Seralutinib in adults with pulmonary arterial hypertension (TORREY): a randomised, double-blind, placebo-controlled phase 2 trial.

BACKGROUND: Morbidity and mortality in pulmonary arterial hypertension (PAH) remain high. Activation of platelet-derived growth factor receptor, colony stimulating factor 1 receptor, and mast or stem cell growth factor receptor kinases stimulates inflammatory, proliferative, and fibrotic pathways driving pulmonary vascular remodelling in PAH. Seralutinib, an inhaled kinase inhibitor, targets these pathways. We aimed to evaluate the efficacy and safety of seralutinib in patients with PAH receiving standard background therapy. METHODS: The TORREY trial was a phase 2, randomised, multicentre, multinational, double-blind, placebo-controlled study. Patients with PAH from 40 hospital and community sites were randomly assigned 1:1 via interactive response technologies to receive seralutinib (60 mg twice daily for 2 weeks, then increased to 90 mg twice daily as tolerated) or placebo by dry powder inhaler twice daily for 24 weeks. Randomisation was stratified by baseline pulmonary vascular resistance (PVR; <800 dyne·s/cm5 and ≥800 dyne·s/cm5). Patients were eligible if classified as WHO Group 1 PH (PAH), WHO Functional Class II or III, with a PVR of 400 dyne·s/cm5 or more, and a 6 min walk distance of between 150 m and 550 m. The primary endpoint was change in PVR from baseline to 24 weeks. Analyses for efficacy endpoints were conducted in randomly assigned patients (intention-to-treat population). Safety analyses included all patients who received the study drug. TORREY was registered with ClinicalTrials.gov (NCT04456998) and EudraCT (2019-002669-37) and is completed. FINDINGS: From Nov 12, 2020, to April 20, 2022, 151 patients were screened for eligibility, and following exclusions, 86 adults receiving PAH background therapy were randomly assigned to seralutinib (n=44; four male, 40 female) or placebo (n=42; four male, 38 female), and comprised the intention-to-treat population. At baseline, treatment groups were balanced except for a higher representation of WHO Functional Class II patients in the seralutinib group. The least squares mean change from baseline to week 24 in PVR was 21·2 dyne·s/cm5 (95% CI -37·4 to 79·8) for the placebo group and -74·9 dyne·s/cm5 (-139·7 to -10·2) for the seralutinib group. The least squares mean difference between the seralutinib and placebo groups for change in PVR was -96·1 dyne·s/cm5 (95% CI -183·5 to -8·8; p=0·03). The most common treatment-emergent adverse event in both treatment groups was cough: 16 (38%) of 42 patients in the placebo group; 19 (43%) of 44 patients in the seralutinib group. INTERPRETATION: Treatment with inhaled seralutinib significantly decreased PVR, meeting the primary endpoint of the study among patients receiving background therapy for PAH. FUNDING: Gossamer Bio.

TORREY, a Phase 2 study to evaluate the efficacy and safety of inhaled seralutinib for the treatment of pulmonary arterial hypertension.

Aberrant kinase signaling that involves platelet-derived growth factor receptor (PDGFR) α/ß, colony stimulating factor 1 receptor (CSF1R), and stem cell factor receptor (c-KIT) pathways may be responsible for vascular remodeling in pulmonary arterial hypertension. Targeting these specific pathways may potentially reverse the pathological inflammation, cellular proliferation, and fibrosis associated with pulmonary arterial hypertension progression. Seralutinib (formerly known as GB002) is a novel, potent, clinical stage inhibitor of PDGFRα/ß, CSF1R, and c-KIT delivered via inhalation that is being developed for patients with pulmonary arterial hypertension. Here, we report on an ongoing Phase 2 randomized, double-blind, placebo-controlled trial (NCT04456998) evaluating the efficacy and safety of seralutinib in subjects with World Health Organization Group 1 Pulmonary Hypertension who are classified as Functional Class II or III. A total of 80 subjects will be enrolled and randomized to receive either study drug or placebo for 24 weeks followed by an optional 72-week open-label extension study. The primary endpoint is the change from baseline to Week 24 in pulmonary vascular resistance by right heart catheterization. The secondary endpoint is the change in distance from baseline to Week 24 achieved in the 6-min walk test. A computerized tomography sub-study will examine the effect of seralutinib on pulmonary vascular remodelling. A separate heart rate monitoring sub-study will examine the effect of seralutinib on cardiac effort during the 6-min walk test.

Lack of a pharmacokinetic interaction between treprostinil diolamine and sildenafil in healthy adult volunteers.

Treprostinil, a stable prostacyclin analogue used in the treatment of pulmonary arterial hypertension, is in development as a sustained release oral tablet, treprostinil diolamine (United Therapeutics Corp, Research Triangle Park, NC). As combination therapy yields additional benefit in pulmonary arterial hypertension, treprostinil diolamine may be used with sildenafil, a phosphodiesterase-5 inhibitor. This study was designed to evaluate the presence of a pharmacokinetic drug interaction between treprostinil diolamine and sildenafil. Treprostinil is primarily metabolized by cytochrome (CYP) P450 2C8 with minor contribution from CYP2C9. Sildenafil is metabolized by CYP3A4 with minor contribution from CYP2C9. Eighteen healthy volunteers were randomized to receive 4.5 days each of (1) treprostinil diolamine alone, (2) sildenafil alone, and (3) combination treprostinil diolamine and sildenafil in an open-label, 3-period, 3-sequence crossover study. The geometric mean ratio (90% confidence intervals) for combination/agent alone of steady state area under the concentration-time curve and peak concentration (Cmax) were 0.972 (0.824-1.145) and 1.030 (0.900, 1.1-9), respectively, for treprostinil diolamine and were 0.881 (0.804-0.966) and 0.910 (0.876-0.946), respectively, for sildenafil. The results suggest lack of a metabolic interaction between treprostinil diolamine and sildenafil, as geometric mean ratio 90% confidence intervals were within 0.8-1.25. Combination therapy was well tolerated but had slightly higher rates of nausea, headache, and extremity pain than monotherapy.

Binding and activity of the prostacyclin receptor (IP) agonists, treprostinil and iloprost, at human prostanoid receptors: treprostinil is a potent DP1 and EP2 agonist.

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 EP1 and IP receptors (Ki 1.1 and 3.9 nM, respectively), low affinity for FP, EP3 or EP4 receptors, and very low affinity for EP2, DP1 or TP receptors. By contrast, treprostinil had high affinity for the DP1, EP2 and IP receptors (Ki 4.4, 3.6 and 32 nM, respectively), low affinity for EP1 and EP4 receptors and even lower affinity for EP3, 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 EP1 receptors (EC50 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 DP1, IP and EP2 receptors (EC50 0.6, 1.9 and 6.2 nM, respectively), but had low activity at the other receptors. Activation of IP, DP1 and EP2 receptors, as with treprostinil, can all result in vasodilatation of human pulmonary arteries. However, activation of EP1 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.

Lack of a pharmacokinetic interaction between oral treprostinil and bosentan in healthy adult volunteers.

Treprostinil diethanolamine is an oral prostacyclin analog currently being evaluated for the treatment of pulmonary arterial hypertension (PAH). Treprostinil is metabolized primarily by cytochrome P450 (CYP) 2C8 with minor contribution from CYP2C9. It is expected that oral treprostinil will be administered with bosentan, approved for the treatment of PAH and known to induce CYP2C9 and 3A4. This study evaluated whether a drug interaction exists between oral treprostinil, bosentan, and its active metabolite Ro 48-5033 during co-administration. Twenty-four participants were randomized in a 3-way crossover study to oral treprostinil 1 mg twice daily, bosentan 125 mg twice daily, and oral treprostinil 1 mg twice daily and bosentan 125 mg twice daily. Treprostinil geometric mean ratios (GMRs) (90% confidence interval [CIs]) for steady-state AUC(0-12) and C(max) (combination/treprostinil) were 0.92 (0.83, 1.03) and 0.96 (0.83, 1.11), respectively, whereas bosentan GMRs (combination/bosentan) were 1.02 (0.95, 1.10) and 1.04 (0.94, 1.15), respectively, and Ro 48-5033 GMRs were 0.99 (0.93, 1.06) and 1.03 (0.94, 1.13). In conclusion, because the GMR and 90% CI are within the equivalence interval of 0.8 to 1.25, co-administration of oral treprostinil and bosentan did not result in a pharmacokinetic interaction for either agent.

Potent effects of aerosol compared with intravenous treprostinil on the pulmonary circulation.

Inhaled vasodilator therapy for pulmonary hypertension may decrease the systemic side effects commonly observed with systemic administration. Inhaled medications only reach ventilated areas of the lung, so local vasodilation may improve ventilation-perfusion matching and oxygenation. We compared the effects of intravenous vs. aerosolized treprostinil on pulmonary and systemic hemodynamics in an unanesthetized sheep model of sustained acute pulmonary hypertension. Acute, stable pulmonary hypertension was induced in instrumented unanesthetized sheep by infusing a PGH(2) analog, U-44069. The sheep were then administered identical doses of treprostinil either intravenously or by aerosol. Systemic and pulmonary hemodynamics were recorded during each administration. Both intravenous and aerosol delivery of treprostinil reduced pulmonary vascular resistance and pulmonary arterial pressure, but the effect was significantly greater with aerosol delivery (P < 0.05). Aerosol delivery of treprostinil had minimal effects on systemic hemodynamics, whereas intravenous delivery increased heart rate and cardiac output and decreased left atrial pressure and systemic blood pressure. Aerosol delivery of the prostacyclin analog treprostinil has a greater vasodilatory effect in the lung with minimal alterations in systemic hemodynamics compared with intravenous delivery of the drug. We speculate that this may result from treprostinil stimulated production of vasodilatory mediators from pulmonary epithelium.

Functional selectivity of dopamine receptor agonists. I. Selective activation of postsynaptic dopamine D2 receptors linked to adenylate cyclase.

Dihydrexidine (DHX), the first high-affinity D(1) dopamine receptor full agonist, is only 10-fold selective for D(1) versus D(2) receptors, having D(2) affinity similar to the prototypical agonist quinpirole. The D(2) functional properties of DHX and its more D(2) selective analog N-n-propyl-dihydrexidine (PrDHX) were explored in rat brain and pituitary. DHX and PrDHX had binding characteristics to D(2) receptors in rat striatum typical of D(2) agonists, binding to both high- and low-affinity sites and being sensitive to guanine-nucleotides. Consistent with these binding data, both DHX and PrDHX inhibited forskolin-stimulated cAMP synthesis in striatum with a potency and intrinsic activity equivalent to that of quinpirole. Unexpectedly, however, DHX and PrDHX had little functional effect at D(2) receptors expressed on dopaminergic neurons that mediate inhibition of cell firing, dopamine release, or dopamine synthesis. Quantitative receptor competition autoradiography demonstrated that DHX bound to D(2) receptors in striatum (predominantly postsynaptic receptor sites) with equal affinity as D(2) sites in the substantia nigra (autoreceptor sites). The data from these experiments, coupled with what is known about the location of specific dopamine receptor isoforms, lead to the hypothesis that DHX, after binding to D(2L) and D(2S) receptors, causes agonist-typical functional changes only at some of these receptors. This phenomenon (herein termed "functional selectivity") suggests that drugs may be targeted not only at specific receptor isoforms but also at separate functions mediated by a single isoform, yielding novel approaches to drug discovery.