cibotercept (KER-012) / Keros Therap - LARVOL DELTA

A Study to Investigate the Safety and Efficacy of KER-012 in Combination With Background Therapy in Adult Participants With Pulmonary Arterial Hypertension (PAH) (TROPOS Study). (clinicaltrials.gov) - P2 | N=113 | Completed | Sponsor: Keros Therapeutics, Inc. | Active, not recruiting ➔ Completed

Trial completion • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

The Cibotercept Analog RKER-012 Did Not Inhibit BMP/ALK1-dependent Retinal Neovascularization (ATS 2025) - P2 | "Sotatercept, an activin receptor type IIA ligand trap, is an approved drug for PAH but has been associated with an increased risk of bleeding1. RKER-012 did not alter retinal vessel growth in neonatal mice, a process largely dependent on BMP/ALK1 activation2. This, along with the observed lack of impact on erythrocytosis in preclinical studies and a Phase 1 trial of cibotercept in healthy volunteers, suggests that cibotercept can potentially avoid or reduce bleeding risk. These preclinical findings further support rationale for the ongoing Phase 2 trial of cibotercept in patients with PAH (NCT05975905)."

Age-related Macular Degeneration • Cardiovascular • Hematological Disorders • Pulmonary Arterial Hypertension • Respiratory Diseases • ACVR2A • ALK1

The Cibotercept Analog, RKER-012, Improved Survival in a Pre-clinical Model of Pulmonary Arterial Hypertension (ATS 2025) - P2 | "Treatment with cibotercept analog RKER-012 significantly improved hemodynamics and survival in an MCT-induced rat model of PAH. These results, along with our previously reported preclinical findings demonstrating RKER-012 improved MCT-induced pulmonary vascular and RV remodeling in a pre-clinical model of PAH, suggest that RKER-012 has the potential to improve time to clinical worsening in PAH. These preclinical findings further support rationale for the ongoing Phase 2 TROPOS trial of cibotercept in patients with PAH (NCT05975905)."

Preclinical • Cardiovascular • Congestive Heart Failure • Heart Failure • Pulmonary Arterial Hypertension • Respiratory Diseases • ACVR2A • TGFB1

A Study to Investigate the Safety and Efficacy of KER-012 in Combination With Background Therapy in Adult Participants With Pulmonary Arterial Hypertension (PAH) (TROPOS Study). (clinicaltrials.gov) - P2 | N=113 | Active, not recruiting | Sponsor: Keros Therapeutics, Inc. | Trial completion date: Jan 2027 ➔ Mar 2025 | Trial primary completion date: Jun 2025 ➔ Mar 2025

Trial completion date • Trial primary completion date • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Keros Therapeutics Announces Additional Update on the Phase 2 TROPOS Trial (GlobeNewswire) - "Keros Therapeutics, Inc...today announced that it has voluntarily halted all dosing in the TROPOS trial, a Phase 2 clinical trial of cibotercept (KER-012) in combination with background therapy in patients with pulmonary arterial hypertension ('PAH'), including the 1.5 mg/kg and placebo treatment arms, based on the ongoing safety review due to new observations of pericardial effusion adverse events...The TROPOS trial is being terminated early, and patients are expected to be monitored through the end-of-trial visits. The Company continues to expect to present topline data from all treatment arms in this trial in the second quarter of 2025."

P2 data • Trial termination • Pulmonary Arterial Hypertension

RKER-012, A Novel Modified ActRIIB Ligand Trap, Reversed Experimental Pulmonary Arterial Hypertension (AHA 2024) - P2 | "Treatment with RKER-012 reversed increased RVSP, RV hypertrophy pulmonary vascular remodeling and restored RV geometry in MCT-induced experimental PAH, suggesting potentially translatable benefit for patients with PAH. These preclinical findings further support the rationale for the ongoing Phase 2 TROPOS trial in patients with PAH (NCT05975905).1 PMID:17496210"

Late-breaking abstract • Cardiovascular • Pulmonary Arterial Hypertension • Respiratory Diseases • ACVR2A • TGFB1

A Study to Investigate the Safety and Efficacy of KER-012 in Combination With Background Therapy in Adult Participants With Pulmonary Arterial Hypertension (PAH) (TROPOS Study). (clinicaltrials.gov) - P2 | N=90 | Active, not recruiting | Sponsor: Keros Therapeutics, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Pulmonary Arterial Hypertension and TGF-β Superfamily Signaling: Focus on Sotatercept. (PubMed, BioDrugs) - "Here, we review the currently available PAH therapies, data highlighting the importance of transforming growth factor-β (TGF-β) superfamily signaling in the development of PAH, and the published and on-going clinical trials evaluating sotatercept in the treatment of PAH. We will also discuss preclinical data supporting the potential use of the fusion protein KER-012 in the inhibition of aberrant TGF-β superfamily signaling to ameliorate the obstructive vasculopathy of PAH."

Journal • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • TGFB1

A Phase 2, Open-label, Single-arm Study to Evaluate the Tolerability, Safety, and Pharmacodynamic Effects of KER-012 in Participants with Chronic Heart Failure. (ANZCTR) - P2 | N=12 | Withdrawn | Sponsor: Keros Therapeutics, Inc. | Not yet recruiting ➔ Withdrawn

Trial withdrawal • Cardiovascular • Congestive Heart Failure • Heart Failure

A Study to Evaluate the Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Effects of KER-012 Administered to Healthy, Postmenopausal Women (ANZCTR) - P1 | N=80 | Completed | Sponsor: Keros Therapeutics, Inc. | Active, not recruiting ➔ Completed

Trial completion

RKER-012, A Novel Modified ActRIIB Ligand Trap, Reduced Pulmonary Vascular Pathology in a Rat Model of Pulmonary Arterial Hypertension Through Attenuation of TGFb Family Autocrine/Paracrine Signaling Within the Vasculature (ATS 2024) - "Future studies will aim to investigate the ability of RKER-012 to attenuate the response of HPASMCs to both ligands. Word Count: 389/400"

Preclinical • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Hypertension • Immunology • Inflammation • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • ACVR2A • COL1A1 • CTGF • TGFB1 • TGFB2

DEVELOPMENT OF KER-012, AN INVESTIGATIONAL MODIFIED ACTRIIB LIGAND TRAP, FOR THE TREATMENT OF CHRONIC HEART FAILURE: TRANSLATION OF PRECLINICAL FINDINGS TO HUMAN BIOMARKERS OF CARDIAC DYSFUNCTION AND HEART FAILURE (ACC 2024) - "A single 4.5 mg/kg dose of KER-012 resulted in altered expression of proteins that may potentially be beneficial in the context of HF. These data, along with the favorable safety and tolerability profile observed in the Phase 1 trial, provided the rationale for the ongoing trial of KER-012 in patients with HF with preserved or reduced ejection fraction."

Preclinical • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology • Inflammation • ACVR2A • IL4 • IL6 • TGFB1

A Phase 2, Open-label, Single-arm Study to Evaluate the Tolerability, Safety, and Pharmacodynamic Effects of KER-012 in Participants with Chronic Heart Failure. (ANZCTR) - P2 | N=12 | Not yet recruiting | Sponsor: Keros Therapeutics, Inc.

New P2 trial • Cardiovascular • Congestive Heart Failure • Heart Failure

A Study to Investigate the Safety and Efficacy of KER-012 in Combination With Background Therapy in Adult Participants With Pulmonary Arterial Hypertension (PAH) (TROPOS Study). (clinicaltrials.gov) - P2 | N=90 | Recruiting | Sponsor: Keros Therapeutics, Inc. | Initiation date: Jun 2023 ➔ Oct 2023

Combination therapy • Trial initiation date • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Improvement in Cardiopulmonary Function in a Rat Model of Pulmonary Arterial Hypertension Observed With RKER-012, a Novel Activin Receptor Type II Ligand Trap, was Associated With Reduced Markers of Inflammation and Fibrosis in the Right Ventricle (AHA 2022) - "CD68 expression was reduced in SH-RKER-012 (p≤0.01) compared to NX but MCP1 expression was not affected (p=0.54). These results support that RKER-012 attenuated upregulation of key inflammation and fibrosis markers in a PAH preclinical model and suggest that KER-012 has a distinct mechanism from vasodilation and could be developed as a cardioprotective treatment for PAH."

Preclinical • Cardiovascular • Congestive Heart Failure • Fibrosis • Hypertension • Immunology • Inflammation • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • ACVR2A • CD68 • COL1A1 • COL3A1 • RUNX2 • TIMP1

A Study to Investigate the Safety and Efficacy of KER-012 in Combination With Background Therapy in Adult Participants With Pulmonary Arterial Hypertension (PAH) (TROPOS). (clinicaltrials.gov) - P2 | N=90 | Recruiting | Sponsor: Keros Therapeutics, Inc.

Combination therapy • New P2 trial • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

RKER-012, a Novel Activin Receptor Type IIB (ActRIIB) Ligand Trap, Inhibited Mediators of Dysregulated Vascular Remodeling in Pulmonary Endothelial and Smooth Muscle Cells (ATS 2023) - "KER-012 treatment reduced TGF-β superfamily-mediated SMAD2/3 activation in pulmonary ECs and SMCs, two major cell types contributing to vascular remodeling in PAH. RKER-012 ActA inhibition restored homeostatic pSMAD in an in vitro model replicating hypoxia in PAH."

Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • ACVR2A • INHBA • INHBB • TGFB1

RKER-012, a Novel Modified Actrii Ligand Trap, Attenuated Cardiac Remodeling and Fibrosis in a Transverse Aortic Constriction Model of Heart Failure (ATS 2023) - "CONCLUSIONS These results demonstrate that administration of RKER-012 in this preclinical animal model can lessen the severity of cardiac fibrosis and remodeling, leading to improvement in left ventricular function. Additionally, this was seen in D1 and D14 treatment groups suggesting benefit when administered both as a preventative or treatment, and could potentially provide meaningful benefit in HF patients."

Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology • Inflammation • ACVR2A • TGFB1

Administration of KER-012, a Modified Activin Receptor IIB Ligand Trap, Led to Changes in Biomarkers of Cardiovascular Health in a Ph1 Study Conducted in Healthy Post-Menopausal Women (ATS 2023) - "Approximately 50% of FSH release is controlled by activin signaling; therefore, complete inhibition of activin signaling could be expected to reduce FSH by half. KER-012 resulted in changes in FSH in both SAD and MAD. In the MAD, maximal FSH suppression was observed at the 4.5 mg/kg dose level with 5 of 6 subjects achieving ≥ 40% reduction in FSH."

Biomarker • Clinical • Cardiovascular • Developmental Disorders • Heart Failure • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • ACVR2A • TGFB1

RKER-012 Therapy Prevented Increased Pulmonary Arterial Pressure and Right Ventricle Hypertrophy in a Rat Model of PAH (ATS 2022) - "These results support that RKER-012 prevented increased sPAP, FI, and expression of markers of inflammation, fibrosis, and HF without affecting RBCs in a rat PAH model. These results provide early evidence that KER-012 has the potential to treat human PAH without a potentially dose-limiting RBC effect."

Late-breaking abstract • Preclinical • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology • Inflammation • ACVR2A

[VIRTUAL] KER-012, a Novel Modified ActrII Ligand Trap, Attenuated Cardiac Pathology in a Pulmonary Arterial Banding Model of Right Ventricle Overload (AHA 2021) - "Treated mice also had reduced cardiac fibrotic tissue (-38.9%, p<0.01). Taken together, these data provide evidence that KER-012 has the potential to reduce cardiac remodeling and improve cardiac performance in pathologies involving constricted pulmonary arterial blood flow and could provide benefit in diseases such as PAH."

Fibrosis • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • ACVR2A • SMAD2

A Study to Evaluate the Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Effects of KER-012 Administered to Healthy, Postmenopausal Women (ANZCTR) - P1; N=80; Not yet recruiting ➔ Recruiting; Sponsor: Keros Therapeutics

Clinical • Enrollment status