BACKGROUND:Treatment of patients with heart failure with reduced ejection fraction (HFrEF) and renal dysfunction (RD) is challenging owing to the risk of further deterioration in renal function, especially after acute decompensated HF (ADHF). METHODS AND RESULTS:We assessed the effect of RD (estimated glomerular filtration rate of ≥30 to <60 mL/min/1.73 m2) on initiation, up-titration, and tolerability of sacubitril/valsartan in hemodynamically stabilized patients with HFrEF admitted for ADHF (RD, n = 476; non-RD, n = 483). At week 10, the target dose of sacubitril/valsartan (97/103 mg twice daily) was achieved by 42% patients in RD subgroup vs 54% in non-RD patients (P < .001). Sacubitril/valsartan was associated with greater estimated glomerular filtration rate improvements in RD subgroup than non-RD (change from baseline least squares mean 4.1 mL/min/1.73 m2, 95% confidence interval 2.2-6.1, P < .001). Cardiac biomarkers improved significantly in both subgroups; however, compared with the RD subgroup, the improvement was greater in those without RD (N-terminal pro-brain natriuretic peptide, -28.6% vs -44.8%, high-sensitivity troponin T -20.3% vs -33.9%) (P < .001). Patients in the RD subgroup compared with those without RD experienced higher rates of hyperkalemia (16.3% vs 6.5%, P < .001), investigator-reported cardiac failure (9.7% vs 5.6%, P = .029), and renal impairment (6.4% vs 2.1%, P = .002). CONCLUSIONS:Most patients with HFrEF and concomitant RD hospitalized for ADHF tolerated early initiation of sacubitril/valsartan and showed significant improvements in estimated glomerular filtration rate and cardiac biomarkers. CLINICAL TRIAL REGISTRATION:NCT02661217.

Abstract Aims Diabetes mellitus is associated with worse outcomes and lower attainment of disease‐modifying therapies in patients with heart failure with reduced ejection fraction (HFrEF). This post hoc analysis of TRANSITION compared the patterns of tolerability and uptitration of sacubitril/valsartan in patients with HFrEF stabilized after hospital admission due to acute decompensated HF depending on the presence or absence of diabetes as a co‐morbidity. Methods TRANSITION, a randomized, open‐label study compared sacubitril/valsartan initiation pre‐discharge vs. post‐discharge (up to14 days) in 991 patients hospitalized for acutely decompensated HFrEF. The impact of diabetes status on tolerability and safety was studied at 10‐week and 26‐week post‐randomization. Results Among the 991 patients analysed at baseline, 460 (46.4%) had diabetes and exhibited a higher risk profile. At 10 weeks, sacubitril/valsartan target dose (97/103 mg bid) was achieved in a similar proportion of patients in each subgroup, when initiated pre‐discharge or post‐discharge respectively [diabetes subgroup: 47% (n = 105/226) vs. 50% (n = 115/228); relative risk ratio (RRR), 0.923; P = 0.412; non‐diabetes subgroup: 45% (n = 119/267) vs. 51% (n = 133/261); RRR, 0.878; P = 0.155]. The proportions of patients achieving and maintaining either 49/51 mg or 97/103 mg bid [diabetes subgroup: 61.1% (n = 138/226) vs. 67.5% (n = 154/228); RRR, 0.909; P = 0.175; non‐diabetes subgroup: 62.9% [n = 168/267] vs 69.3% [n = 181/261]; RRR, 0.906; P = 0.118] or any dose for ≥2 weeks leading to Week 10 [diabetes subgroup: 85% (n = 192/226) vs. 88.2% (n = 201/228); RRR, 0.966; P = 0.356; non‐diabetes subgroup: 86.9% (n = 232/267) vs. 90.8% (n = 237/261); RRR, 0.963; P = 0.215] were also similar in each subgroup, when initiated pre‐discharge or post‐discharge, respectively. At 10 weeks, hypotension and renal dysfunction rates were similar, although hyperkalaemia was higher among patients with diabetes (15.9% vs. 9.5%). The rate of permanent discontinuation due to adverse events was similar in the diabetes and non‐diabetes subgroups at 10 weeks, respectively: pre‐discharge (7.5% vs. 7.1%) or post‐discharge (5.7% vs. 4.2%). Similar patterns of uptitration and tolerability were observed at 26 weeks. Cardiac biomarkers including NT‐proBNP (P < 0.005) and hs‐TnT (P < 0.005) reduced significantly from baseline levels in both subgroups at Weeks 4 and 10; however, the response was greater among patients without diabetes. Mortality (diabetes vs. non‐diabetes subgroups: 3.3% vs 4.0%; P = 0.438) and HF rehospitalization (diabetes vs. non‐diabetes subgroups: 36.3% vs. 33.0%; P = 0.295) did not differ between the groups at 26 weeks. Conclusions Despite a higher risk profile among patients with diabetes, sacubitril/valsartan initiation either before or shortly after discharge in hospitalized patients with HFrEF resulted in comparable rates of dose up‐titration and tolerability as in those without diabetes.

OBJECTIVES This study examined the effects of sacubitril/valsartan on N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and determined patient characteristics associated with favorable NT-proBNP reduction response. BACKGROUND NT-proBNP levels reflect cardiac wall stress and predict event risk in patients with acute decompensated heart failure (ADHF). METHODS Post-hoc analysis of the TRANSITION (Comparison of Pre- and Post-discharge Initiation of Sacubitril/Valsartan Therapy in HFrEF Patients After an Acute Decompensation Event) study, including stabilized ADHF patients with reduced ejection fraction, randomized to open-label sacubitril/valsartan initiation in-hospital (pre-discharge) versus post-discharge. NT-proBNP was measured at randomization (baseline), discharge, and 4 and 10 weeks post-randomization. A favorable NT-proBNP response was defined as reduction to <= 1,000 pg/ml or >30% from baseline. RESULTS In patients receiving sacubitril/valsartan in-hospital, NT-proBNP was reduced by 28% at discharge, with 46% of patients obtaining favorable NT-proBNP reduction response compared with a 4% reduction and 18% favorable response rate in patients initiated post-discharge (p < 0.001). NT-proBNP was reduced similarly in patients initiating sacubitril/valsartan preand post-discharge (reduction at 4 weeks: 25%/22%; 10 weeks: 38%/34%) with comparable favorable response rates (46%/42% and 51%/48% at 4 and 10 weeks, respectively). NT-proBNP favorable response at 4 weeks was associated with lower risk of first heart failure (HF) rehospitalization or cardiovascular death through 26 weeks (hazard ratio: 0.57; 95% confidence interval [CI]: 0.38 to 0.86; p 1/4 0.007). Predictors of a favorable response at 4 weeks were starting dose $49/51 mg twice daily, higher baseline NT-proBNP, lower baseline serum creatinine, de novo HF, no atrial fibrillation, angiotensin-converting enzyme inhibitor-naive or angiotensin receptor blocker-naive, and no prior myocardial infarction. CONCLUSIONS In-hospital initiation of sacubitril/valsartan produced rapid reductions in NT-proBNP, statistically significant at discharge. A favorable NT-proBNP response over time was associated with a better prognosis and predicted by higher starting dose and predisposing clinical profile. (c) 2020 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Aims Sacubitril/valsartan has shown efficacy and tolerability in patients with heart failure (HF) and reduced ejection fraction (HFrEF) in the ambulatory setting (PARADIGM-HF), and following stabilisation of acutely decompensated HF (ADHF) (PIONEER-HF and TRANSITION). However, data are lacking for the initiation of sacubitril/valsartan in newly diagnosed (de novo) HFrEF. Here, we assess the tolerability of initiating sacubitril/valsartan following ADHF in TRANSITION subgroups of patients with a de novo vs. prior diagnosis of HFrEF. Methods and results TRANSITION randomised 1002 patients to pre- and post-discharge initiation of sacubitril/valsartan (analysis set n = 991, following exclusions for mis-randomisation). In this post-hoc analysis, tolerability to sacubitril/valsartan [proportion of patients achieving target dose (97/103 mg b.i.d.) at 10 weeks post-randomisation], adverse events (AEs) and serious AEs (SAEs) were compared in de novo (n = 286) and prior HFrEF (n = 705) subgroups. More de novo than prior HFrEF patients achieved target dose at Week 10 (56% vs. 45%; relative risk ratio 1.30, 95% confidence interval 1.12-1.52, P < 0.001), and fewer had SAEs and permanent treatment discontinuations. Initiation of sacubitril/valsartan did not prevent the concomitant initiation and up-titration of guideline-directed HF therapies. De novo patients showed faster and greater decreases in N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin-T, and lower rates of HF and all-cause rehospitalisation vs. prior HFrEF. Conclusions After ADHF, first-line initiation of sacubitril/valsartan in de novo HFrEF, alongside the initiation of other guideline-directed therapies, is feasible and is associated with a better risk-benefit profile than in patients with prior HFrEF. Early intervention with sacubitril/valsartan may be considered to delay disease progression in patients with de novo HFrEF. Clinical Trial Registration: , NCT02661217.

AimsTo assess tolerability and optimal time point for initiation of sacubitril/valsartan in patients stabilised after acute heart failure (AHF).Methods and resultsTRANSITION was a randomised, multicentre, open‐label study comparing two treatment initiation modalities of sacubitril/valsartan. Patients aged ≥ 18 years, hospitalised for AHF were stratified according to pre‐admission use of renin–angiotensin–aldosterone system inhibitors and randomised (n = 1002) after stabilisation to initiate sacubitril/valsartan either ≥ 12‐h pre‐discharge or between Days 1–14 post‐discharge. Starting dose (as per label) was 24/26 mg or 49/51 mg bid with up‐ or down‐titration based on tolerability. The primary endpoint was the proportion of patients attaining 97/103 mg bid target dose after 10 weeks. Median time of first dose of sacubitril/valsartan fromthe day of discharge was Day –1 and Day +1 in the pre‐discharge group and the post‐discharge group, respectively. Comparable proportions of patients in the pre‐ and post‐discharge initiation groups met the primary endpoint [45.4% vs. 50.7%; risk ratio (RR) 0.90; 95% confidence interval (CI) 0.79–1.02]. The proportion of patients who achieved and maintained for ≥ 2 weeks leading to Week 10, either 49/51 or 97/103 mg bid was 62.1% vs. 68.5% (RR 0.91; 95% CI 0.83–0.99); or any dose was 86.0% vs. 89.6% (RR 0.96; 95% CI 0.92–1.01). Discontinuation due to adverse events occurred in 7.3% vs. 4.9% of patients (RR 1.49; 95% CI 0.90–2.46).ConclusionsInitiation of sacubitril/valsartan in a wide range of heart failure with reduced ejection fraction patients stabilised after an AHF event, either in hospital or shortly after discharge, is feasible with about half of the patients achieving target dose within 10 weeks.Clinical Trial Registration: ClinicalTrials.gov ID: NCT02661217

Abstract Background NT-proBNP has diagnostic and prognostic value in patients with heart failure (HF). Compared with enalapril, sacubitril/valsartan (S/V) significantly reduced NT-proBNP within 1 week (wk) of administration and reduced HF re-hospitalisation in patients with acute decompensated HF (ADHF) in PIONEER-HF. Identification of predictors of NT-proBNP reduction with S/V could aid prognostication following hospitalisation. Methods TRANSITION (NCT02661217) is an open label study in stabilised ADHF patients with HFrEF that compared S/V initiation pre- versus post-discharge (within 2 wk of discharge). Baseline NT-proBNP was measured at randomisation in both S/V groups (n=950). Clinical predictors of favourable response of NT-proBNP to S/V therapy (defined as reduction to <1000 pg/ml or >30% reduction vs. baseline) were studied at discharge, 4 wk and 10 wk post-randomisation. Results Median NT-proBNP at randomisation was similar in patients with S/V started pre- and post-discharge (1919 vs 1659 pg/ml). In patients receiving S/V in-hospital, NT-proBNP was reduced by 28% at discharge, compared to a 3% reduction in patients receiving optimised standard of care (between group p<0.001). A favorable response was reached in 46% vs 18% patients at discharge, 46% vs 42% at 4 weeks and 51% vs 48% at 10 weeks in pre- vs post-discharge groups. (Figure 1). Predictors of favourable NT-proBNP response to S/V at discharge were hypertension and shorter time from admission to first S/V dose. At 4 wk after randomisation, NT-proBNP was reduced similarly in patients started on S/V pre- and post-discharge. When the two S/V initiation groups were combined, predictors of favorable NT-proBNP response at 4 wk were higher initial dose of S/V (≥49/51 mg b.i.d.), higher baseline levels of NT-proBNP, de novo HF hospitalisation, ACEI/ARB naïve, lower baseline creatinine, no atrial fibrillation (AFib), no prior myocardial infarction (MI). A further reduction in NT-proBNP was seen at 10 wk post-randomisation in patients started on S/V pre- and post-discharge (38% vs 34%, between group p=0.250). Predictors of favourable NT-proBNP response to S/V were similar at 4 wk and 10 wk post-randomisation. Conclusion In-hospital initiation of sacubitril/valsartan shortly after stabilisation was associated with a prompt improvement of NT-proBNP already at discharge, whereas higher baseline levels of NT-proBNP, higher starting dose, absence of AFib and MI history, de novo HF and ACEI/ARB naïve status were associated with favourable NT-proBNP response in the vulnerable phase after discharge. Acknowledgement/Funding The TRANSITION study was funded by Novartis

Background: In the PIONEER-HF study, in-hospital initiation of sacubitril/valsartan (S/V) versus enalapril in patients with heart failure (HF) and reduced ejection fraction (HFrEF), stabilised after acute decompensation, was associated with superior reduction of NT-proBNP, irrespective of prior use of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). Methods: In TRANSITION (NCT02661217), 1002 patients with HFrEF, hospitalised for acute decompensated HF after haemodynamic stabilisation, were randomised 1:1 and initiated open-label S/V either pre- or post-discharge (1–14 days). Primary endpoint was the proportion of patients achieving the target dose (97/103 mg, bid) at 10 weeks post-randomisation. Endpoints, adverse events (AEs) and serious AEs (SAEs) were compared by ACEi/ARB status in the combined pre- and post-discharge arms. Results: ACEi/ARB-naïve group [326 (32.9%)] had lower systolic blood pressure, serum creatinine, higher heart rate, and more often had non-ischaemic HF aetiology. Similar proportions of ACEi/ARB-naïve and non-naïve patients achieved the target dose of S/V (48.3% vs 47.9%, RRR 1.01 [0.88–1.16]) (Figure) and 88% patients from both groups were maintained on any S/V dose at Week 10. The rate of permanent discontinuation of S/V due to AEs was low and comparable. Overall incidence of AEs was 65.3% in ACEi/ARB-naïve and 68.3% in non-naïve patients (RRR 0.96 [0.87–1.05]) and incidence of SAEs was 16.3% and 19.4% respectively (RRR 0.83 [0.63–1.12]) (Table). Conclusion: In hospitalised patients with HFrEF naïve to ACEi/ARB, S/V can be safely initiated pre-discharge or shortly after discharge, and up-titration is well tolerated.

Abstract Background Patients with acute decompensated heart failure (ADHF) are at high risk of recurrent hospitalisations and death. In-hospital initiation of sacubitril/valsartan (S/V) reduced the risk for HF re-hospitalisation by 44% compared to enalapril in the PIONEER-HF study during the 8-week follow-up period. We aimed to describe the pattern of readmissions and their causes in the TRANSITION study, which randomised participants to pre-discharge or post-discharge initation of S/V. Methods TRANSITION (NCT02661217) was a randomised, open-label study comparing S/V initiation pre- vs. post-discharge (1–14 days) in haemodynamically stabilised patients with HF with reduced ejection fraction, admitted for ADHF. The primary endpoint was the proportion of patients achieving 97/103 mg S/V twice daily at 10 weeks post-randomisation. Information on rehospitalisation was collected throughout the study up to 26 weeks. Results A total of 493 patients received S/V in the pre-discharge arm and 489 patients in the post-discharge arm. Readmissions due to any cause were reported in 9.7% and 18.1% in the pre-discharge arm vs. 10.6% and 21.3% in the post-discharge arm within 30 days, and 10 weeks respectively. During the 26-weeks follow-up, all-cause readmission was reported in 34.5% of patients in the pre-discharge arm vs. 34.6% in the post-discharge arm. Median time to first rehospitalisation was 67 days in the pre-discharge arm (IQR: 26–110 days) and 50 days (IQR: 23–108 days) in the post-discharge arm. At least one HF hospitalisation was reported in 7.5% of patients in the pre-discharge arm and 7.4% in the post-discharge arm during 10 weeks and in 11.8% and 12.3% of patients, respectively, during 26 weeks of follow-up. Median duration of HF readmission was 7 days (IQR: 4–11 days) in the pre-discharge group and 6.5 days (IQR: 6.5–10 days) in the post-discharge arm. In total 2.6% and 5.5% patients in pre-discharge arm and 3.9% and 7% in the post-discharge arm visited an emergency room during 10 weeks and 26 weeks, respectively. Conclusions Initiation of S/V in patients hospitalised for ADHF either before or shortly after discharge, results in comparable rates of all cause and HF rehospitalisations, as well as emergency room visits without hospital admission over the 26 week follow-up period. HF re-hospitalisations rates at 10 weeks in TRANSITION are in line with the 8% in S/V arm reported in PIONEER-HF during the 8-weeks follow-up. Acknowledgement/Funding The TRANSITION study was funded by Novartis

Background: Initiation of sacubitril/valsartan (S/V) in hospitalised patients with heart failure (HF) with reduced ejection fraction (HFrEF), stabilised after admission due to decompensated HF (ADHF), was associated with superior NT-proBNP reduction compared to enalapril in the PIONEER-HF study. Treatment effect was similar in patients with and without a prior diagnosis of HFrEF. Methods: In TRANSITION (NCT02661217), 1002 patients with HFrEF, hospitalised for ADHF, after haemodynamic stabilisation, were randomised 1:1 to start open-label S/V either pre- or post-discharge (1–14 days). Primary endpoint was the proportion of patients achieving the target dose (97/103 mg bid) at 10 weeks post-randomisation. Endpoints, adverse events (AEs) and serious AEs (SAEs) were compared by HF history status in the combined pre- and post-discharge arms. Results: 286 patients had de novo HFrEF and 705 had a prior diagnosis of HFrEF. At baseline, de novo HF patients were younger, had lower systolic BP, serum creatinine, and hs-TnT levels; and higher pulse rate and, eGFR; more non-ischaemic HF, and fewer had comorbidities. More de novo HF patients achieved the target dose versus subjects with a prior diagnosis of HF (56.0% vs 44.8%, RRR1.30 [1.12–1.52]) and 90% were able to achieve and maintain any dose (Figure). The number of SAEs and treatment interruptions due to AEs was lower in patients with de novo HFrEF (Table). Conclusions: Patients with de novo HFrEF can be safely initiated on S/V and are more likely to achieve the target dose and maintain treatment by Week 10, compared to patients with a previous diagnosis of HFrEF.

Abstract Background Optimisation of chronic heart failure (HF) therapy remains the key strategy to improve outcomes after hospitalisation for acute decompensated HF (ADHF) with reduced ejection fraction (HFrEF). Initiation and uptitration of disease-modifying therapies is challenging in this vulnerable patient population. We aimed to describe the patterns of treatment optimisation including sacubitril/valsartan (S/V) in the TRANSITION study. Methods TRANSITION (NCT02661217) was a randomised, open-label study comparing S/V initiation pre- vs. post-discharge (1–14 days) in patients admitted for ADHF after haemodynamic stabilisation. The primary endpoint was the proportion of patients achieving 97/103 mg S/V twice daily (bid) at 10 weeks post-randomisation. Up-titration of S/V was as per label. Information on dose of S/V and on the use of concomitant HF medication was collected at each study visit up to week 26. Results A total of 493 patients received at least one dose of S/V in the pre-discharge arm and 489 patients in the post-discharge arm. One month after randomisation, 45% of patients in the pre-d/c arm vs. 44% in the post-discharge arm used 24/26 mg bid starting dose and 42% vs. 40% were on 49/51 mg S/V bid, respectively. At week 10, 47% of patients had achieved the target dose in the pre-discharge arm vs. 51% in the post-discharge arm. At the end of the follow-up at 26 weeks, the proportion of patients on S/V target dose further increased to 53% in the pre-discharge and 61% in the post-discharge arm (Figure 1). At week 10, the mean dose of S/V was 132 mg in the pre-discharge arm and 136 mg in the post-discharge arm, and at week 26, it was 140 mg and 147 mg, respectively. Before hospital admission, 52% and 54% of the patients received a beta-blocker (BB) in the pre-discharge and post-discharge group, respectively, and 42% in both arms received a mineralcorticoid receptor antagonist (MRA). At time of discharge, 68% and 71%% of the patients received a BB and 68% and 65% an MRA, in the pre-discharge and post-discharge groups, respectively. These proportions remained stable to week 10 and week 26. Uptitration of sacubitril/valsartan Conclusions In the vulnerable post-ADHF population, initiation of S/V and up-titration to target dose was feasible within 10 weeks in half of the patients alongside with a 20% increase in the use of other disease-modifying medications that remained stable through the end of the 6-month follow-up. Acknowledgement/Funding The TRANSITION study was funded by Novartis

BackgroundSacubitril/valsartan (S/V) is indicated for the treatment of chronic heart failure with reduced ejection fraction (HFrEF). The TRANSITION study aims to provide evidence of safety and tolerability of S/V initiated early after decompensation requiring hospitalization in HFrEF patients.MethodsTRANSITION (NCT02661217) is a randomized, open-label study comparing S/V initiation pre- vs. post-discharge, after hemodynamic stabilization, in HFrEF patients admitted for acute decompensated HF, including patients with newly diagnosed HF. Patients were stratified by pre-admission treatment status: on an angiotensin converting enzyme inhibitor (ACEI), on an angiotensin receptor blocker (ARB), or ACEI/ARB-naive. Patients completed acute HF treatment, were 24 hours free from intravenous diuretics, and then were randomized 1:1 within each stratum for initiation of S/V treatment either pre-discharge or during days 1-14 post-discharge. The primary endpoint is the proportion of patients achieving 200 mg S/V twice daily at 10 weeks post-randomization. Secondary objectives assess the proportion of patients who achieve and maintain (i) a S/V dose of 100 and/or 200 mg twice daily or (ii) any dose of S/V for at least 2 weeks up to Week 10, and also (iii) the proportion of patients who permanently discontinue S/V owing to adverse events during the 10 week treatment period.ResultsTRANSITION randomized 1002 patients. At baseline, mean age was 67 years and 75% were male. Mean LVEF was 29%, and 64% of patients were in NYHA Class II and 34% in NYHA Class III (Table). 287 patients (29%) had new-onset HFrEF and 243 (24%) were ACEI/ARB naïve. The last patient completed the 10 week visit in February 2018. Primary and secondary results data are expected in May and will be presented.ConclusionsTRANSITION recruited a HFrEF population similar to everyday clinical practice. This includes de novo as well worsening chronic HrEF and also patients naïve to ACEI/ARB therapy. The TRANSITION results will allow conclusions about safety and tolerability of early initiation of S/V during or following hospitalization for decompensated HFrEF.

Introduction: The benefit of sacubitril/valsartan (S/V) in patients with chronic heart failure and reduced ejection fraction (HFrEF) is associated with a reduction of biomarkers of myocardial stret...

The prognosis after hospitalization for acute decompensated heart failure (ADHF) remains poor, especially <30 days post‐discharge. Evidence‐based medications with prognostic impact administered at discharge improve survival and hospital readmission, but robust studies comparing pre‐discharge with post‐discharge initiation are rare. The PARADIGM‐HF trial established sacubitril/valsartan as a new evidence‐based therapy in patients with heart failure (HF) and reduced left ventricular ejection fraction (<40%) (rEF). In common with other landmark studies, it enrolled patients who were ambulatory at the time of inclusion. In addition, there is also still limited knowledge of initiation and up‐titration of sacubitril/valsartan in ACEi/ARB‐ naïve patients and in de novo HF with rEF patients.

Pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor, has been studied in familial chylomicronemia syndrome. To evaluate the effects of supratherapeutic concentrations of pradigastat on the QTc interval, 2 studies were conducted. The first study assessed the safety, tolerability, and pharmacokinetics of single escalating intravenous doses of pradigastat (10, 30, 100, and 115 mg over 60 minutes) in healthy adults. Single intravenous doses were safe, well tolerated, and at the higher doses resulted in supratherapeutic pradigastat exposure. The second was a parallel, 3-arm thorough QTc study in which healthy male subjects were randomized to pradigastat (115 mg intravenously), moxifloxacin (400 mg oral, positive control), or placebo. Following intravenous administration, pradigastat exposure peaked at 4 times the therapeutic concentration and did not prolong the baseline-adjusted and placebo-corrected QTc intervals. During the 60-minute pradigastat infusion, a number of infusion reactions and a small mean decrease in QTc were observed. Both effects disappeared when the infusion was stopped, suggesting that an infusate excipient may have been responsible. As expected, moxifloxacin significantly increased the QTc interval at multiple points, confirming the study's sensitivity to detect a true positive effect. Pradigastat is therefore unlikely to increase the risk of dysrhythmias associated with QTc prolongation in humans.

The DGAT1 inhibitor, pradigastat, demonstrated a mild phototoxicity signal in preclinical studies. Therefore, this clinical trial was conducted to assess the risk of photosensitivity in humans. 47 healthy adults were randomized to part A (double-blind, placebo-controlled; 3 : 1 pradigastat : placebo) or part B (open-label positive control ciprofloxacin, investigator blind). Three irradiation conditions (1. full range UVB/UVA, 2. UVA only, 3. 1/2 MED from UVB/UVA + 16 J cm(-2) UVA) were applied to simulate different sunlight exposure conditions. Photosensitizing potential was assessed by determining the minimum erythemal dose (MED) and calculating the photosensitivity index (PI) at 1 and 24 h. Local skin reactions were recorded as a secondary endpoint. Following full UVB/UVA irradiation, there were no significant differences in MED or PI between groups. With UVA-only, no changes in MED or PI were observed for the pradigastat or placebo groups. For ciprofloxacin, there was a significant reduction in MED at 24 h (-32%, vs. 24 h baseline), which correlated to a PI of 1.61. The difference in mean PI between ciprofloxacin-pradigastat, and ciprofloxacin-placebo, was significant at 24 h (p < 0.001). Local skin erythema scores were comparable between pradigastat and placebo, but higher with ciprofloxacin. Pradigastat was not shown to induce photosensitivity reactions, while significant responses were seen with the positive control. These results strongly suggest that pradigastat will not induce photosensitivity reactions in individuals administered doses up to 40 mg per day, which is the highest intended clinical dose. Furthermore, the design of this clinical trial may serve as a prototype for future regulatory clinical photosensitivity studies.