Dawn Wilson

A single ascending‐dose study of muscle regulator ace‐031 in healthy volunteers

ACE‐031 is a soluble form of activin receptor type IIB (ActRIIB). ACE‐031 promotes muscle growth by binding to myostatin and other negative regulators of muscle mass.

Multiple‐dose, safety, pharmacokinetic, and pharmacodynamic study of sotatercept (ActRIIA‐IgG1), a novel erythropoietic agent, in healthy postmenopausal women

Ligands of the transforming growth factor‐beta superfamily and activin‐receptor signaling play an important role in erythropoiesis. Sotatercept, an activin receptor type IIA (ActRIIA) ligand trap, is a novel, recombinant, fusion protein comprising the extracellular domain of human ActRIIA linked to the Fc portion of human immunoglobulin G1. Sotatercept, originally developed to increase bone mineral density, was noted to have robust effects on erythropoiesis. Here, we evaluated the safety, pharmacokinetic properties, and pharmacodynamic effects of sotatercept in 31 healthy postmenopausal women. Sotatercept was administered at dose level 0.1, 0.3, or 1 mg/kg every 28 days subcutaneously for up to four doses. Sotatercept was generally safe and well tolerated, and elicited clinically significant, dose‐dependent increases in hemoglobin, hematocrit, and red blood cell counts that persisted for up to 4 months. The effect of sotatercept on hemoglobin was dose‐limiting. Sotatercept also increased bone mineral density and biomarkers of bone formation. The sotatercept serum exposure–dose relationship was linear, with a mean terminal half‐life of approximately 23 days. ActRIIA ligands are important regulators of erythrocyte production in healthy individuals. Clinical studies are ongoing to explore the potential of sotatercept to treat anemia and diseases of ineffective erythropoiesis as well as an agent to increase bone mineral density.

Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Dalantercept, an Activin Receptor–like Kinase-1 Ligand Trap, in Patients with Advanced Cancer

Purpose: The angiogenesis inhibitor dalantercept (formerly ACE-041) is a soluble form of activin receptor–like kinase-1 (ALK1) that prevents activation of endogenous ALK1 by bone morphogenetic protein-9 (BMP9) and BMP10 and exhibits antitumor activity in preclinical models. This first-in-human study of dalantercept evaluated its safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity in adults with advanced solid tumors. Experimental Design: Patients in dose-escalating cohorts received dalantercept subcutaneously at one of seven dose levels (0.1–4.8 mg/kg) every 3 weeks until disease progression. Patients in an expansion cohort received dalantercept at 0.8 or 1.6 mg/kg every 3 weeks until disease progression. Results: In 37 patients receiving dalantercept, the most common treatment-related adverse events were peripheral edema, fatigue, and anemia. Edema and fluid retention were dose-limiting toxicities and responded to diuretic therapy. No clinically significant, treatment-related hypertension, proteinuria, gross hemorrhage, or gastrointestinal perforations were observed. One patient with refractory squamous cell cancer of the head and neck had a partial response, and 13 patients had stable disease according to RECISTv1.1, eight of whom had prolonged periods (≥12 weeks) of stable disease. Correlative pharmacodynamic markers included tumor metabolic activity and tumor blood flow, which decreased from baseline in 63% and 82% of evaluable patients, respectively, and telangiectasia in eight patients. Conclusion: Dalantercept was well-tolerated at doses up to 1.6 mg/kg, with a safety profile distinct from inhibitors of the VEGF pathway. Dalantercept displayed promising antitumor activity in patients with advanced refractory cancer, and multiple phase II studies are underway. Clin Cancer Res; 20(2); 480–9. ©2013 AACR.

A phase 1 study of ACE‐536, a regulator of erythroid differentiation, in healthy volunteers

ACE‐536, a recombinant protein containing a modified activin receptor type IIB, is being developed for the treatment of anemias caused by ineffective erythropoiesis, such as thalassemias and myelodysplastic syndromes. ACE‐536 acts through a mechanism distinct from erythropoiesis‐stimulating agents to promote late‐stage erythroid differentiation by binding to transforming growth factor‐β superfamily ligands and inhibiting signaling through transcription factors Smad 2/3. The goal of this Phase 1 study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of ascending dose levels of ACE‐536 in healthy volunteers. Thirty‐two postmenopausal women were randomized in sequential cohorts of eight subjects each to receive up to two doses of either ACE‐536 (0.0625–0.25 mg/kg) or placebo (3:1 randomization) given subcutaneously every 2 weeks. Mean baseline age was 59.4 years, and hemoglobin was 13.2 g/dL. ACE‐536 was well tolerated at dose levels up to 0.25 mg/kg over the 1‐month treatment period. There were no serious or severe adverse events, nor clinically meaningful changes in safety laboratory measures or vital signs. Mean ACE‐536 AUC0–14d and Cmax increased proportionally after first dose; mean t½ was 15–16 days. Dose‐dependent increases in hemoglobin concentration were observed, beginning 7 days after initiation of treatment and maintained for several weeks following treatment. The proportion of subjects with a hemoglobin increase ≥1.0 g/dL increased in a dose‐dependent manner to 83.3% of subjects in the highest dose group, 0.25 mg/kg. ACE‐536 was well tolerated and resulted in sustained increases in hemoglobin levels in healthy postmenopausal women. Am. J. Hematol. 89:766–770, 2014.

Myostatin inhibitor ACE‐031 treatment of ambulatory boys with Duchenne muscular dystrophy: Results of a randomized, placebo‐controlled clinical trial

Introduction: ACE‐031 is a fusion protein of activin receptor type IIB and IgG1‐Fc, which binds myostatin and related ligands. It aims to disrupt the inhibitory effect on muscle development and provide potential therapy for myopathies like Duchenne muscular dystrophy (DMD). Methods: ACE‐031 was administered subcutaneously every 2–4 weeks to DMD boys in a randomized, double‐blind, placebo‐controlled, ascending‐dose trial. The primary objective was safety evaluation. Secondary objectives included characterization of pharmacokinetics and pharmacodynamics. Results: ACE‐031 was not associated with serious or severe adverse events. The study was stopped after the second dosing regimen due to potential safety concerns of epistaxis and telangiectasias. A trend for maintenance of the 6‐minute walk test (6MWT) distance in the ACE‐031 groups compared with a decline in the placebo group (not statistically significant) was noted, as was a trend for increased lean body mass and bone mineral density (BMD) and reduced fat mass. Conclusion: ACE‐031 use demonstrated trends for pharmacodynamic effects on lean mass, fat mass, BMD, and 6MWT. Non–muscle‐related adverse events contributed to the decision to discontinue the study. Myostatin inhibition is a promising therapeutic approach for DMD. Muscle Nerve 55: 458–464, 2017

A phase 2 study of dalantercept, an activin receptor-like kinase-1 ligand trap, in patients with recurrent or metastatic squamous cell carcinoma of the head and neck.

Patients with platinum‐refractory, recurrent or metastatic squamous cell carcinoma of the head and neck (RM‐SCCHN) have limited options. Activin receptor‐like kinase 1 (ALK1) is a type I receptor of the transforming growth factor β superfamily expressed on activated endothelial cells. Dalantercept is an ALK1 receptor fusion protein that acts as a ligand trap to block signaling through ALK1 and inhibits stages of angiogenesis involved in blood vessel maturation and stabilization. In a phase 1 study, dalantercept demonstrated clinical activity in patients with RM‐SCCHN. The objective of the current study was to evaluate the activity of dalantercept in RM‐SCCHN.

The DART Study: Results from the dose-escalation and expansion cohorts evaluating the combination of dalantercept plus axitinib in advanced renal cell carcinoma

Purpose: Activin receptor-like kinase 1 (ALK1) is a novel target in angiogenesis. Concurrent targeting of ALK1 and VEGF signaling results in augmented inhibition of tumor growth in renal cell carcinoma (RCC) xenograft models. Dalantercept is an ALK1-receptor fusion protein that acts as a ligand trap for bone morphogenetic proteins 9 and 10. The DART Study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of dalantercept plus axitinib in patients with advanced RCC and determined the optimal dose for further testing. Experimental Design: Patients received dalantercept 0.6, 0.9, or 1.2 mg/kg subcutaneously every 3 weeks plus axitinib 5 mg by mouth twice daily until disease progression or intolerance. Results: Twenty-nine patients were enrolled in the dose escalation (n = 15) and expansion (n = 14) cohorts. There were no dose-limiting toxicities or grade 4/5 treatment-related adverse events. In addition to common VEGFR tyrosine kinase inhibitor effects, such as fatigue and diarrhea, commonly seen treatment-related adverse events were peripheral edema, epistaxis, pericardial effusion, and telangiectasia. The objective response rate by RECIST v1.1 was 25% with responses seen at all dose levels. The overall median progression-free survival was 8.3 months. Conclusions: The combination of dalantercept plus axitinib is well tolerated and associated with clinical activity. On the basis of safety and efficacy results, the 0.9 mg/kg dose level was chosen for further study in a randomized phase II trial of dalantercept plus axitinib versus placebo plus axitinib. Clin Cancer Res; 23(14); 3557–65. ©2016 AACR.

Abstract 3276: A Phase 1 dose escalating study with ACE-041, a novel inhibitor of ALK1 mediated angiogenesis, in patients with advanced solid tumors

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Background: Activin receptor-like kinase-1 (ALK1) is a type I receptor predominantly expressed on activated vascular endothelial cells that mediates signaling by members of the TGFs superfamily of proteins. ACE-041, a soluble receptor fusion protein consisting of the extracellular domain of ALK1 linked to the IgG1-Fc region, binds with high affinity to BMP9 and BMP10 but not TGFs1, 2, or 3, VEGF, or bFGF. ACE-041 is able to inhibit both VEGF- and bFGF-stimulated angiogenesis, indicating that ALK1 is downstream of VEGF and bFGF signaling. In a variety of murine tumors, ACE-041 has demonstrated the ability to decrease both tumor vascularity and growth. Methods: The primary objective of this ongoing phase 1 study is to evaluate the safety and tolerability of ACE-041. Secondary objectives include identifying MTD, PK, preliminary activity on PD markers, and antitumor activity by RECIST, PET-CT, and DCE-MRI. Cohorts of 3-6 patients were enrolled at escalating dose levels. Once the MTD has been determined, 12-24 additional patients may be enrolled at the MTD or lower dose levels. ACE-041 is administered SC every 3 weeks for a total of 4 doses or until disease progression. Patients with stable or responding disease may continue treatment for up to 12 months. Results: The dose escalation phase of the study has completed enrollment of 25 patients (13M/12F) at seven dose levels (0.1 to 4.8 mg/kg). An expansion cohort of 12 additional patients at1.6 mg/kg is currently being enrolled. The mean t½ was approximately 13 to 23 days and the mean Tmax was 4 to 7 days. ACE-041 was generally well-tolerated; preliminary data show that common treatment-related AEs included peripheral edema, fatigue, nausea, headache, anorexia, and anemia. Most AEs were Grade 1 or 2. Grade 3 congestive heart failure was reported in one patient as possibly related to drug. Based on preliminary results, stable disease lasting at least 6 cycles was observed in 4 patients having previously progressed on prior therapies. Several patients were noted to have had a positive 18-FDG-PET response with a decrease in metabolic activity approximately 2 weeks following the first dose. Conclusions: ACE-041 is a first-in-class angiogenesis inhibitor that targets the ALK1 pathway. Treatment by subcutaneous injection every 3 weeks has been generally well-tolerated to date and preliminary evidence of antitumor activity has been observed in this ongoing study. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3276. doi:10.1158/1538-7445.AM2011-3276

Locally acting ACE-083 increases muscle volume in healthy volunteers: ACE-083 Increases Muscle Volume

Introduction: ACE‐083 is a locally acting follistatin‐based therapeutic that binds myostatin and other muscle regulators and has been shown to increase muscle mass and force in neuromuscular disease mouse models. This first‐in‐human study examined these effects. Methods: In this phase 1, randomized, double‐blind, placebo‐controlled, dose‐ranging study in healthy postmenopausal women, ACE‐083 (50–200 mg) or placebo was administered unilaterally into rectus femoris (RF) or tibialis anterior (TA) muscles as 1 or 2 doses 3 weeks apart. Results: Fifty‐eight postmenopausal women were enrolled, 42 ACE‐083 and 16 placebo. No serious adverse events (AE), dose‐limiting toxicities, or discontinuations resulting from AEs occurred. Maximum (mean ± SD) increases in RF and TA muscle volume were 14.5% ± 4.5% and 8.9% ± 4.7%, respectively. No significant changes in mean muscle strength were observed. Discussion: ACE‐083 was well tolerated and resulted in significant targeted muscle growth. ACE‐083 may have the potential to increase muscle mass in a wide range of neuromuscular disorders. Muscle Nerve 57: 921–926, 2018

The DASH Study: A phase 1b study of dalantercept plus sorafenib in advanced hepatocellular carcinoma.

TPS495 Background: The activin receptor-like kinase (ALK1) pathway is a novel target in angiogenesis that promotes blood vessel maturation and stabilization. ALK1 binds to the ligand bone morphogenetic protein 9 (BMP9) which is overexpressed in hepatocellular carcinoma (HCC) compared to normal hepatocytes. Dalantercept is an ALK1 receptor fusion protein that binds BMP9 and acts as a ligand trap. Sorafenib, a multi-kinase and vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI), is the standard therapy for advanced HCC. In a preclinical model of HCC, simultaneous blockade of ALK1 and VEGF signaling with dalantercept and sorafenib resulted in additive tumor growth inhibition. In a completed Phase 1 study in thirty-seven subjects with solid tumors, dalantercept monotherapy demonstrated preliminary anti-tumor activity and a safety profile that was generally non-overlapping with VEGFR TKIs. Methods: An open label, multi-center, dose escalating, phase 1b study to evaluate dalanterce...