key: cord-1037206-zdnxoce8
authors: Frantz, Robert P.; Benza, Raymond L.; Channick, Richard N.; Chin, Kelly; Howard, Luke S.; McLaughlin, Vallerie V.; Sitbon, Olivier; Zamanian, Roham T.; Hemnes, Anna R.; Cravets, Matt; Bruey, Jean-Marie; Roscigno, Robert; Mottola, David; Elman, Erin; Zisman, Lawrence S.; Ghofrani, Hossein-Ardeschir
title: TORREY, a Phase 2 study to evaluate the efficacy and safety of inhaled seralutinib for the treatment of pulmonary arterial hypertension
date: 2021-11-11
journal: Pulm Circ
DOI: 10.1177/20458940211057071
sha: c252af3181825a14dd915dd5bf81f57a9aa34205
doc_id: 1037206
cord_uid: zdnxoce8

Aberrant kinase signaling that involves platelet-derived growth factor receptor (PDGFR) α/β, 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/β, 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.

and c-KIT play key roles in cellular overgrowth in the pulmonary arteriolar lesions associated with PAH. 2, [6] [7] [8] Aberrant PDGFR signaling drives proliferation of smooth muscle cells (in the vessel media) and myofibroblasts (in the vessel lumen) leading to pulmonary arteriolar medial hypertrophy, neointimal lesions, and fibrosis. c-KIT is expressed on endothelial progenitor cells and mast cells, potentially contributing to perivascular inflammation and vascular remodeling. 7, 9, 10 Increased infiltration of c-KIT-positive cells has been observed in pulmonary arterial plexiform lesions in PAH patient lungs. 7 CSF1R is expressed on monocytes and macrophages. 11 CSF1R-positive perivascular/adventitial macrophages secrete PDGF ligands and proinflammatory cytokines, contributing to pathological remodeling in PAH. [12] [13] [14] PDGF activation decreases bone morphogenetic protein receptor type 2 (BMPR2) and can also activate transforming growth factor beta (TGFb), which further drives PASMC proliferation in the media of the pulmonary arterioles. 15, 16 Effects of CSF1R, PDGFR, and c-KIT activation can be mediated by multiple intracellular kinases including PI3K, AKT, ERK, and STATs. Fig. 1 highlights the interactions between CSF1R, PDGFR, and c-KIT signaling as well as PDGF modulation of BMPR2, which lead to abnormal proliferation of PASMCs, and myofibroblasts within the pulmonary arterioles, thereby leading to elevated PVR, a hallmark of PAH. Targeting these specific pathways (PDGFRa/b, CSF1R, and c-KIT) may potentially reverse the pathological inflammation, cellular proliferation, and fibrosis associated with PAH. Thus, there is a compelling rationale to target PDGFR, CSF1R, and c-KIT as a treatment for this disease.

Seralutinib (formerly known as GB002) is a smallmolecule, selective kinase inhibitor that targets PDGFRa/b, CSF1R, and c-KIT, and increases BMPR2. This novel chemical entity has been specifically developed to target these pathways involved in the pathogenesis of PAH (Fig. 1 ). Seralutinib is administered by dry power inhalation to potentially maximize the therapeutic index of this kinase inhibitor by directly targeting diseased pulmonary arterioles, minimizing systemic exposure, and decreasing the potential for offtarget adverse effects. The results of preclinical studies are consistent with an inhaled lung deposition profile such that a significantly higher lung tissue exposure compared to plasma exposure was observed. 17 Seralutinib was evaluated in two preclinical animal models: the monocrotaline/pneumonectomy (MCTPN) model and the Sugen5416 hypoxia (SU5416/H) model. These models were chosen because they replicate key features of human PAH, including the development of neointimal proliferative lesions in the pulmonary arterioles and severe pulmonary hypertension. In these models, seralutinib reversed pulmonary vascular remodeling, improved hemodynamics by significantly decreasing right ventricular systolic pressure, reducing circulating levels of N-terminal pro b-type natriuretic peptide (NT-proBNP), and increasing lung BMPR2 protein expression compared to controls. 17, 18 Two Phase 1a randomized, double-blind, placebocontrolled studies in healthy volunteers were conducted to determine the safety and tolerability of a range of doses of seralutinib. 19 These single-and multiple-ascending dose studies found that exposure to seralutinib increased in a dose-proportional manner. Seralutinib was rapidly Aberrant PDGFR signaling drives proliferation of smooth muscle cells in the pulmonary arteriolar media and myofibroblasts within the vessel lumen, leading to pulmonary arteriolar medial hypertrophy, neointimal lesions, and fibrosis. c-KIT is expressed on endothelial progenitor cells and mast cells, potentially contributing to perivascular inflammation and vascular remodeling. PDGF can mediate a decrease in BMPR2 and activation of TGFb, which activates proliferative signaling. Perivascular/adventitial CSF1R-positive macrophages secrete PDGF ligands thereby activating PDGF receptors on PASMCs and myofibroblasts and abnormal proliferation of these cells within the diseased pulmonary arterioles. Effects of CSF1R, PDGFR, and c-KIT activation are mediated by multiple intracellular kinases including PI3K, AKT, ERK, and STATs. The interactions between CSF1R, PDGFR, and c-KIT signaling as well as PDGF-mediated decrease in BMPR2 lead to abnormal proliferation of PASMCs, and myofibroblasts within the pulmonary arterioles, and thereby to elevated PVR, a hallmark of pulmonary arterial hypertension (PAH). Seralutinib, by targeting these pathways, has the potential to reverse the abnormal pulmonary vascular remodeling characteristic of PAH. AKT: AK strain transforming (protein kinase B); BMPR2: bone morphogenetic protein receptor type 2; c-KIT: stem cell factor receptor; CSF1R: colony stimulating factor 1 receptor; ERK: extracellular signal-regulated kinase; PAEC: pulmonary arterial endothelial cells; PASMC: pulmonary arterial smooth muscle cells; PDGF: platelet-derived growth factor; PDGFR: platelet-derived growth factor receptor; PI3K: phosphoinositide 3kinase; STATs: signal transducer and activator of transcription; TGFb: transforming growth factor beta.

absorbed into and cleared from the systemic circulation. Doses of seralutinib up to 90 mg (the highest dose tested) twice daily were well tolerated. Preliminary results from a Phase 1b, randomized, double-blind, placebo-controlled multicenter trial (NCT03926793) that assessed seralutinib doses of 45 and 90 mg twice daily in patients with PAH showed similar results. Doses were selected based on allometric scaling and PK/PD modeling. A Phase 2 trial evaluating the efficacy and safety of seralutinib in subjects with WHO Group 1 PH (PAH) (TORREY, NCT04456998) is ongoing and described herein.

The TORREY study is a randomized, double-blind, placebo-controlled trial (NCT04456998) designed to examine the efficacy and safety of inhaled seralutinib in subjects with PAH over a 24-week course of treatment. Rather than being an acronym, TORREY was named for the rare, critically endangered Torrey pine tree (Pinus torreyana) that is native only to San Diego County and immediate environs in

California. This open-crowned pine tree creates and emits oxygen and as such, is symbolic of a life-sustaining resource.

The study will include investigational sites in United States, Canada, Europe, Israel, and Australia. Prior to study initiation, the study protocol, amendments, informed consent forms, and other relevant documents will be reviewed by the institutional review board or independent ethics committee for each site. The study will be conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation-Good Clinical Practice guidelines.

The primary objectives of the TORREY study are to determine the effect of inhaled seralutinib on pulmonary hemodynamics and to assess safety in subjects with WHO Group 1 PH (PAH) who are classified as Functional Class (FC) II or III. The secondary objective is to determine the effect of seralutinib on exercise capacity in this population.

Eighty subjects will be enrolled. Key inclusion and exclusion criteria are summarized in Table 1 . Eligible subjects must have an established diagnosis of WHO group 1 PH (PAH) receiving standard of care background therapies (on stable doses for at least four weeks) and documentation of right heart catheterization (RHC) consistent with a PAH diagnosis, including a mean pulmonary artery pressure (mPAP) !25 mmHg at rest, PVR !400 dyne Á s/cm 5 , and pulmonary capillary wedge pressure (PCWP) or left Fig. 2 . Following informed consent, subjects will be assessed for eligibility during a screening period of up to five weeks in duration. Subjects will be maintained on previously prescribed PAH background therapies. Prostacyclins will be allowed except for those administered by inhalation. Medication regimens should remain stable for the four weeks prior to consent and throughout the screening period. As needed diuretics for intermittent weight gain and/or edema will be allowed.

Eligible subjects will be randomized 1:1 to one of two treatment groups to receive seralutinib twice per day (BID) or matched placebo by dry powder inhaler (Plastiape RS01L, Model 7, Osnago, Italy). Randomization will be stratified by PVR (< and !800 dyne Á s/cm 5 ). Subjects will have periodic study visits to monitor safety, tolerability and for efficacy assessments. Accommodations and other interventions may be implemented as needed due to the COVID-19 pandemic.

The primary and secondary endpoints of the TORREY study are summarized in Table 2 . The primary endpoint is the change from baseline to Week 24 in PVR determined by RHC. The secondary endpoint is the change in distance from baseline to Week 24 achieved on the 6-min walk test (6MWT). 21 Safety will be evaluated throughout the study by determining the incidence of treatment-emergent adverse events, changes in laboratory values, and vital signs. Other exploratory studies may include whole blood gene expression, proteomics, and epigenetic analyses.

In light of serious events of subdural hematoma reported with oral imatinib in the IMPRES trial, 22 the TORREY study will exclude subjects receiving anticoagulation therapy (Table 3 ). In addition, subjects with any history of intracranial hemorrhage will be excluded. An Independent Data Monitoring Committee comprised of external expert physicians and an external biostatistician will regularly monitor emerging efficacy and overall safety data, including potential for bleeding-related events and other adverse events, as well as general aspects of study conduct, to ensure that the benefits and risks to subjects of study participation remain acceptable.

Assuming a mean (SD) treatment effect of 300 (340) dyne Á s/cm 5 in the seralutinib group vs. a treatment effect of 79 (270) dyne Á s/cm 5 in the placebo group 23 , a sample size of 40 subjects per treatment group has approximately 90% power to detect a statistically significant difference between seralutinib and placebo with a ¼ 0.05, two-sided.

Subjects may be eligible to participate in a 72-week openlabel extension (OLE) study provided they have completed study treatment and all associated assessments of the blinded parent study (TORREY) or another seralutinib study. The objectives of this OLE are to investigate the long-term safety/tolerability and efficacy of inhaled (Table 3 ). Subjects will receive seralutinib for up to 18 months. Safety data will be collected from subjects entering the OLE from a blinded parent study (e.g., TORREY) periodically through Week 72. Right heart catheterization will be performed at Week 48 to evaluate ongoing efficacy on PVR.

Two sub-studies are planned in the TORREY protocol and subjects at select sites will be offered the option to participate. These sub-studies will explore novel endpoints relevant to the underlying pathophysiology of the disease. In the functional respiratory imaging study, CT imaging will evaluate the effect of seralutinib on pulmonary vascular remodeling by quantifying changes in pulmonary arterial blood volume. In the heart rate monitoring sub-study, cardiac effort will be measured during the 6MWT. 24

Patients with PAH experience high levels of disease burden resulting in severe impairment of functional status and associated quality of life. 25, 26 The goals of PAH therapy are to improve exercise capacity, decrease the frequency of hospitalization, improve quality of life, and ultimately, prolong survival by reversing disease pathology. 27, 28 Current therapies target three established pathways contributing to pathologic vasoconstriction in PAH: the nitric oxide/cGMP pathway, the endothelin pathway, and the prostacyclin pathway. However, these therapies do not adequately reverse the underlying pathological remodeling and cellular overgrowth that characterize PAH. PAH progression involves multiple pathways of aberrant kinase signaling, including PDGFR, CSF1R, c-KIT as well as BMPR2 deficiency. 2,6-8 Imatinib is an antiproliferative agent developed to target BCR-ABL tyrosine kinase in patients with chronic myeloid leukemia; however, inhibitory effects of imatinib on PDGFRa/b and c-KIT suggested that it might be efficacious in PAH. In the IMPRES study, improvements in exercise capacity and cardiopulmonary hemodynamics were observed in patients treated with imatinib, but serious adverse events limited further development in PAH. 22 Seralutinib is an inhaled small molecule PDGFR/ CSF1R/c-Kit kinase inhibitor that was developed to target these key pathways and, in so doing, may impact the underlying pathological remodeling and cellular overgrowth that characterize PAH. Preclinical models of PAH demonstrated that seralutinib reversed pulmonary vascular remodeling, improved hemodynamic parameters, increased lung BMPR2, and reduced circulating NT-proBNP. 17, 18 In early clinical trials in healthy volunteers and subjects with PAH, seralutinib was well tolerated and demonstrated a pharmacokinetic profile characteristic of an inhaled product.

Seralutinib addresses critical cellular and molecular mechanisms driving vascular remodeling. By targeting inflammatory, proliferative, and fibrotic pathways implicated in PAH, seralutinib has the potential to be a paradigmshifting, disease-modifying therapy in PAH. The primary endpoint of the Phase 2 TORREY study is change in PVR from baseline to Week 24. This physiologic measure is directly relevant to demonstrating a significant effect of seralutinib on the course of disease. The secondary endpoint, change in 6MWD from baseline to Week 24, constitutes an accepted measure of functional improvement. Although the study is not powered to show a significant effect of seralutinib on 6MWD, a trend or directionality of a favorable response could be demonstrated. Other exploratory endpoints are relevant to understanding the potential effect of seralutinib on right heart function, quality of life measures, hospitalization for PAH, time to clinical worsening, and risk score. Other exploratory studies may include whole blood gene expression, proteomics, and epigenetic analyses. The planned sub-studies are designed to explore novel endpoints relevant to pulmonary vascular remodeling and cardiac performance. The Phase 2 TORREY study (NCT04456998) is now enrolling patients with WHO Group 1 PH, FC II or III currently receiving standard of care background therapies.

Cellular and molecular pathobiology of pulmonary arterial hypertension

Plateletderived growth factor up-regulates Ca 2þ -sensing receptors in idiopathic pulmonary arterial hypertension

Kinases as potential targets for treatment of pulmonary hypertension and right ventricular dysfunction

Pulmonary arterial hypertension: the clinical syndrome

Pathobiology of pulmonary arterial hypertension: understanding the roads less travelled

Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension

C-kit-positive cells accumulate in remodeled vessels of idiopathic pulmonary arterial hypertension

Circuit design features of a stable two-cell system

Plexiform lesions in pulmonary arterial hypertension composition, architecture, and microenvironment

Evidence of dysfunction of endothelial progenitors in pulmonary arterial hypertension

CSF-1 receptor signaling in myeloid cells

CCR2/CCR5-mediated macrophage-smooth muscle cell crosstalk in pulmonary hypertension

Cell autonomous and non-cell autonomous regulation of SMC progenitors in pulmonary hypertension

A spatially restricted fibrotic niche in pulmonary fibrosis is sustained by M-CSF/M-CSFR signalling in monocyte-derived alveolar macrophages

Multi-omics analysis reveals regulators of the response to PDGF-BB treatment in pulmonary artery smooth muscle cells

Platelet-derived growth factor b-receptor, transforming growth factor b type I receptor, and CD44 protein modulate each other's signaling and stability

GB002, a novel inhaled PDGFR kinase inhibitor, demonstrates efficacy in the SU5416 hypoxia rat model of PAH

In vivo efficacy of a novel, inhaled PDGFRa/b inhibitor, GB002, in the rat monocrotaline and pneumonectomy model of pulmonary arterial hypertension

Phase 1A randomized double-blind placebo-controlled single-ascending dose and multiple-ascending dose studies of orally inhaled GB002 in healthy adult subjects

Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension

ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test

Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study

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

Heart rate monitoring improves clinical assessment during 6-min walk

Health-related quality of life and survival in pulmonary arterial hypertension

Quality of life as a prognostic marker in pulmonary arterial hypertension

Treatment goals of pulmonary hypertension

The low-risk profile in pulmonary arterial hypertension

The authors gratefully acknowledge Andrea R. Gwosdow, Ph.D. and Jill Luer, PharmD, CMPP, Gossamer Bio, Inc., for medical writing and editorial assistance.

The author(s) disclosed receipt of the following financial support for the research, authorship, and publication of this article: The TORREY study is sponsored and supported by Gossamer Bio, Inc.

Kelly Chin https://orcid.org/0000-0002-1214-6723

All authors made a substantial contribution to the concept or design of the work; or acquisition, analysis or interpretation of data; drafted the article or revised it critically for important intellectual content; approved the version to be published; and participated sufficiently in the work to take public responsibility for appropriate portions of the content. Table 3 . Open-label extension study: objectives and endpoints.

Primary: Evaluate the long-term safety and tolerability of orally inhaled seralutinib Secondary: Evaluate the long-term effect of orally inhaled seralutinib on exercise capacity