cardiomyopathy: The Impact of Late Sodium Current Inhibition on Exercise Capacity in Subjects with Symptomatic Hypertrophic Cardiomyopathy (LIBERTY-HCM) Trial.

UNLABELLED: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder, with an overall prevalence of at least 1:500 in the adult population although only a fraction of affected patients come to clinical recognition. It is also the most common cause of sudden cardiac death in young adults and a major cause of morbidity caused by chronic heart failure symptoms. However, more than half a century since the original description of the disease, there is no currently approved therapy for the treatment of patients with HCM, and to date there have been only 5 randomized studies of medical therapies in HCM. As such, unmet medical need in HCM has been highlighted by the National Heart, Lung, and Blood Institute (NHLBI) as a research priority. Encouragingly, the infrastructure needed to conduct rigorous clinical trials in HCM has recently emerged because of the heightened awareness and understanding of the disease, development of clinical centers of excellence, and advances in diagnostic imaging. In this article, we will discuss the complex pathophysiology of HCM, review the current therapeutic landscape, describe new mechanistic insights into the central role of the late sodium current in HCM, and introduce the scientific rationale and execution of the Impact of Late Sodium Current Inhibition on Exercise Capacity in Subjects with Symptomatic Hypertrophic Cardiomyopathy (LIBERTY-HCM) trial, the largest randomized, double-blind, placebo controlled clinical trial, now underway, designed to evaluate the effect of a novel pharmacological approach in patients with symptomatic HCM. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02291237.