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Positioning imatinib for pulmonary arterial hypertension: A phase I/II design comprising dose finding and single-arm efficacy.

ABSTRACT: Pulmonary arterial hypertension is an unmet clinical need. Imatinib, a tyrosine kinase inhibitor, 200 to 400 mg daily reduces pulmonary artery pressure and increases functional capacity in this patient group, but is generally poorly tolerated at the higher dose. We have designed an open-label, single-arm clinical study to investigate whether there is a tolerated dose of imatinib that can be better targeted to patients who will benefit. The study consists of two parts. Part 1 seeks to identify the best tolerated dose of Imatinib in the range from 100 and up to 400 mg using a Bayesian Continuous Reassessment Method. Part 2 will measure efficacy after 24 weeks treatment with the best tolerated dose using a Simon's two-stage design. The primary efficacy endpoint is a binary variable. For patients with a baseline pulmonary vascular resistance (PVR) >1000 dynes · s · cm^-5, success is defined by an absolute reduction in PVR of ≥300 dynes · s · cm^-5 at 24 weeks. For patients with a baseline PVR ≤1000 dynes · s · cm^-5, success is a 30% reduction in PVR at 24 weeks. PVR will also be evaluated as a continuous variable by genotype as an exploratory analysis. Evaluating the response to that dose by genotype may inform a prospective biomarker-driven study.

SUBMITTER: Wilkins MR

PROVIDER: S-EPMC8642118 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy.

Project description:RationalePulmonary arterial hypertension (PAH) is a progressive condition with a poor prognosis. Platelet-derived growth factor receptor (PDGFR) signaling plays an important role in its pathobiology.ObjectivesTo assess safety, tolerability, and efficacy of the PDGFR inhibitor imatinib in patients with PAH.MethodsPatients with PAH in functional classes II-IV were enrolled in a 24-week randomized, double-blind, placebo-controlled pilot study. Patients received imatinib (an inhibitor of PDGFR activity) 200 mg orally once daily (or placebo), which was increased to 400 mg if the initial dose was well tolerated. The primary endpoints were safety and change from baseline in the 6-minute-walk distance (6MWD). Secondary endpoints included hemodynamics and functional classification.Measurements and main resultsFifty-nine patients enrolled (imatinib [n = 28]; placebo [n = 31]); 42 completed the study. Dropouts were equally matched between the two groups. In the intention-to-treat (ITT) population there was no significant change in the 6MWD (mean ± SD) in the imatinib versus placebo group (+22 ± 63 versus -1.0 ± 53 m). There was a significant decrease in pulmonary vascular resistance (imatinib -300 ± 347 versus placebo -78 ± 269 dynes · s · cm⁻⁵, P < 0.01) and increase in cardiac output (imatinib +0.6 ± 1.2 versus placebo -0.1 ± 0.9 L/min, P = 0.02). Serious adverse events occurred in 11 imatinib recipients (39%) and 7 placebo recipients (23%). Three deaths occurred in each group. Post hoc subgroup analyses suggest that patients with greater hemodynamic impairment may respond better than patients with less impairment.ConclusionsThese data from a Phase II study are consistent with imatinib being well tolerated in patients with PAH, and provide proof of concept for further studies evaluating its safety, tolerability, and efficacy in PAH. Clinical trial registered with www.clinicaltrials.gov (NCT00477269).

| S-EPMC3001259 | biostudies-literature

Blood pulmonary arterial hypertension

Project description:Microarray analysis of peripheral blood mononuclear (PBMC) cells in pulmonary arterial hypertension. Keywords = mononuclear cells Keywords = gene microarray Keywords = pulmonary arterial hypertension Keywords = Herpesvirus Keywords = biomarker Keywords: other

2003-11-15 | GSE703 | GEO

IMPAHCT: A randomized phase 2b/3 study of inhaled imatinib for pulmonary arterial hypertension.

Project description:AV-101 (imatinib) powder for inhalation, an investigational dry powder inhaled formulation of imatinib designed to target the underlying pathobiology of pulmonary arterial hypertension, was generally well tolerated in healthy adults in a phase 1 single and multiple ascending dose study. Inhaled Imatinib Pulmonary Arterial Hypertension Clinical Trial (IMPAHCT; NCT05036135) is a phase 2b/3, randomized, double-blind, placebo-controlled, dose-ranging, and confirmatory study. IMPAHCT is designed to identify an optimal AV-101 dose (phase 2b primary endpoint: pulmonary vascular resistance) and assess the efficacy (phase 3 primary endpoint: 6-min walk distance), safety, and tolerability of AV-101 dose levels in subjects with pulmonary arterial hypertension using background therapies. The study has an operationally seamless, adaptive design allowing for continuous recruitment. It includes three parts; subjects enrolled in Part 1 (phase 2b dose-response portion) or Part 2 (phase 3 intermediate portion) will be randomized 1:1:1:1 to 10, 35, 70 mg AV-101, or placebo (twice daily), respectively. Subjects enrolled in Part 3 (phase 3 optimal dose portion) will be randomized 1:1 to the optimal dose of AV-101 and placebo (twice daily), respectively. All study parts include a screening period, a 24-week treatment period, and a 30-day safety follow-up period; the total duration is ∼32 weeks. Participation is possible in only one study part. IMPAHCT has the potential to advance therapies for patients with pulmonary arterial hypertension by assessing the efficacy and safety of a novel investigational drug-device combination (AV-101) using an improved study design that has the potential to save 6-12 months of development time. ClinicalTrials.gov Identifier: NCT05036135.

| S-EPMC10963589 | biostudies-literature

Clinical trial design and new therapies for pulmonary arterial hypertension.

Project description:Until 20 years ago the treatment of pulmonary arterial hypertension (PAH) was based on case reports and small series, and was largely ineffectual. As a deeper understanding of the pathogenesis and pathophysiology of PAH evolved over the subsequent two decades, coupled with epidemiological studies defining the clinical and demographic characteristics of the condition, a renewed interest in treatment development emerged through collaborations between international experts, industry and regulatory agencies. These efforts led to the performance of robust, high-quality clinical trials of novel therapies that targeted putative pathogenic pathways, leading to the approval of more than 10 novel therapies that have beneficially impacted both the quality and duration of life. However, our understanding of PAH remains incomplete and there is no cure. Accordingly, efforts are now focused on identifying novel pathogenic pathways that may be targeted, and applying more rigorous clinical trial designs to better define the efficacy of these new potential treatments and their role in the management scheme. This article, prepared by a Task Force comprised of expert clinicians, trialists and regulators, summarises the current state of the art, and provides insight into the opportunities and challenges for identifying and assessing the efficacy and safety of new treatments for this challenging condition.

| S-EPMC6351342 | biostudies-literature

Metabolomic heterogeneity of severe pulmonary arterial hypertension

Project description:Although multiple gene and protein expression have been extensively profiled in human pulmonary arterial hypertension (PAH), the mechanism for the development and progression of pulmonary hypertension remains elusive. Analysis of the global metabolomic heterogeneity within the pulmonary vascular system leads to a better understanding of disease progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we showed unbiased metabolomic profiles of disrupted glycolysis, increased TCA cycle, and fatty acid metabolites with altered oxidation pathways in the severe human PAH lung. The results suggest that PAH has specific metabolic pathways contributing to increased ATP synthesis for the vascular remodeling process in severe pulmonary hypertension. These identified metabolites may serve as potential biomarkers for the diagnosis of severe PAH. By profiling metabolomic alterations of the PAH lung, we reveal new pathogenic mechanisms of PAH in its later stage, which may differ from the earlier stage of PAH, opening an avenue of exploration for therapeutics that target metabolic pathway alterations in the progression of PAH. Global profiles were determined in human lung tissue and compared across 11 normal and 12 severe pulmonary arterial hypertension patients. Using a combination of microarray and high-throughput liquid-and-gas-chromatography-based mass spectrometry, we showed unbiased metabolomic profiles of disrupted glycolysis, increased TCA cycle, and fatty acid metabolites with altered oxidation pathways in the severe human PAH lung.

2014-11-14 | E-GEOD-53408 | biostudies-arrayexpress

Heart ventricles proteomic profile in pulmonary arterial hypertension

Project description:Arterial pulmonary hypertension is a rare disease, with little knowledge regarding its etiology, and high mortality. Development of right and later on also left ventricular heart insufficiency, secondary to pulmonary hypertension, is a negative predictive factor. Genetic and molecular processes underlying left heart ventricle remodeling over the course of pulmonary hypertension remain unknown. In particular, there is no knowledge regarding the mechanisms of left heart ventricle atrophy which was completely avoided by researchers until recently.The aim of this study was to assess changes in protein abundance in left and right heart ventricle free wall of rats in monocrotaline model of PAH.

2020-09-07 | PXD015896 | Pride

Pharmacokinetic interactions among imatinib, bosentan and sildenafil, and their clinical implications in severe pulmonary arterial hypertension.

Project description:AimsThis study characterized the population pharmacokinetics (PK) of imatinib in patients with severe pulmonary arterial hypertension (PAH), investigated drug-drug interactions (DDI) among imatinib, sildenafil and bosentan, and evaluated their clinical implications.MethodsPlasma concentrations of imatinib, bosentan and sildenafil were collected in a phase III study and were used to characterize the PK of imatinib in this population. DDIs among the three drugs were quantified using a linear mixed model and log-transformed drug concentrations.ResultsThe population mean estimates of apparent clearance (CL/F) and volume (V/F) were 10.8 l h(-1) (95% CI 9.2, 12.4 l h(-1) ) and 267 l (95% CI 208, 326 l), respectively. It was estimated that sildenafil concentrations increased, on average, by 64% (95% CI 32%, 103%) and bosentan concentrations by 51% (95% CI 12%, 104%), in the presence of imatinib. Despite increased concentrations of co-medications, treatment differences between imatinib and placebo for change in 6 min walk distance and pulmonary vascular resistance were relatively constant across the entire concentration range for sildenafil and bosentan. Overall, higher concentrations of imatinib and bosentan were not associated with increasing liver enzymes (serum glutamic oxaloacetic transaminases [SGOT]/serum glutamic-pyruvic transaminase [SGPT]).ConclusionsPopulation PKs of imatinib in patients with severe PAH were found comparable with those of patients with chronic myeloid leukemia. Imatinib was found effective regardless of the co-medications and showed intrinsic efficacy beyond merely elevating the concentrations of the co-medications due to DDIs. There was no evidence of increased risk of liver toxicity upon co-administration with bosentan.

| S-EPMC4500327 | biostudies-literature

Reversible Cardiac Hypertrophy in Pulmonary Arterial Hypertension Treated With High-Dose Epoprostenol.

Project description:Although current guidelines recommend the use of prostanoid infusion that includes epoprostenol for high-risk pulmonary arterial hypertension patients, epoprostenol has many adverse effects. We report a case of a heritable pulmonary arterial hypertension patient who had transient biventricular hypertrophy during high-dose administration of epoprostenol. In this case, biventricular hypertrophy with worsening of dyspnea was observed during the uptitration of epoprostenol. Inflammatory diseases and endocrine disorders were ruled out as causes of the ventricular hypertrophy. After epoprostenol was changed to intravenous treprostinil, the biventricular hypertrophy normalized, in connection with dyspnea improvement. The use of high-dose epoprostenol may contribute to cardiac hypertrophy.

| S-EPMC9486866 | biostudies-literature

HIV protease inhibitors in pulmonary hypertension: rationale and design of a pilot trial in idiopathic pulmonary arterial hypertension.

Project description:We propose an exploratory clinical study, the first of its kind to our knowledge, to determine the safety and potential clinical benefit of the combination of the HIV protease inhibitors (HIV-PIs) saquinavir and ritonavir (SQV+RIT) in patients with idiopathic pulmonary arterial hypertension (IPAH). This study is based on evidence that (1) HIV-PIs can improve pulmonary hemodynamics in experimental models; (2) both Toll-like receptor 4 and high-mobility group box 1 (HMGB1) participate in the pathogenesis of experimental pulmonary hypertension; and (3) a high-throughput screen for inhibitors of HMGB1-induced macrophage activation yielded HIV-PIs as potent inhibitors of HMGB1-induced cytokine production. In this proposed open-label, pre-post study, micro, low, and standard doses of SQV+RIT will be given to IPAH patients for 14 days. Patients will receive follow-up for the next 14 days. The primary outcome to be evaluated is change in HMGB1 level from baseline at 14 days. The secondary outcome is changes in tumor necrosis factor α, interleukin 1β, interleukin 6, C-reactive protein, pulmonary arterial pressure based on echocardiography parameters and New York Heart Association/World Health Organization functional class, and Brog dyspnea scale index from baseline at 14 days. Other secondary measurements will include N-terminal pro-brain natriuretic peptide, atrial natriuretic peptide, and 6-minute walk distance. We propose that SQV+RIT treatment will improve inflammatory disorders and pulmonary hemodynamics in IPAH patients. If the data support a potentially useful therapeutic effect and suggest that SQV+RIT is safe in IPAH patients, the study will warrant further investigation. (ClinicalTrials.gov identifier: NCT02023450.).

| S-EPMC4556505 | biostudies-literature

Schistosomiasis Pulmonary Arterial Hypertension.

Project description:Pulmonary arterial hypertension (PAH) is a disease of the lung blood vessels that results in right heart failure. PAH is thought to occur in about 5% to 10% of patients with hepatosplenic schistosomiasis, particularly due to S. mansoni. The lung blood vessel injury may result from a combination of embolization of eggs through portocaval shunts into the lungs causing localized Type 2 inflammatory response and vessel remodeling, triggering of autonomous pathology that becomes independent of the antigen, and high cardiac output as seen in portopulmonary hypertension. The condition is likely underdiagnosed as there is little systematic screening, and risk factors for developing PAH are not known. Screening is done by echocardiography, and formal diagnosis requires invasive right heart catheterization. Patients with Schistosoma-associated PAH show reduced functional capacity and can be treated with pulmonary vasodilators, which improves symptoms and may improve survival. There are animal models of this disease that might help in understanding disease pathogenesis and identify novel targets to screen and treatment. Pathogenic mechanisms include Type 2 immunity and activation and signaling in the TGF-β pathway. There are still major uncertainties regarding Schistosoma-associated PAH development, course and treatment.

| S-EPMC7758287 | biostudies-literature

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