RATIONALE:Wearable devices provide an objective measurement of activity in the home setting and are complementary to 6-minute walk distance. Patients with pulmonary arterial hypertension (PAH) have low daily activity time, which is likely related to physiologic impairment and behavioral changes. Actigraphy may be a functional outcome assessment capable of detecting changes in activity mediated by improvement in physiology in a therapy trial. OBJECTIVES:ELEVATE-2 was a phase 2 trial evaluating rodatristat ethyl versus placebo in PAH. We hypothesized rodatristat ethyl would improve measures of activity, specifically peak steps, at week 24, and further that changes in actigraphy measures would correlate with changes in stroke volume index. METHODS:ELEVATE-2 was a randomized, double-blinded, placebo-controlled trial. All participants wore an ActiGraph on their wrist. We compared changes in average peak 5-minute steps (steps during the most active 5 minutes of a day, whether or not consecutive), daily steps, moderate activity time, and vigorous activity time at baseline, week 12, and week 24. Linear mixed methods with repeated measures were performed to assess treatment-time interaction at week 24, and least squares means were used to compare groups. Linear regression was performed to evaluate the changes in stroke volume index on activity parameters. RESULTS:Of the 108 participants, 100 were included in the analysis. Adjusted least squares mean showed that peak 5-minute steps (-49 steps [95% CI, -80 to -18]), moderate activity time (-17.3 minutes/day [95% CI, -29.3 to -5.3]), and daily steps (-656 [95% CI, -1171 to -140]) all decreased at week 24 after treatment with rodatristat ethyl compared to placebo. Peak 5-minute steps were weakly associated with changes in stroke volume index (0.74 [95% CI, 0.11-1.37]). CONCLUSIONS:Rodatristat ethyl reduced multiple activity parameters in this small, randomized multicenter study. Peak steps, daily steps, and moderate activity time seem to capture different aspects of movement in the home setting. Activity parameters were not strongly associated with resting hemodynamics, underscoring the influence of behavioral and external factors on activity. CLINICAL TRIALS REGISTRATION:NCT04712669.

Background The role of serotonin in pulmonary arterial hypertension has been extensively studied in recent decades, with preclinical data strongly indicating involvement in disease pathogenesis; however, clinical studies have yielded mixed results. Methods ELEVATE-2 was a phase 2b dose-ranging, randomised, double-blind, placebo-controlled, multicentre trial investigating rodatristat ethyl as a treatment for patients with pulmonary arterial hypertension. The study was conducted at 64 sites across 16 countries in Europe and North America. Eligible participants were aged 18 years or older, had pulmonary arterial hypertension with WHO functional class II or III symptom severity, and had received a stable dose and regimen of one or more pulmonary arterial hypertension treatments for at least 12 weeks. Participants were randomly assigned 1:1:1 to receive two placebo tablets, one placebo and one rodatristat ethyl 300 mg tablet, or two rodatristat ethyl 300 mg tablets twice daily using an interactive response system. Participants, investigators, site personnel, and sponsors were masked to treatment allocation. Participants who completed the 24 week treatment period were invited to continue in an open-label extension. The primary endpoint was percent change in pulmonary vascular resistance (PVR) from baseline to week 24. Primary efficacy analyses were conducted on the intention-to-treat population and analyses of harms were conducted in the safety population, which included all patients who received any amount of the study drug. This trial is registered with ClinicalTrials.gov, NCT04712669, and is now complete. Findings Between March 18, 2021 and Dec 13, 2022, 108 participants were enrolled and randomly assigned. 36 participants received placebo, 36 received rodatristat ethyl 300 mg, and 36 received rodatristat ethyl 600 mg twice daily. Overall, 85 (79%) of participants were female and 23 (21%) were male. The mean age was 52·8 years (SD 14·7) in the full analysis set. In the open-label extension phase, 62 (82%) of participants were female and 14 (18%) were male, and the mean age was 52·8 years (SD 14·7); this phase was terminated following sponsor review of unmasked main study results. Least-squares mean percent change in PVR from baseline to week 24 favoured placebo and was 5·8% (SE 18·1) for the placebo group, 63·1% (18·5) for the rodatristat ethyl 300 mg group, and 64·2% (18·0) for the rodatristat ethyl 600 mg group. Treatment-emergent adverse events (TEAE) were reported for 29 (81%) patients in the placebo group, 33 (92%) patients in the rodatristat ethyl 300 mg group, and all 36 (100%) patients in the rodatristat ethyl 600 mg group. TEAE leading to study discontinuation were reported for three (8%) patients in the placebo group, four (11%) patients in the rodatristat ethyl 300 mg group, and four (11%) in the rodatristat ethyl 600 mg group. There was one (3%) TEAE leading to death in the rodatristat ethyl 300 mg group. Interpretation Our results indicate that reducing peripheral serotonin concentrations via rodatristat ethyl has a negative effect on pulmonary haemodynamics and cardiac function in patients with pulmonary arterial hypertension. This finding suggests that manipulating this pathway might not be a suitable option for pulmonary arterial hypertension therapy. Funding Enzyvant Therapeutics (now Sumitomo Pharma America).

Background: Rodatristat ethyl (RE) targets peripheral serotonin (5HT) biosynthesis and is in Phase IIb development (ELEVATE 2) for pulmonary arterial hypertension (PAH). Upregulated 5HT signaling in lung drives pulmonary artery smooth muscle cell proliferation and vascular remodeling in PAH. Here, in healthy subjects, we characterize the magnitude and time to maximal reductions in peripheral 5HT biosynthesis to levels associated with efficacy in nonclinical PAH models, and the reversibility following RE withdrawal. Methods: Healthy subjects (n=79) received 100-800 mg BID of RE over 14-16 days. 5HT reductions were assessed via plasma and urine 5-HIAA (biomarker of 5HT levels) at baseline, last day of treatment and 7 days later. Results: Maximal 5-HIAA reductions in plasma and urine were achieved by 7 days of RE treatment. Reductions in plasma and urine 5-HIAA were correlated (Pearson R=0.5514; p<0.05). RE ≤ 300 mg BID led to a dose proportional decrease in plasma and urine 5-HIAA (-46% plasma; -47% urine at 300 mg BID). Doses >300 mg BID yielded only a further ~10% reduction in 5-HIAA (-54% plasma; -59%, urine at 800 mg BID). Doses of ≥300 mg BID achieved ~40% reduction in urine 5-HIAA associated with efficacy in rat monocrotaline and SUGEN hypoxia PAH models. Inhibition of 5HT biosynthesis was reversible as 5-HIAA returned to near baseline values by 7 days post dosing. Conclusions: RE achieved dose-dependent reductions in serotonin synthesis in healthy subjects. A target ~40% reduction associated with efficacy in rat PAH models was achieved by day 7 for RE doses ≥300mg BID. Inhibition of 5HT biosynthesis was reversible.

Background: Rodatristat ethyl (RE) is a prodrug for rodatristat (R), a peripheral inhibitor of tryptophan hydroxylase (TPH). TPH isoform 1 is over expressed in lungs of pulmonary arterial hypertension (PAH) patients resulting in enhanced serotonin production and pulmonary arterial remodeling. R did not reduce brain 5HT in healthy nor PAH model rats. Here we predict potential for RE to reduce CNS 5HT in humans and report incidence of mood changes in healthy human subjects. Methods: Maximal exposure (Cmax) of pharmacologically active unbound R (Ru) in human brain was predicted from PK and QWBA data in rat, in vitro tissue binding, and PK in healthy human subjects. Cumulative mood-related safety data including nervous system, psychiatric disorders, and Columbia-Suicide Severity Rating Scale assessments were collated from Phase 1 studies in healthy adults administered repeat 100mg-800mg BID doses (14-16 days). Results: Predicted steady-state Ru Cmax in human brain was 0.22/0.34ng/mL (300mg/600mg BID) reflecting sub-pharmacological levels of only 4.4% and 6.8% of the CNS TPH isoform 2 IC50 (5ng/mL). In 89 healthy subjects, incidence of total nervous system disorder AEs was 19.1% (dizziness or headache) for RE, and 20.0% (dizziness, headache, somnolence) for placebo. Psychiatric disorders were limited to anxiety in 2 (2.2%) RE-treated subjects. No RE treated subjects (0/53) reported suicidal ideation, suicidal behavior, or self-injurious behavior without suicidal intent. Conclusion: RE is predicted to have low risk for impacting brain 5HT consistent with no changes in mood or suicidal ideation in healthy subjects.

Serotonin plays a key role in the development and maintenance of the pathobiology associated with pulmonary arterial hypertension (PAH). Platelet-driven and locally produced serotonin from lung tissue and arterial endothelial cells induce excessive growth of pulmonary artery smooth muscle cells. The unchecked growth of these cells is a major driver of PAH including the remodeling of pulmonary arteries that dramatically reduces the diameter and flexibility of the arterial lumen. Tryptophan hydroxylase 1 (TPH1) is the rate-limiting enzyme for biosynthesis of serotonin and is upregulated in PAH arterial endothelial cells, supporting TPH1 inhibition to treat PAH. Targeting the serotonin pathway via inhibition of peripheral serotonin and local production in diseased tissues, rather than individual receptor-mediated or receptor-independent mechanisms, may result in the ability to halt or reverse pulmonary vascular remodeling. Rodatristat ethyl, a prodrug for rodatristat, a potent, peripheral inhibitor of TPH1, has demonstrated efficacy in monocrotaline and SUGEN hypoxia nonclinical models of PAH and robust dose-dependent reductions of 5-hydroxyindoleacetic acid, the major metabolite of serotonin in plasma and urine of healthy human subjects. ELEVATE 2 (NCT04712669) is a Phase 2b, double-blind, multicenter trial where patients with PAH are randomized to placebo, 300 or 600 mg twice daily of rodatristat ethyl. The trial incorporates endpoints to generate essential clinical efficacy, safety, pharmacokinetic, and pharmacodynamic data needed to evaluate the ability of rodatristat ethyl to ameliorate PAH by halting or reversing pulmonary vascular remodeling through its unique mechanism of TPH1 inhibition. Herein we describe the experimental design highlighting the trial's unique features.

Aim: ELEVATE 2 (NCT04712669) is a dose-ranging, randomized, double-blind, placebo-controlled, multicenter study of rodatristat ethyl (RE) in patients with WHO Group 1 PAH, Functional Class 2,3. Method: PAH has been linked to excessive serotonin (5-HT) biosynthesis that drives pulmonary arterial smooth muscle cell contraction and proliferation. RE, a first-in-class oral treatment for PAH, lowers peripheral and lung 5-HT levels by inhibiting the biosynthetic enzyme tryptophan hydroxylase. Results: RE significantly reduced pulmonary vascular remodeling in monocrotaline and SUGEN hypoxia PAH models. RE alone was more effective in reducing pulmonary vascular remodeling induced by SUGEN hypoxia than tadalafil + ambrisentan. Further, RE + ambrisentan was more effective in lowering mPAP than tadalafil + ambrisentan. RE reduced lung 5-HT by ~50% (SUGEN model) and urinary 5-HIAA (biomarker for 5-HT) by ~50% (healthy rats). In healthy humans, 14 days of 800mg RE BID reduced 5-HIAA by ~60%. Dose selection for ELEVATE 2 (1:1:1 placebo:300mg RE BID:600mg RE BID, 24 weeks) targeted >40% reduction in 5-HT. RE can be administered with background PAH medications. The primary endpoint is % change from baseline in PVR by right heart catheterization. Secondary endpoints include cardiopulmonary hemodynamics, Time to Clinical Worsening, all cause death, FC, 6MWD, NT-proBNP, RV function at echocardiography, and the PAH-SYMPACT & REVEAL Lite 2 scores. Exploratory endpoints include Time to Clinical improvement and actigraphy. Conclusion: RE, with its novel MoA distinct from those of approved therapies, has potential to be a new treatment option for PAH patients.

We assessed the presence of hepatitis C virus (HCV) RNA in liver explants from 39 patients awaiting liver transplantation who were treated with an interferon-free regimen and had undetectable serum HCV RNA at the time of liver transplantation. Interestingly, HCV RNA was detected in most liver explants (67%). Patients with HCV RNA-positive explants had received shorter courses of treatment, and HCV RNA was undetectable in serum for shorter periods before transplantation compared to patients with HCV RNA-negative explants (P = .014 and P = .013, respectively). Levels of HCV RNA in explants were significantly higher in patients with a relapse of HCV infection than patients who responded to treatment (P = .016), but most patients (85%) with residual HCV-RNA in the explant achieved a sustained virologic response after receiving their liver transplant.

Background Treatment options are limited for patients infected by hepatitis C virus (HCV) with advanced liver disease. We assessed the safety and efficacy of ledipasvir, sofosbuvir, and ribavirin in patients with HCV genotype 1 or 4 and advanced liver disease.Methods We did an open-label study at 34 sites in Europe, Canada, Australia, and New Zealand. Cohort A included patients with Child-Turcotte-Pugh class B (CTP-B) or CTP-C cirrhosis who had not undergone liver transplantation. Cohort B included post-transplantation patients who had either no cirrhosis; CTP-A, CTP-B, or CTP-C cirrhosis; or fibrosing cholestatic hepatitis. Patients in each group were randomly assigned (1:1) using a computer-generated randomisation sequence to receive 12 or 24 weeks of ledipasvir (90 mg) and sofosbuvir (400 mg) once daily (combination tablet), plus ribavirin (600-1200 mg daily). The primary endpoint was the proportion of patients achieving a sustained virological response 12 weeks after treatment (SVR12). All patients who received at least one dose of study drug were included in the safety analysis and all patients who received at least one dose of study drug and did not undergo liver transplantation during treatment were included in the efficacy analyses. Estimates of SVR12 and relapse rates and their two-sided 90% CI (Clopper-Pearson method) were provided. This exploratory phase 2 study was not powered for formal comparisons among treatment groups; no statistical hypothesis testing was planned or conducted. The trial is registered with EudraCT (number 2013-002802-30) and ClinicalTrials.gov (number NCT02010255).Findings Between Jan 14,2014, and Aug 19,2014,398 patients were screened. Of 333 patients who received treatment, 296 had genotype 1 HCV and 37 had genotype 4 HCV. In cohort A, among patients with genotype 1 HCV, SVR12 was achieved by 20 (87%, 90% CI 70-96) of 23 CTP-B patients with 12 weeks of treatment; 22 (96%, 81-100) of 23 CTP-B patients with 24 weeks of treatment; 17 (85%, 66-96) of 20 CTP-C patients (12 weeks treatment); and 18 (78%, 60-91) of 23 CTP-C patients (24 weeks treatment). In cohort B, among patients with genotype 1 HCV, SVR12 was achieved by 42 (93%, 84-98) of 45 patients without cirrhosis (12 weeks treatment); 44 (100%, 93-100) of 44 patients without cirrhosis (24 weeks treatment); 30 (100%, 91-100) of 30 CTP-A patients (12 weeks treatment); 27 (96%, 84-100) of 28 CTP-A patients (24 weeks treatment); 19 (95%, 78-100) of 20 CTP-B patients (12 weeks treatment); 20 (100%, 86-100) of 20 CTP-B patients (24 weeks treatment); one (50%, 3-98) of two CTP-C patients (12 weeks treatment); and four (80%, 34-99) of five CTP-C patients (24 weeks treatment). All five patients with fibrosing cholestatic hepatitis achieved SVR12 (100%, 90% CI 55-100). Among all patients with genotype 4 HCV, SVR12 was achieved by 14 (78%, 56-92) of 18 patients (12 weeks treatment) and 16 (94%, 75-100) of 17 patients (24 weeks treatment). Seven patients (2%) discontinued ledipasvir sofosbuvir prematurely due to adverse events. 17 patients died, mainly from complications of hepatic decompensation.Interpretation Ledipasvir-sofosbuvir and ribavirin provided high rates of SVR12 for patients with advanced liver disease, including those with decompensated cirrhosis before or after liver transplantation.

Recurrent hepatitis C virus (HCV) infection after liver transplantation (LT) is associated with accelerated progression of liver disease, frequently leading to graft loss and early death. Existing treatment options for severe recurrent HCV infection are limited by suboptimal efficacy, poor tolerability, and numerous drug interactions. We provided sofosbuvir (SOF) and ribavirin (RBV) on a compassionate‐use basis to patients with severe recurrent hepatitis C, including those with fibrosing cholestatic hepatitis (FCH) and decompensated cirrhosis who had a life expectancy of 1 year or less. All patients were to receive 24‐48 weeks of SOF plus RBV. Investigators could add pegylated interferon to the regimen at their discretion. Data from the first 104 patients who completed or prematurely discontinued treatment by January 1, 2014 are presented. Of the 104 patients analyzed, 52 had an early severe recurrence (diagnosed <12 months after LT) and 52 had cirrhosis (diagnosed >12 months after LT). Twelve patients who underwent retransplantation were excluded from our efficacy analysis. Of the 92 patients assessed, 54 (59%) achieved sustained virological response (SVR) at 12 weeks after the end of treatment, with a higher rate (73%; 35 of 48) in patients with early severe recurrence. Of the 103 patients assessed for clinical outcome, 59 (57%) reported clinical improvement at the last study visit, 23 (22%) were unchanged, 3 (3%) had a worsened clinical status, and 13 (13%) died. Overall, 123 serious adverse events (SAEs) occurred in 49 patients (47%). SAEs associated with hepatic decompensation were the most frequent, with 26 SAEs occurring in 19 patients (18%). Conclusion : SOF and RBV provide high rates of SVR in patients with severe recurrent HCV, including patients with early severe recurrence, FCH, and cirrhosis. (H epatology 2015;61:1485–1494)

BACKGROUND & AIMS:Patients with detectable hepatitis C virus (HCV) RNA at the time of liver transplantation universally experience recurrent HCV infection. Antiviral treatment before transplantation can prevent HCV recurrence, but existing interferon-based regimens are poorly tolerated and are either ineffective or contraindicated in most patients. We performed a trial to determine whether sofosbuvir and ribavirin treatment before liver transplantation could prevent HCV recurrence afterward.METHODS:In a phase 2, open-label study, 61 patients with HCV of any genotype and cirrhosis (Child-Turcotte-Pugh score, ≤7) who were on waitlists for liver transplantation for hepatocellular carcinoma, received up to 48 weeks of sofosbuvir (400 mg) and ribavirin before liver transplantation. The primary end point was the proportion of patients with HCV-RNA levels less than 25 IU/mL at 12 weeks after transplantation among patients with this HCV-RNA level at their last measurement before transplantation.RESULTS:Sixty-one patients received sofosbuvir and ribavirin, and 46 received transplanted livers. The per-protocol efficacy population consisted of 43 patients who had HCV-RNA level less than 25 IU/mL at the time of transplantation. Of these 43 patients, 30 (70%) had a post-transplantation virologic response at 12 weeks, 10 (23%) had recurrent infection, and 3 (7%) died (2 from nonfunction of the primary graft and 1 from complications of hepatic artery thrombosis). Of all 61 patients given sofosbuvir and ribavirin, 49% had a post-transplantation virologic response. Recurrence was related inversely to the number of consecutive days of undetectable HCV RNA before transplantation. The most frequently reported adverse events were fatigue (in 38% of patients), headache (23%), and anemia (21%).CONCLUSIONS:Administration of sofosbuvir and ribavirin before liver transplantation can prevent post-transplant HCV recurrence. ClinicalTrials.gov: NCT01559844.