Triangle Therapeutics

Los Angeles, CA, United States

Triangle Therapeutics

Los Angeles, CA, United States
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Arneson C.,Triangle Therapeutics | Klinger J.R.,Brown University
Pulmonary Circulation | Year: 2014

There are limited data on the management of pulmonary arterial hypertension (PAH) in the elderly; therefore, this analysis compared the safety and efficacy of tadalafil between patients ≥65 and <65 years old. This was a post hoc analysis of the randomized, double-blind, placebo-controlled phase 3 Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST-1) study. Patients who completed the 16-week study or who discontinued because of clinical worsening and were not receiving tadalafil 40 mg were eligible for a long-term, open-label extension study. Adverse events (AEs) and efficacy outcomes were assessed in patients ≥65 versus <65 years old, and the dose dependency of common AEs was determined. Twenty-eight percent (112 of 405) of patients were ≥65 years of age (mean in this subset, 72 ± 5 years). Compared with younger patients, elderly patients were more likely to be World Health Organization functional class III/IV (75% vs. 65%, respectively) and to have lower exercise capacity as assessed by 6-minute walk distance (6MWD; mean, 299 vs. 366 m). Compared with placebo, tadalafil increased 6MWD by a mean of 35 and 43 m in patients ≥65 and <65 years, respectively. Common AEs (including headache, dyspepsia, and myalgia) were similar in both groups and tended to decrease in incidence with longer treatment duration. No differences in AEs were observed between elderly patients who received tadalafil 20 or 40 mg. In conclusion, the safety and efficacy of tadalafil for treatment of PAH are similar between elderly patients and patients <65 years old. © 2014 by the Pulmonary Vascular Research Institute. All rights reserved.

Jing Z.-C.,Tongji University | Parikh K.,Care Institute of Medical Science | Pulido T.,Instituto Nacional Of Cardiologia | White R.J.,University of Rochester | And 6 more authors.
Circulation | Year: 2013

BACKGROUND-: Pulmonary arterial hypertension (PAH) is a progressive, fatal disease with no cure. Parenteral and inhaled prostacyclin analogue therapies are effective for the treatment of PAH, but complicated administration requirements can limit the use of these therapies in patients with less severe disease. This study was designed to evaluate the safety and efficacy of the oral prostacyclin analogue treprostinil diolamine as initial treatment for de novo PAH. METHODS AND RESULTS-: Three hundred forty-nine patients (intent-to-treat population) not receiving endothelin receptor antagonist or phosphodiesterase type-5 inhibitor background therapy were randomized (treprostinil, n=233; placebo, n=116). The primary analysis population (modified intent-to-treat) included 228 patients (treprostinil, n=151; placebo, n=77) with access to 0.25-mg treprostinil tablets at randomization. The primary end point was change from baseline in 6-minute walk distance at week 12. Secondary end points included Borg dyspnea index, clinical worsening, and symptoms of PAH. The week 12 treatment effect for 6-minute walk distance (modified intent-to-treat population) was 23.0 m (P=0.0125). For the intent-to-treat population, 6-minute walk distance improvements were observed at peak (26.0 m; P=0.0001) and trough (17.0 m; P=0.0025) plasma study drug concentrations. Other than an improvement in the combined 6-minute walk distance/Borg dyspnea score, there were no significant changes in secondary end points. Oral treprostinil therapy was generally well tolerated; the most common adverse events (intent-to-treat) were headache (69%), nausea (39%), diarrhea (37%), and pain in jaw (25%). CONCLUSIONS-: Oral treprostinil improves exercise capacity in PAH patients not receiving other treatment. Oral treprostinil could provide a convenient, first-line prostacyclin treatment option for PAH patients not requiring more intensive therapy. CLINICAL TRIAL REGISTRATION:-: URL: Unique identifier: NCT00325403. © 2012 American Heart Association, Inc.

Mathai S.C.,Johns Hopkins University | Lam D.,Triangle Therapeutics | Wise R.A.,Johns Hopkins University
American Journal of Respiratory and Critical Care Medicine | Year: 2012

Rationale: Although commonly used as the primary outcome measure of clinical trials in pulmonary arterial hypertension (PAH), the minimal important difference (MID) of the 6-minute walk test (6MWT) has not been well defined for this population of patients. Objectives: To estimate the MID in the 6MWT in patients with PAH. Methods: Study subjects from the clinical trial of tadalafil in PAH, a 16-week, parallel-group, randomized clinical trial of patients who were treatment naive or on background therapy with an endothelin receptor antagonist, were eligible. 6MWT was performed using a standardized protocol. Distributional and anchor-based methods were used to estimate the MID; the latter method used the Physical Component Summary Score (PCS) of the Medical Outcomes Study 36-item short form (SF-36). Measurements and Main Results: Four hundred five subjects were analyzed. Domains of the SF-36 were weakly to modestly associated with 6MWT. Change in the PCS of the SF-36 was most strongly associated with change in 6MWT (r = 0.40, P < 0.001) and thus was selected as the anchor for subsequent anchor-based analyses. Distributional analyses yielded estimates of the MID ranging from 25.1 to 38.5 m, whereas anchor-based analyses yielded an estimate of 38.6 m. Conclusions: Using both distributional and anchor-based methods, the estimated consensus MID in the 6MWT for PAH is approximately 33 m. These results have important implications for (1) assessing treatment responses from clinical trials and metaanalyses of specific PAH therapy, and (2) sample size calculations for future study design. Copyright © 2012 by the American Thoracic Society.

Benza R.L.,Allegheny General Hospital | Gomberg-Maitland M.,University of Chicago | Naeije R.,Erasme University Hospital | Arneson C.P.,Triangle Therapeutics | Lang I.M.,Medical University of Vienna
Journal of Heart and Lung Transplantation | Year: 2011

Background: Because of the challenges associated with conducting large survival studies of patients with pulmonary arterial hypertension (PAH), we analyzed the surrogate markers predictive of long-term survival in a large cohort of patients treated with subcutaneous treprostinil. Methods: A retrospective review was conducted using data from a total of 811 patients with New York Heart Association Functional Class (NYHA FC) II to IV PAH, who were treated with subcutaneous treprostinil. Patient baseline disease and on-treatment parameters were analyzed by uni- and multivariate analyses for predictive value of 3-year survival with PAH. Results: Among the baseline disease-related factors analyzed, there was a significantly higher risk of death (p < 0.001) associated with connective tissue diseaseassociated PAH relative to idiopathic PAH (hazard ratio for death [HR] 1.93), NYHA FC IV vs III (HR 2.31), pulmonary vascular resistance index (PVRI) >30 vs ≤16 mm Hg/liter/min/m 2 (HR 2.44) and mixed venous oxygen saturation (SVO 2) ≤55% vs >55%. The 6-minute walk distance (6MWD) of ≤295 m after 12 weeks of treprostinil treatment was associated with reduced survival at 3 years (58%). A <20-m increase from baseline in 6MWD was associated with greater survival (80%) vs smaller walk increments (69%; p = 0.039). Treprostinil dose of <40 ng/kg/min (p < 0.001) and every 10-ng/kg/min dose increase (p = 0.009) resulted in improved long-term survival. In a multivariate analysis, only SVO 2, 6MWD and treprostinil dose were significant on-treatment predictors (p < 0.02) of survival. Conclusions: Disease etiology, baseline factors (NYHA FC, PVRI and SVO 2) and on-treatment factors (6MWD, SVO 2 and treprostinil dose) were predictors of survival in this study and may be used to aid in treatment optimization. © 2011 International Society for Heart and Lung Transplantation. All rights reserved.

Frantz R.P.,Mayo Medical School | McDevitt S.,Triangle Therapeutics | Walker S.,Triangle Therapeutics
Journal of Heart and Lung Transplantation | Year: 2012

Background: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a biomarker of disease severity in pulmonary arterial hypertension (PAH). In this study we aimed to determine whether baseline NT-proBNP levels correlate with improvement in 6-minute walk distance (6MWD) in the pivotal randomized, placebo-controlled, double-blind study of the addition of inhaled treprostinil to oral therapy for PAH. Methods: A post hoc analysis of data from the TRIUMPH-1 study was performed in patients who had assessments of NT-proBNP levels and baseline and Week 12 6MWD. Least-squares mean analysis was used to compare patients in the highest quartile of baseline NT-proBNP with those in lower quartiles with regard to change from baseline in 6MWD, stratified by treatment. Results: The NT-proBNP within-treatment median changes from baseline to Week 12 were +44 and -72 pg/ml, and the median changes in 6MWD from baseline to Week 12 were +5 and +40 m for the placebo (n = 94) and inhaled treprostinil (n = 84) groups, respectively. Baseline NT-proBNP levels demonstrated a strong interaction with treatment in predicting change from baseline for 6MWD (p < 0.01), indicating that, in the upper quartile (<1,513.5 pg/ml), patients on inhaled treprostinil had a better response (+64 vs +32 m), whereas patients on placebo fared worse (-13 vs +20 m) when compared with the lower 3 quartiles (<1,513.5 pg/ml). Furthermore, least-squares mean difference in 6MWD between active and placebo groups was +67 and +16 m for the upper and lower 3 quartiles of NT-proBNP, respectively. Conclusions: Greater improvement in 6MWD in actively treated patients with high levels of NT-proBNP enhances understanding of the robustness of clinical response to inhaled treprostinil in more advanced disease. © 2012 International Society for Heart and Lung Transplantation.

Mathier M.A.,University of Pittsburgh | McDevitt S.,Triangle Therapeutics | Saggar R.,University of California at Los Angeles
Journal of Heart and Lung Transplantation | Year: 2010

Treprostinil, which is available for subcutaneous (SC) and intravenous (IV) administration, has demonstrated efficacy in increasing exercise capacity, reducing signs and symptoms of pulmonary arterial hypertension (PAH), and improving cardiopulmonary hemodynamics in patients with PAH; however, the infusion site pain commonly experienced with SC treprostinil has limited its use. Prospective and observational clinical studies have shown that the dose of SC treprostinil can be escalated at a higher rate than described in early clinical trials to achieve symptom relief, in part because of favorable tolerability of treatment and the apparent dose independence of site pain. In addition, pain management protocols that include non-pharmacologic and pharmacologic (i.e., topical and systemic) approaches provide analgesic relief from infusion site pain. With experience, physicians and patients have recognized that some infusion sites are better than others, and the frequency of site rotation can be reduced to improve tolerability. Dosing to achieve rapid onset of efficacy and proactively managing infusion site pain enhance the likelihood for a patient with PAH to maintain and derive benefit from SC treprostinil therapy. © 2010 International Society for Heart and Lung Transplantation.

Whittle B.J.,Queen Mary, University of London | Silverstein A.M.,Triangle Therapeutics | Mottola D.M.,Triangle Therapeutics | Clapp L.H.,University College London
Biochemical Pharmacology | Year: 2012

The prostacyclin analogues, iloprost and treprostinil are extensively used in treating pulmonary hypertension. Their binding profile and corresponding biochemical cellular responses on human prostanoid receptors expressed in cell lines, have now been compared. Iloprost had high binding affinity for EP 1 and IP receptors (K i 1.1 and 3.9 nM, respectively), low affinity for FP, EP 3 or EP 4 receptors, and very low affinity for EP 2, DP 1 or TP receptors. By contrast, treprostinil had high affinity for the DP 1, EP 2 and IP receptors (K i 4.4, 3.6 and 32 nM, respectively), low affinity for EP 1 and EP 4 receptors and even lower affinity for EP 3, FP and TP receptors. In functional assays, iloprost had similar high activity in elevating cyclic AMP levels in cells expressing the human IP receptor and stimulating calcium influx in cells expressing EP 1 receptors (EC 50 0.37 and 0.3 nM, respectively) with the rank order of activity on the other receptors comparable to the binding assays. As with binding studies, treprostinil elevated cyclic AMP with a similar high potency in cells expressing DP 1, IP and EP 2 receptors (EC 50 0.6, 1.9 and 6.2 nM, respectively), but had low activity at the other receptors. Activation of IP, DP 1 and EP 2 receptors, as with treprostinil, can all result in vasodilatation of human pulmonary arteries. However, activation of EP 1 receptors can provoke vasoconstriction, and hence may offset the IP-receptor mediated vasodilator effects of iloprost. Treprostinil may therefore differ from iloprost in its overall beneficial pulmonary vasorelaxant profile and other pharmacological actions, especially in diseases where the IP receptor is down-regulated. © 2012 Elsevier Inc.

Mathai S.C.,Johns Hopkins University | Hassoun P.M.,Johns Hopkins University | Puhan M.A.,University of Zürich | Zhou Y.,Triangle Therapeutics | Wise R.A.,Johns Hopkins University
Chest | Year: 2015

Background: Pulmonary arterial hypertension (PAH) is a progressive disease with high rates of morbidity and mortality. Current therapies improve symptoms, functional capacity, and, in select cases, survival. Little is known about patient factors that may predict the likelihood of patient-important, clinically relevant responses to therapy such as the 6-min walk distance (6MWD) and health-related quality of life (HRQoL). Methods: Data from the randomized clinical trial of tadalafil in PAH were used. Adjusted logistic regression models were created to examine the relationship between baseline characteristics and odds of achieving the minimal important difference (MID) in three parameters, defined as either a > 33-m increase in 6MWD, a > 5-unit increase in physical component summary score of the Medical Outcomes Study Short Form-36 (SF-36), or a > 5-unit increase in mental component summary score of the SF-36. Results: The study included 405 subjects. Younger age, male sex, lower baseline 6MWD, and disease etiology were associated with greater odds of achieving the MID for the 6-min walk test. Active treatment, younger age, and male sex were associated with greater odds of achieving the MID for the physical component summary score. Male sex was associated with greater odds of achieving the MID for the mental component summary score. Conclusions: Age, sex, baseline functional capacity, and disease etiology are variably associated with the likelihood of achieving clinically relevant responses in patient-important outcomes to PAH-specific therapy such as 6MWD and HRQoL. The increased likelihood of response in men compared with women is a novel finding and may reflect pathophysiologic differences between sexes. © 2015 American College Of Chest Physicians.

Patterson K.B.,University of North Carolina at Chapel Hill | Prince H.A.,University of North Carolina at Chapel Hill | Kraft E.,University of North Carolina at Chapel Hill | Kraft E.,Glaxosmithkline | And 6 more authors.
Science Translational Medicine | Year: 2011

A mainstay of strategies to prevent HIV-1 transmission is to use antiretroviral therapy (ART) for pre-exposure prophylaxis (PrEP). Critical to the design and interpretation of PrEP prevention trials is the ability to make accurate pharmacological measurements of ART drugs in human genital and colorectal mucosal tissues, the principal route of HIV transmission. Here, we evaluated two drugs that are preferentially used for PrEP: tenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine (FTC). A single oral dose of TDF/FTC (Truvada) was administered to 15 healthy individuals. Over the next 14 days, TFV and FTC were measured in blood plasma and genital secretions using a sensitive assay (lower level of quantification, 0.1 ng/ml). The active intracellular phosphorylated metabolites of these drugs [TFV diphospate (TFV-DP) and FTC triphosphate (FTC-TP)] were measured in homogenates prepared from rectal, vaginal, and cervical tissues. TFV and FTC were detected in blood plasma 14 days after administration of a single dose. The area under the concentration-time curve from 24 hours to 14 days (AUC 1-14d) for FTC in genital secretions was 27-fold greater than in blood plasma, whereas the AUC 1-14d for TFV was only 2.5-fold greater in genital secretions than in blood plasma. In rectal tissue, TFV and TFV-DP concentrations were detectable for 14 days and were 100-fold higher than the concentrations in vaginal and cervical tissues. Vaginal and cervical tissue concentrations of FTC were 10- to 15-fold higher than in rectal tissue. Despite high concentrations of FTC in vaginal and cervical tissue, FTC-TP concentrations in all tissue types were detected for only 2 days after dose. The exposure to TFV, TFV-DP, FTC, and FTC-TP was wide ranging depending on the type of mucosal tissue. These results demonstrate the need for detailed pharmacological studies to improve the application of ART for PrEP to prevent transmission of HIV.

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