The safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis (IPF) have been characterized using data from clinical trials. We further characterized the safety and tolerability of nintedanib in patients with IPF in clinical practice using the global pharmacovigilance database. The database included spontaneously reported adverse events and data collected via solicited reporting in patients treated with nintedanib from 15 October 2014 to 15 October 2018. Adverse events were coded using the Medical Dictionary for Regulatory Activities. Cumulative exposure to nintedanib was estimated on the basis of sales data. Cumulative exposure to nintedanib was estimated as 60,107 patient-years. Diarrhea was the most frequent event (301.6 events per 1000 patient-years). Most (97.0%) diarrhea events were non-serious. The median (25th, 75th percentile) time to onset of the first diarrhea event was 60 (11, 182) days. Elevated liver enzyme or bilirubin levels were reported at a rate of 31.5 events per 1000 patient-years. Bleeding was reported at a rate of 36.8 events per 1000 patient-years; 81.0% of events were non-serious. Major cardiovascular adverse events were reported at a rate of 13.4 events per 1000 patient-years and myocardial infarction at a rate of 4.3 events per 1000 patient-years. Gastrointestinal perforation was reported at a rate of 1.0 event per 1000 patient-years. On the basis of pharmacovigilance data collected over 4 years, the safety profile of nintedanib in patients with IPF was consistent with that observed in clinical trials and described in the product label, with no new safety concerns observed.
Abstract Pulmonary hypertension (PH) has been linked to worse outcomes in chronic lung diseases. The presence of PH in the setting of underlying Interstitial Lung Disease (ILD) is strongly associated with decreased exercise and functional capacity, an increased risk of hospitalizations and death. Examining the scope of this issue and its impact on patients is the first step in trying to define a roadmap to facilitate and encourage future research in this area. The aim of our working group is to strengthen the communities understanding of PH due to lung diseases and to improve the care and quality of life of affected patients. This introductory statement provides a broad overview and lays the foundation for further in‐depth papers on specific topics pertaining to PH‐ILD.
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.
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.
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.
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