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Published: 9 March 2023

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1

Abdulkadyrov, Kudrat M., Galina N. Salogub, Nuriet K. Khuazheva, Rachel Woolf, Eric Haltom, Niels G. Borgstein, Robert Knight, Gary Renshaw, Yijun Yang, and Matthew L. Sherman. "ACE-011, a Soluble Activin Receptor Type Iia IgG-Fc Fusion Protein, Increases Hemoglobin (Hb) and Improves Bone Lesions in Multiple Myeloma Patients Receiving Myelosuppressive Chemotherapy: Preliminary Analysis." Blood 114, no. 22 (November 20, 2009): 749. http://dx.doi.org/10.1182/blood.v114.22.749.749.

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Abstract Abstract 749 Background: Anemia is frequently observed in multiple myeloma (MM) patients and can result from cumulative marrow suppression by chemotherapy, invasion of bone marrow by tumor cells, renal insufficiency and other causes. The vast majority of therapies approved or in development for anemia target the erythropoietin (EPO) pathway. However, recent studies suggest that the use of recombinant EPO and its derivatives may be associated with an increased risk of mortality by stimulating tumor progression and/or the occurrence of thromboembolic events. The TGF-β superfamily of proteins has been reported to play a major role in red blood cell (RBC) development, but utilizes a fundamentally different pathway from EPO. ACE-011 is a novel, fully human, fusion protein derived from the activin receptor type IIA (ActRIIA) that binds to and prevents signaling of certain members of the TGF-β superfamily through the ActRIIA receptor. In animal studies, administration of ACE-011 has been shown to increase hemoglobin and RBC levels, promote bone formation, and inhibit breast cancer and MM tumor growth. We previously reported significant increases of hemoglobin, RBC levels, and bone mineral density observed in healthy volunteers who received ACE-011 (ASH, 2008). Here, we report the preliminary results of a randomized, double-blind, placebo-controlled study of ACE-011 in MM patients receiving a regimen of melphalan, prednisolone, and thalidomide (MPT). Methods: Patients with stage II/III multiple myeloma and evidence of osteolytic bone disease were eligible to be enrolled in this study, and randomized to receive either up to 4 monthly subcutaneous (SC) doses of ACE-011 at 0.1, 0.3 and 0.5 mg/kg (n=8 each) or placebo (n=6). All patients received a standardized regimen of MPT. Patients could not have received ESAs ≤ 21 days prior to initiation or during the course of study; bisphosphonate (BP) use was allowed only as a continuation of established therapy at stable doses (≥ 2 months). Results: A total of 30 patients were enrolled. The median age was 61.5 years (ranging from 41 to 79 years). Twenty-eight patients had at least one prior MM therapy (range 1-7 prior therapies), and 13 were on stable BPs. A total of 20 patients skipped at least one dose of ACE-011 or placebo based on dose modification rules. Two patients discontinued study drug prematurely: 1 withdrew consent and 1 due to an adverse event. An SAE of sudden death, cause unknown and considered “probably”-related to MPT or “possibly”-related to ACE-011, occurred 18 days after the last dose of ACE-011 (0.1 mg/kg). Dose-dependent increases in hemoglobin were observed after the first dose of ACE-011. After the first dose, the mean maximum Hb increase was 1.3 g/dL (±1.1) in the 0.5 mg/kg cohort compared to 0.68 g/dL (±0.29) in the placebo group. On day 29 of the study, 75% patients had an increase in Hb of ≥1 g/dL in the 0.5 mg/kg cohort compared to 33% in placebo group. A hemoglobin response defined as an increase of at least 1.5 g/dL increase for consecutive 28 days during study was achieved by 10 (45%) ACE-011 treated patients and 1 (17%) patient on placebo. ACE-011 substantially increased BSAP and slightly decreased S-CTX levels among BP-naïve patients. After the first dose of ACE-011, 6 patients (20%) were reported to have ≥10 mm reduction in pain, as measured by the Visual Analog Scale (VAS), which was sustained during the study. A greater trend to improvement in osteolytic lesions by skeletal X-rays was seen in ACE-011-treated patients. Of 22 evaluable patients treated with ACE-011, 7 patients (32%) achieved a CR or VGPR. Conclusions: ACE-011 is well-tolerated and has significant hematologic activity in MM patients receiving myelosuppressive chemotherapy. ACE-011 treatment also demonstrated clinically significant increases in biomarkers of bone formation, improvement in skeletal metastases, decreases in bone pain, and anti-tumor activity. The unique pharmacology of ACE-011 enables it to address multiple complications of MM, and presents a novel target to treat the underlying disease as well. These findings also demonstrate that ACE-011 has potential as a novel therapy for chemotherapy-induced anemia and may be an effective alternative to EPO-based treatments. To further explore the potential of this novel agent, a phase 2 study investigating ACE-011 in metastatic breast cancer patients with chemotherapy-induced anemia is currently underway. This study was supported in part by a grant from the Multiple Myeloma Research Foundation. Disclosures: Abdulkadyrov: Acceleron: Research Funding. Salogub:Acceleron: Research Funding. Khuazheva:Acceleron: Research Funding. Woolf:Acceleron: Employment, Equity Ownership. Haltom:Acceleron: Employment, Equity Ownership. Borgstein:Acceleron: Employment, Equity Ownership. Knight:Celgene: Employment, Equity Ownership. Renshaw:Celgene: Employment, Equity Ownership. Yang:Acceleron: Employment, Equity Ownership. Sherman:Acceleron: Employment, Equity Ownership.
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2

Kim, Kenneth T., Niels G. Borgstein, Yijun Yang, Eric Haltom, Louisa Mook, Michelle D. Ababa, Sandeep K. Reddy, and Matthew Leigh Sherman. "ACE-011, a Soluble Activin Receptor Type IIa IgG-Fc Fusion Protein, Increases Hemoglobin and Hematocrit Levels in Postmenopausal Healthy Women." Blood 112, no. 11 (November 16, 2008): 3866. http://dx.doi.org/10.1182/blood.v112.11.3866.3866.

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Abstract ACE-011 is a soluble fusion protein consisting of the extracellular domain of activin receptor IIA linked to the Fc portion of human IgG1 and is a potent activin antagonist. ACE-011 is currently in clinical development for the treatment of bone loss in a variety of disease indications. In addition to its effect on bone forming cells, activin is also known as erythroid differentiation factor (EDF) and has been reported to have proerythrocytic effects and induced terminal differentiation of red blood cells (RBC). In preclinical studies, ACE-011 administration to mice and cynomolgus monkeys is associated with increases in erythropoiesis. A randomized, double-blind, placebo-controlled, multiple-dose, dose-escalation study was conducted in healthy postmenopausal women to evaluate the safety, tolerability and pharmacodynamics of ACE-011 in 4 cohorts of 10 subjects (8 active: 2 placebo). Subjects were to receive 4 monthly doses of ACE-011 at 0.1, 0.3, 1.0 and 2.0 mg/kg or placebo by subcutaneous (SC) route of administration and followed up for 3 months. Safety evaluations were conducted on each cohort prior to dose escalation. A total of 31 subjects received at least one dose of ACE-011 or placebo; 9 subjects in cohort 1 (0.1 mg/kg) received all 4 doses, 10 subjects in cohort 2 (0.3 mg/kg) received 3 doses and 9 subjects in cohort 3 (1 mg/kg) received 2 doses of either ACE-011 or placebo. A dose and time dependent increase in hemoglobin values was observed in all treatment groups; these elevations were statistically significant in the 0.3 and 1.0 mg/kg cohorts. A maximum tolerated dose level was determined to be 1 mg/kg after one subject experienced progressive and persistent hypertension that was attributed to a rapid and significant rise in hemoglobin levels approximately 1 week following her second dose of ACE-011. Increases in hemoglobin and hematocrit represent the dose limiting pharmacodynamic effects of ACE-011, and further dose escalation to the 2 mg/kg dose was suspended. These effects were seen in the red cell lineage; no significant effects on white blood cells or platelets were observed. JAK2 kinase activity was measured in 3 subjects with elevated hemoglobin levels after ACE-011 treatment and was negative. Preliminary analysis of the data, 29 days after the administration of the first dose, is shown below. Δ Hemoglobin (g/dL) from baseline Placebo (n=7) 0.1 mg/kg (n=8) 0.3 mg/kg (n=8) 1 mg/kg (n=8) * p<0.05, ** p<0.01 compared to placebo Day 8 Mean (SD) 0.171 (0.399) 0.675 (0.403) 0.85 (0.563)* 1.213 (0.506)** Median 0.3 0.65 0.75 1.25 Min, Max −0.3, 0.7 0.20, 1.2 0.2, 1.6 0.4, 2.0 Day 15 Mean (SD) −0.35 (0.695) 0.425 (0.413) 0.438 (0.912)* 1.75 (0.685)** Median −0.55 0.6 0.3 1.5 Min, Max −1.1, 0.8 −0.3, 0.9 −0.6, 2.4 0.9, 3.1 Day 29 Mean (SD) 0.34 (0.207) 0.613 (0.323) 1.212 (0.909) * 2.675 (0.997)** Median 0.4 0.7 1.15 2.45 Min, Max 0, 0.5 −0.1, 1.0 0.1, 2.8 1.7, 4.4 In one of the subjects with a history of chronic anemia, as a result of iron deficiency, the hemoglobin level increased by almost 2 g/dL from a baseline value of 8.4 g/dL following the first SC dose of 1 mg/kg ACE-011, and reached a level of 11 g/dL within 3 weeks after the second dose of ACE-011. ACE-011 was generally well tolerated, except for the case described above with uncontrolled hypertension at the 1 mg/kg dose level. The majority of the non-hematological treatment-emergent adverse events were mild in severity and not related to study drug. A dose-dependent decrease in serum FSH levels, a biological marker of activin inhibition, was also observed in postmenopausal subjects following treatment with ACE-011. These data indicate that ACE-011 is associated with increases in hemoglobin and hematocrit levels in both healthy volunteers as well as in a subject with iron deficiency anemia and may be a potential novel agent for the treatment of patients with impaired erythropoiesis.
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3

Bose, Prithviraj, Naveen Pemmaraju, Lucia Masarova, Sharon D. Bledsoe, Naval Daver, Elias Jabbour, Tapan M. Kadia, et al. "Sotatercept (ACE-011) for Anemia of Myelofibrosis: A Phase 2 Study." Blood 136, Supplement 1 (November 5, 2020): 10–11. http://dx.doi.org/10.1182/blood-2020-140441.

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Background Anemia is common in patients (pts) with myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF). Furthermore, anemia is an on-target effect of therapeutic Janus kinase 2 (JAK2) inhibition, and may be the most frequent cause of ruxolitinib (rux) discontinuation (d/c) in clinical practice (Kuykendall, Ann Hematol 2018). Current therapies for anemia of MF (erythropoietin and analogs, danazol, IMiDs®) are unsatisfactory. Sotatercept (ACE-011) is a first-in-class, activin receptor type IIA ligand trap that may improve anemia by sequestering stromal transforming growth factor beta superfamily ligands that suppress terminal erythropoiesis (Iancu-Rubin, Exp Hematol 2013). Methods This is a phase 2, investigator-initiated, open-label, single institution study of sotatercept, administered subcutaneously every 3 weeks, in 2 cohorts of anemic pts (Hgb &lt;10 g/dl on every determination for 12 weeks (wks) or transfusion-dependent (TD) per IWG-MRT criteria (Tefferi, Blood 2013)) with MF: as a single agent, and in combination with a stable dose of rux. Pts on rux must have been on rux for ≥6 months with a stable dose for ≥8 weeks, and receive sotatercept at a dose of 0.75 mg/kg. Monotherapy pts receive either 0.75 or 1 mg/kg of sotatercept. In both cohorts, anemia response is defined as achievement of transfusion independence (TI) in TD pts, and an increase in Hgb level from baseline of ≥1.5 g/dl sustained for ≥12 wks in non-TD pts (Gale, Leuk Res 2011). Pts must have received ≥5 cycles of sotatercept to be response-evaluable. Results A total of 53 pts have been treated; one pt received only 0.3 mg/kg of sotatercept and is not considered further. Thirty one pts received sotatercept alone and 21 in combination with rux. Baseline characteristics appear in Table 1, panel A. Sixteen TD and 15 non-TD pts received sotatercept alone for a median of 5 (1-67) cycles. Thirteen pts received 0.75 mg/kg and 18, 1 mg/kg. Seven of 24 (29%) evaluable pts responded. Of these, 4 were anemia responses; 3 TD pts achieved TI. Five responses occurred at the 0.75 mg/kg dose, and 2 at the 1 mg/kg dose. Median time to response (TTR) was 21 (1-22) days and median duration of response (DOR) 13 (3.9-56.4) months. Seven pts (22.6%) received &lt;5 cycles and were not response-evaluable: 2 proceeded to stem cell transplant (SCT), 2 had logistical (travel) issues, and 1 each d/ced sotatercept because of hypertension (HTN), unrelated medical problems and pt decision. Three pts continue on study. Reasons for d/c included no response (11), progressive MF (6), SCT (3), travel logistics (3), patient decision (2), hypertension (1), unrelated medical complications (1) and transformation to AML (1). The combination cohort comprised 15 non-TD pts and 6 TD pts. The median number of cycles was 8 (2-43). Five of 17 (29%) evaluable pts in the combination cohort responded, all non-TD pts. Median TTR was 14 (7-147) days and median DOR 34.6 (3.1-47.9) months. Four pts (19%) received &lt;5 cycles and were not response-evaluable, 1 each due to MF progression, loss of insurance, SCT and pt decision. Five pts remain on study. Reasons for d/c included no response (6), SCT (4), progressive MF (2), travel logistics (2), loss of insurance (1) and pt decision (1). Several non-response-evaluable pts in both cohorts achieved ≥1.5 g/dl increments in Hgb from baseline that were not sustained for ≥12 wks because of early d/c of sotatercept. An additional pt in the combination cohort required a rux dose increase, leading to failure to sustain a ≥1.5 g/dl Hgb improvement. Across both cohorts, several responding pts required multiple protocol-specified drug holidays because of Hgb levels ≥11.5 g/dl, with resumption of sotatercept once Hgb was &lt;11 g/dl. Sotatercept was well-tolerated (Table 1, panel B). Grade 3 adverse events possibly related to sotatercept were HTN (n=7), limb (bone/muscle/joint) pain (n=3) and headache (1). Conclusions Sotatercept is safe and effective against anemia of MPN-associated MF, both in non-TD and TD pts, with a response rate of 29% both when used alone and in conjunction with a stable dose of rux. A total of 60 pts are planned to be treated on this trial (NCT01712308). Disclosures Bose: Blueprint Medicines Corporation: Honoraria, Research Funding; NS Pharma: Research Funding; Constellation Pharmaceuticals: Research Funding; Astellas Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene Corporation: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Promedior, Inc.: Research Funding; Kartos Therapeutics: Honoraria, Research Funding. Pemmaraju:Samus Therapeutics: Research Funding; AbbVie: Honoraria, Research Funding; MustangBio: Honoraria; SagerStrong Foundation: Other: Grant Support; Roche Diagnostics: Honoraria; Pacylex Pharmaceuticals: Consultancy; Plexxikon: Research Funding; Daiichi Sankyo: Research Funding; Stemline Therapeutics: Honoraria, Research Funding; Celgene: Honoraria; Incyte Corporation: Honoraria; Cellectis: Research Funding; Blueprint Medicines: Honoraria; Affymetrix: Other: Grant Support, Research Funding; Novartis: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; DAVA Oncology: Honoraria. Daver:Fate Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jabbour:BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding. Kadia:Astellas: Research Funding; Pulmotec: Research Funding; Incyte: Research Funding; Ascentage: Research Funding; JAZZ: Honoraria, Research Funding; Cyclacel: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Cellenkos: Research Funding; Genentech: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria; Abbvie: Honoraria, Research Funding; Astra Zeneca: Research Funding. Andreeff:Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Amgen: Research Funding; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees. Cortes:Bristol-Myers Squibb: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sun Pharma: Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Telios: Research Funding; Astellas: Research Funding; Amphivena Therapeutics: Research Funding; Arog: Research Funding; BiolineRx: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Research Funding; Immunogen: Research Funding; Novartis: Consultancy, Research Funding. Jain:BMS: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aprea Therapeutics: Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. Borthakur:Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; PTC Therapeutics: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Polaris: Research Funding; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Curio Science LLC: Consultancy; FTC Therapeutics: Consultancy; Argenx: Consultancy; PTC Therapeutics: Consultancy; BioLine Rx: Consultancy; BioTherix: Consultancy; Cyclacel: Research Funding; GSK: Research Funding; BioLine Rx: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding. Alvarado:Sun Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Tolero Pharmaceuticals: Research Funding; FibroGen: Research Funding; Jazz Pharmaceuticals: Research Funding; BerGenBio ASA: Research Funding. Huynh-Lu:Incyte Corporation: Speakers Bureau. Nguyen-Cao:Incyte Corporation: Speakers Bureau. Garcia-Manero:Acceleron Pharmaceuticals: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Novartis: Research Funding; Onconova: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; AbbVie: Honoraria, Research Funding; H3 Biomedicine: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amphivena Therapeutics: Research Funding. Kantarjian:Oxford Biomedical: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Delta Fly: Honoraria; Janssen: Honoraria; Ascentage: Research Funding; BioAscend: Honoraria; Amgen: Honoraria, Research Funding; Aptitute Health: Honoraria; Immunogen: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; BMS: Research Funding; Adaptive biotechnologies: Honoraria; Abbvie: Honoraria, Research Funding. Verstovsek:Sierra Oncology: Consultancy, Research Funding; Gilead: Research Funding; Celgene: Consultancy, Research Funding; CTI Biopharma Corp: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Novartis: Consultancy, Research Funding; AstraZeneca: Research Funding; ItalPharma: Research Funding; Protagonist Therapeutics: Research Funding; PharmaEssentia: Research Funding; Incyte Corporation: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; Genentech: Research Funding.
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4

Bose, P., N. Pemmaraju, N. Daver, E. Jabbour, S. Bledsoe, T. Kadia, Z. Estrov, et al. "S829 SOTATERCEPT (ACE-011) IN SUBJECTS WITH MPN-ASSOCIATED MYELOFIBROSIS AND ANEMIA." HemaSphere 3, S1 (June 2019): 367–68. http://dx.doi.org/10.1097/01.hs9.0000561596.81498.79.

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Garbowski, Maciej W., Olivier Hermine, Maria Domenica Cappellini, Raffaella Origa, Gian Luca Forni, Ersi Voskaridou, Frédéric Galactéros, et al. "GDF15 and Erythroferrone Mark Erythropoietic Response to ACE-011 (Sotatercept) in Thalassemia." Blood 132, Supplement 1 (November 29, 2018): 3633. http://dx.doi.org/10.1182/blood-2018-99-111770.

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Abstract Background The hemoglobin (Hb) response to the activin receptor type IIA ligand trap ACE-011 (Sotatercept) in non-transfusion-dependent thalassemia (NTDT), and the transfusion requirement response in TDT are described, but the mechanisms of action, clinical predictors and markers of response, are unclear. In principle, ACE-011 may act on early and/or late erythroblasts to decrease ineffective erythropoiesis (IE), both in healthy subjects and in thalassemia. As erythropoiesis intimately links to iron metabolism, changes in markers of iron metabolism relative to those of erythropoiesis may inform the mechanisms and developmental stage at which ACE-011 acts. Methods Markers of IE and iron metabolism in 46 thalassemia patients (30 NTDT, 16 TDT) were taken before and during a median follow up of 722.5 days, (IQR 830.5, range 152-1427) of escalating doses of ACE-011 (3-weekly 0.1 to 1.0 mg/kg s.c. injections), depending on the protocol, as part of the approved study (Cappellini, et al. 2018 under review). Markers of erythropoiesis included Hb, Reticulocytes (Ret), soluble transferrin receptor 1 (sTfR), growth differentiation factor 11 and 15 (GDF11, GDF15), erythroferrone (ERFE). Markers of iron metabolism included plasma hepcidin, serum ferritin (SF), transferrin saturation (TSAT), and non-transferrin-bound iron (NTBI). Data were analyzed using longitudinal multilevel model for change (LMMC) on STATA (Version 14) as generalized linear mixed model with random and fixed effects to account for repeated measures and highly complex temporal data structure. Final LMMCs were built to explain the change in Hb from baseline and the behavior of key biomarkers. Independent variables were entered into the models based on the study design (predictors from design) and theoretical background (predictors of interest and control variables). P value <0.05 was considered statistically significant. Results Predictors of response. In NTDT, Hb response associated positively with dose and duration of exposure (both at p<0.0001), and negatively with baseline EPO (p=0.002), GDF15 (p<0.0001) or TSAT. In TDT, accounting for transfusion effect, baseline GDF15 and EPO positively predicted Hb response while ERFE was a negative predictor (all at p<0.0001). Biomarker changes with time In NTDT, significant changes with time on study were increases in Hb, sTfR, ERFE and Ret and decreases in hepcidin, bilirubin, and NTBI. GDF15 showed no change. In TDT, GDF15, sTfR and ERFE increased, whereas hepcidin decreased. The Hb change was insignificant in TDT (as expected per protocol) and was dose-independent, however the mean 41% reduction in transfusion iron load rate (ILR) was dose dependent, implying an equivalent net production of Hb in TDT (Table 1). Other significant relationships Absolute hepcidin level in NTDT and TDT was negatively predicted by ERFE (p<0.0001): the first longitudinal demonstration of this association in thalassemia patients. GDF11, the target for ACE-011 that was shown previously to negatively regulate erythroid differentiation (Dussiot et al, Nat Med 2014), fell significantly on study (preliminary data). Significant reduction in indirect bilirubin in NTDT, implying reduced hemolysis, suggests improved quality of produced erythrocytes. Interpretation and conclusions NTDT patients allow a cleaner interpretation of biomarker changes as these are confounded in TDT by increased bone marrow stress from less transfusion. In NTDT, sTfR and ERFE (total erythropoiesis) increase on study while GDF15 (IE) and EPO do not. Thus Hb gain may result from increased effectiveness of late stage erythropoiesis (sTfR+ and ERFE+) possibly from decreased apoptosis and more rapid maturation (Carrancio et al, BJH 2014) in this compartment. We speculate that increased survival of those erythroid progenitor cells expressing TfR (and hence sTfR) and ERFE (hence increased ERFE) also explains the observed hepcidin reduction. Despite exposure to lower hepcidin, there is no iron loading: NTBI falls against stable SF in NTDT, consistent with shunting of iron into the sink of effective erythropoiesis. The reduction in GDF11 in vivo, not previously reported for ACE-011, is also consistent with increased apoptosis of the early progenitor pool and with improved erythroblast differentiation relative to proliferation as suggested in murine β-thalassemia treated with ACE-011 (Dussiot, et al. Nat Med 2014). Disclosures Garbowski: Vifor: Consultancy. Hermine:Erythec: Research Funding; AB Science: Consultancy, Equity Ownership, Honoraria, Research Funding; Celgene Corporation: Research Funding; Hybrigenics: Research Funding; Novartis: Research Funding. Cappellini:Sanofi/Genzyme: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Vifor: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Origa:Bluebird Bio: Consultancy; Novartis: Honoraria; Cerus Corporation: Research Funding; Apopharma: Honoraria. Forni:Celgene: Research Funding; Novartis: Other: travel expenses, Research Funding; Shire: Research Funding; Roche: Consultancy; Apopharma: Other: DSM Board. Voskaridou:Acceleron: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding. Galactéros:Addmedica: Other: grant; Novartis: Other: grant. Taher:Novartis: Consultancy, Honoraria, Research Funding; La Jolla Pharmaceutical: Research Funding; Protagonist Therapeutics: Consultancy; Celgene Corp.: Research Funding; Ionis Pharmaceuticals: Consultancy. Ribeil:bluebird bio: Consultancy; Vitalaire: Other: grant; Addmedica: Other: grant; Cydan: Consultancy; Novartis: Consultancy. Laadem:Celgene: Employment, Equity Ownership. Miteva:Celgene Corporation: Employment, Other: grants. Zou:Celgene Corporation: Employment, Equity Ownership. Zinger:Celgene Corporation: Employment. Schwickart:Celgene Corporation: Employment, Equity Ownership. Sung:Celgene Corporation: Employment, Equity Ownership. Porter:Novartis: Consultancy; Cerus: Honoraria; Agios: Honoraria.
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Bose, Prithviraj, Naval Daver, Elias J. Jabbour, Allison Pike, Kate J. Newberry, Lingsha Zhou, Sherry Pierce, Xuemei Wang, Hagop M. Kantarjian, and Srdan Verstovsek. "Phase-2 Study of Sotatercept (ACE-011) in Myeloproliferative Neoplasm-Associated Myelofibrosis and Anemia." Blood 128, no. 22 (December 2, 2016): 478. http://dx.doi.org/10.1182/blood.v128.22.478.478.

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Abstract Introduction: Anemia is common in MPN-associated myelofibrosis (MF), and current therapies (e.g., erythropoiesis stimulating agents, androgens, danazol, immune modulatory drugs and corticosteroids) are unsatisfactory. Furthermore, anemia is not improved and initially worsened by ruxolitinib, an important MF therapy. New drugs with novel mechanisms of action are needed. Sotatercept is a first-in-class activin receptor type IIA (ActRIIA) ligand trap consisting of the extracellular domain of ActIIRA linked to the human IgG1 Fc domain. Sotatercept binds to and sequesters ligands of the transforming growth factor beta (TGF-ß) superfamily, thus relieving their blockade of terminal erythroid differentiation. Pre-clinically, sotatercept corrects ineffective erythropoiesis in ß-thalassemia (Dussiot, M. et al. Nat Med 2014) and its murine ortholog RAP-011 improves erythropoiesis in Diamond Blackfan anemia (Ear, J. et al. Blood 2015). Clinical trials in persons with lower risk myelodysplastic syndromes (Komrokji, R. et al. ASH 2014) and chemotherapy-induced anemia (Raftopoulos, H. et al. Support Care Cancer 2016) have shown promising results. Methods: This is an ongoing phase-2 study of sotatercept, 0.75 or 1 mg/kg subcutaneously every 3 weeks (1 cycle), in subjects with MF, whether primary (PMF) or post-polycythemia vera/essential thrombocythemia (post-PV/ET MF). Subjects must be RBC-transfusion-dependent (Gale, R.P. et al. Leuk Res 2011), have hemoglobin <10 g/dL on every determination during the 84 days preceding study entry without RBC transfusions, or have hemoglobin <10 g/dL despite intermittent RBC transfusions without fulfilling the criteria for transfusion dependence. Primary endpoints include anemia response and safety. Secondary endpoints include time to and duration of anemia response. Anemia response is a composite of RBC-transfusion-independence and hemoglobin response (increase of ≥1.5 g/dL from baseline on every determination consecutively over ≥84 days without RBC transfusions). Subjects must have received ≥5 cycles of sotatercept to be evaluable for response. Results: 18 subjects are enrolled to date. 1 subject received 6 cycles at a sub-therapeutic dose of 0.3 mg/kg and was not considered for efficacy evaluation, but was evaluable for safety. Of the remaining 17 subjects, 11 received 0.75 mg/kg and 6, 1 mg/kg. Median age was 67 years (range, 47-84 years); 10 were male and 7 female. 14 had PMF and 3, post-ET MF. 12 subjects had JAK2 V617F, 1 had MPLW515L and 2 had CALR exon 9 mutations. 1 subject was triple negative and 1 subject had no JAK2 or MPL mutation but was not tested for CALR mutations. All 17 subjects had intermediate-2 or high risk disease by the Dynamic International Prognostic Scoring System. Table 1 summarizes baseline variables for these 17 subjects. Median number of cycles of sotatercept received is 5 (range, 1-13). 14 of the 17 subjects received ≥5 cycles and were evaluable for response. The 3 other subjects received 1, 2 and 2 cycles and discontinued due to unrelated medical problems, hypertension and stem cell transplant (SCT), respectively. 5 of 14 (36%) evaluable subjects have responded; 4 of whom continue on study in ongoing response. All responders are female and all female subjects evaluable for response responded. Responses occurred across phenotypic driver mutation categories and in both transfusion-dependent (n=3) and -independent (n=2) subjects. 40% and 25% of evaluable patients responded in the 0.75 mg/kg and 1 mg/kg dose cohorts, respectively. Most adverse events (AEs) were grades 1 or 2. The only AEs possibly attributable to sotatercept include grade 3 hypertension leading to discontinuation, and grade 1 myalgia, bone pain, pain in extremity and injection site reaction. 5 subjects remain on study. 12 have discontinued because of no response (5), SCT (2), unrelated medical problems (1), hypertension (1), disease progression (1), transformation to AML (1) and withdrawal of consent (1). Conclusion: Sotatercept improves anemia and RBC-transfusion-dependence in persons with MF and is well-tolerated. Enrollment to the trial is ongoing; updated results will be presented. A separate cohort of subjects receiving ruxolitinib has been added and will also be discussed. Based on the preponderance of responses at the 0.75 mg/kg dose, this dose has been selected for the combination cohort. Disclosures Daver: Incyte: Consultancy, Other: Advisory board, Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.
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Reichel, Christian, Letizia Farmer, Günter Gmeiner, Katja Walpurgis, and Mario Thevis. "Detection of Sotatercept (ACE-011) in human serum by SAR-PAGE and western single blotting." Drug Testing and Analysis 10, no. 6 (December 27, 2017): 927–37. http://dx.doi.org/10.1002/dta.2346.

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Ear, Jason, Haigen Huang, Zahra Tehrani, Victoria Sung, Thomas Daniel, Rajesh Chopra, and Shuo Lin. "RAP-011 Efficiently Rescues Erythropoiesis In Zebrafish Models Of Diamond Blackfan Anemia." Blood 122, no. 21 (November 15, 2013): 3702. http://dx.doi.org/10.1182/blood.v122.21.3702.3702.

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Abstract Diamond Blackfan Anemia (DBA) is a bone marrow failure disorder characterized by low red blood cell count but normal levels of platelets and white blood cells. Ribosomal mutations in RPS19, RPS26, RPL5, and RPL11 have been identified in approximately 50% of all DBA cases. Corticosteriod therapy and bone marrow transplantion are the most common treatment options for DBA patients. However, corticosteroids have severe side effects and bone marrow transplantation is risky; thus, novel therapeutics for DBA are needed. Sotatercept (ACE-011), an activin receptor IIA ligand trap which rapidly increased hemoglobin and hematocrit in both pharmacologic models and in healthy volunteers, is currently being evaluated in diseases of ineffective erythropoiesis such as ß-thalassemia and MDS. Non-clinical studies in mice have demonstrated that RAP-011, a murine ortholog of sotatercept, stimulates RBC parameters in mice through stimulating expansion of late-stage erythroblasts through a mechanism distinct from EPO. Here, we evaluated the effect of RAP-011 in zebrafish models of ribosome insufficiency in RPS19 and RPL11 that recapitulate the anemic phenotype seen in DBA patients. Treatment with RAP-011 treatment dramatically restored hemoglobin levels compromised by ribosome stress. Furthermore, the beneficial effect of RAP-011 is synergistic with corticosteriod treatment. In zebrafish embryos, RAP-011 likely stimulates erythropoietic activity by altering the microenvironment of erythroid cells, reducing p21 levels through a p53-independent manner. These findings uncover a novel signaling pathway in the pathogenesis of DBA and support the potential use of Sotatercept for the treatment of DBA patients with ribosomal disorders. Our studies also demonstrate, for the first time, that protein drugs can be effectively evaluated in zebrafish human disease models, which offer a unique opportunity to identify the targets and study their mechanisms of action. Disclosures: Sung: Celgene Corp.: Employment. Daniel:Celgene: Employment. Chopra:Celgene: Employment, Equity Ownership. Lin:Celgene: Research Funding.
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Vallet, Sonia, Kishan Patel, Diana Cirstea, Katie Luly, Samantha Pozzi, Loredana Santo, Homare Eda, et al. "Lenalidomide In Combination with the Activin Receptor Type II Murine Fc Protein RAP-011: Preclinical Rationale for a Novel Anti-Myeloma Strategy." Blood 116, no. 21 (November 19, 2010): 4075. http://dx.doi.org/10.1182/blood.v116.21.4075.4075.

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Abstract Abstract 4075 The introduction of novel treatment strategies targeting tumor cells within their microenvironment have resulted in prolonged survival for Multiple Myeloma (MM) patients. Lenalidomide belongs to this category of agents working via tumoricidal, anti-osteoclast and immunomodulatory activities. However, lenalidomide lacks bone anabolic effects. We have recently reported that activin A mediates osteoblast inhibition in MM and neutralizing activin A via a soluble receptor, RAP-011 (murinized form of ACE-011) (Acceleron Pharma, Cambridge, MA), restores bone architecture and reduces tumor burden in vivo. We therefore hypothesized that the combination with RAP-011 may potentiate lenalidomide effects and vice versa as they act via complementary mechanisms. Our previous data demonstrates that 50% of MM patients have increased bone marrow (BM) levels of activin A that correlate with osteolytic burden. Here, we observed that 2 and 10 μ M lenalidomide (Selleck Chemicals, Houston, TX) upregulated activin A in 3 out 6 bone marrow stromal cell (BMSC) samples by 1.9 and 2.8 fold (average ± st.dev. 1052 ± 190 and 1667 ± 732 pg/ml respectively, compared to 734 ± 553 in control, p=0.2). There was no time-dependent upregulation of activin A. Of note, no augmentation of activin A was noted in BMSC which already expressed high baseline levels of the cytokine (average ± st.dev 3638 ± 3755 pg/ml in control vs 3074 ± 2997 after lenalidomide 10 μ M). Previous data suggest that high concentrations of activin A induce growth arrest and apoptosis in myeloma and breast cancer cells and may therefore mediate lenalidomide cytotoxicity. To ensure that inhibition of activin would not antagonize lenalidomide anti-tumor effects, we investigated whether activin A inhibition affected the cytotoxic and anti-proliferative effects of lenalidomide on MM cells alone and in co-culture with BMSC. As previously demonstrated, RAP-011 did not exert any direct anti-tumor effects. Lenalidomide 10 μ M induced between 20 and 40% of apoptosis in several myeloma cell lines, such as MM1.S, LR5, DOX40 and RPMI, independent of activin A inhibition. Similarly, lenalidomide almost completely reversed the proliferative advantage conferred by BMSC to tumor cells. Combining lenalidomide and RAP-011 was not antagonistic to the inhibition of the proliferative advantage conferred by BMSC to myeloma cells, suggesting that lenalidomide's direct anti-tumor activity is not mediated through activin A. Finally we assessed OB differentiation in the presence of both RAP-011 and lenalidomide. We have previously reported that activin A inhibitory effects on OB differentiation are reversed by RAP-011 treatment. Here, we noted diminished alkaline phosphatase (ALP, a marker of osteoblast activity) expression during osteoblastogenesis in the presence of increasing concentrations of lenalidomide (17% ± 3 decrease by 2 μ M and 26% ± 11 by 10 μ M compared to control, p=0.01 and 0.06 respectively). In contrast, combination with RAP-011 restored the osteogenic potential by increasing ALP expression close to control levels in healthy donor-derived BMSC and above control levels in MM-derived BMSC. These preliminary data suggest that lenalidomide results in upregulation of activin A expression in MM BMSCs which have low baseline levels. Combining lenalidomide with RAP-011 results in restored osteogenesis presumably by inhibiting activin signaling. Importantly, we observed no antagonistic effect of RAP-011 on lenalidomide's anti-tumor activity, confirming that activin A does not mediate the anti-tumor activity of lenalidomide. Ongoing in vivo studies using a murine model of myeloma will confirm the efficacy of this promising combination. Our results provide a preclinical rationale for combining lenalidomide with ACE-011 to target myeloma by manipulating the microenvironmental compartment, specifically the bone compartment. Disclosures: Seehra: Acceleron Pharma: Employment. Scadden:Fate Therapeutics: Consultancy, Equity Ownership, Patents & Royalties. Raje:Celgene, Novartis: Consultancy; Astrazeneca, Acetylon: Research Funding; Celgene, Amgen: Membership on an entity's Board of Directors or advisory committees.
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Ruckle, Jon, Mark Jacobs, William Kramer, Amelia E. Pearsall, Ravindra Kumar, Kathryn W. Underwood, Jasbir Seehra, Yijun Yang, Carolyn H. Condon, and Matthew L. Sherman. "Single-Dose, Randomized, Double-Blind, Placebo-Controlled Study of ACE-011 (ActRIIA-IgG1) in Postmenopausal Women*." Journal of Bone and Mineral Research 24, no. 4 (April 2009): 744–52. http://dx.doi.org/10.1359/jbmr.081208.

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De Rosa, Gianluca, Immacolata Andolfo, Roberta Marra, Francesco Manna, Barbara Eleni Rosato, Achille Iolascon, and Roberta Russo. "RAP-011 Rescues the Disease Phenotype in a Cellular Model of Congenital Dyserythropoietic Anemia Type II by Inhibiting the SMAD2-3 Pathway." International Journal of Molecular Sciences 21, no. 15 (August 4, 2020): 5577. http://dx.doi.org/10.3390/ijms21155577.

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Congenital dyserythropoietic anemia type II (CDA II) is a hypo-productive anemia defined by ineffective erythropoiesis through maturation arrest of erythroid precursors. CDA II is an autosomal recessive disorder due to loss-of-function mutations in SEC23B. Currently, management of patients with CDA II is based on transfusions, splenectomy, or hematopoietic stem-cell transplantation. Several studies have highlighted benefits of ACE-011 (sotatercept) treatment of ineffective erythropoiesis, which acts as a ligand trap against growth differentiation factor (GDF)11. Herein, we show that GDF11 levels are increased in CDA II, which suggests sotatercept as a targeted therapy for treatment of these patients. Treatment of stable clones of SEC23B-silenced erythroleukemia K562 cells with the iron-containing porphyrin hemin plus GDF11 increased expression of pSMAD2 and reduced nuclear localization of the transcription factor GATA1, with subsequent reduced gene expression of erythroid differentiation markers. We demonstrate that treatment of these SEC23B-silenced K562 cells with RAP-011, a “murinized” ortholog of sotatercept, rescues the disease phenotype by restoring gene expression of erythroid markers through inhibition of the phosphorylated SMAD2 pathway. Our data also demonstrate the effect of RAP-011 treatment in reducing the expression of erythroferrone in vitro, thus suggesting a possible beneficial role of the use of sotatercept in the management of iron overload in patients with CDA II.
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12

Bose, Prithviraj, Lucia Masarova, Naveen Pemmaraju, Sharon D. Bledsoe, Naval Daver, Elias J. Jabbour, Tapan M. Kadia, et al. "Final Results of a Phase 2 Study of Sotatercept (ACE-011) for Anemia of MPN-Associated Myelofibrosis." Blood 138, Supplement 1 (November 5, 2021): 144. http://dx.doi.org/10.1182/blood-2021-150908.

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Abstract Background Anemia is common in patients (pts) with myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF). Furthermore, anemia is an on-target effect of therapeutic Janus kinase 2 (JAK2) inhibition, and is a frequent cause of ruxolitinib (rux) discontinuation (d/c) in clinical practice (Kuykendall, Ann Hematol 2018). Current therapies for anemia of MF (erythropoietin and analogs, danazol, IMiDs®) are unsatisfactory. Sotatercept (ACE-011) is a first-in-class, activin receptor type IIA ligand trap that may improve anemia by sequestering stromal transforming growth factor beta superfamily ligands that suppress terminal erythropoiesis (Iancu-Rubin, Exp Hematol 2013). Methods This is a phase 2, investigator-initiated, open-label, single institution study of sotatercept, administered subcutaneously every 3 weeks, in 2 cohorts of anemic pts (Hgb &lt;10 g/dl on every determination for 12 w or transfusion-dependent (TD) per IWG-MRT criteria (Tefferi, Blood 2013)) with MF: as a single agent, and in combination with a stable dose of rux. Pts on rux must have been on it for ≥6 months with a stable dose for the preceding ≥8 weeks, and receive sotatercept at a dose of 0.75 mg/kg. Monotherapy pts receive either 0.75 or 1 mg/kg of sotatercept. In both cohorts, anemia response is defined as achievement of transfusion independence (TI) in TD pts, or an increase in Hgb level from baseline of ≥1.5 g/dl sustained for ≥12 wks in non-TD pts (Gale, Leuk Res 2011). Pts must be on-study for ≥12 w (84 d) to be response-evaluable. Results A total of 56 pts have been treated; one pt received only 0.3 mg/kg of sotatercept and is not considered further. Thirty four pts received sotatercept alone and 21 in combination with rux. Baseline characteristics appear in Table 1, panel A. Seventeen TD and 17 non-TD pts received sotatercept alone for a median of 11 (3-73) cycles. Sixteen pts received 0.75 mg/kg and 18, 1 mg/kg. Eight of 27 (30%) evaluable pts responded. Of these, 5 were anemia responses; 3 TD pts achieved TI. Six responses occurred at the 0.75 mg/kg dose, and 2 at the 1 mg/kg dose. Median time to response (TTR) was 19 (1-22) days and median duration of response (DOR), 23.3 (3.9-68.4) months. Seven pts (21%) were on-study for &lt;84 d and hence not response-evaluable: 2 because of stem cell transplant (SCT), 2 due to logistical (travel) issues, and 1 each d/ced sotatercept because of hypertension (HTN), unrelated medical problems and pt decision. Two pts continue on study. Reasons for d/c include lack or loss of response (14), progressive MF (6), SCT (4), travel logistics (3), patient decision (2), hypertension (1), unrelated medical complications (1) and transformation to AML (1). The combination cohort comprised 15 non-TD pts and 6 TD pts. Median rux dose at study entry was 10 (5-25) mg bid. Median number of cycles was 25 (2-49). Six of 19 (32%) evaluable pts in the combination cohort responded, all non-TD pts. Median TTR was 14 (6-147) days and median DOR, 18.2 (3.7-56.8) months. Two pts (10%) were on-study for &lt;84 d and hence not response-evaluable, 1 due to SCT and 1 due to loss of insurance. Two pts remain on study. Reasons for d/c include lack or loss of response (8), SCT (4), progressive MF (3), travel logistics (2), loss of insurance (1) and pt decision (1). Several non-response-evaluable pts in both cohorts achieved ≥1.5 g/dl increments in Hgb from baseline that were not sustained for ≥12 w because of early d/c from the study. An additional pt in the combination cohort required a rux dose increase, leading to failure to sustain a ≥1.5 g/dl Hgb improvement for ≥12 w. Across both cohorts, several responding pts required multiple protocol-specified drug holidays because of Hgb levels ≥11.5 g/dl, with resumption of sotatercept once Hgb was &lt;11 g/dl. Sotatercept was well-tolerated (Table 1, panel B). Grade 3 adverse events possibly related to sotatercept were HTN (n=7) and limb (bone/muscle/joint) or back pain (n=2). Conclusions Sotatercept is safe and effective against anemia of MPN-associated MF, both in non-TD and TD pts, with a response rate of 30% when used alone and 32% when used in conjunction with a stable dose of rux. All responses in the rux cohort occurred in non-TD pts. The trial (NCT01712308) has been closed to new pt enrollment. Figure 1 Figure 1. Disclosures Bose: Sierra Oncology: Honoraria; NS Pharma: Research Funding; Astellas: Research Funding; Pfizer: Research Funding; Constellation Pharmaceuticals: Research Funding; Blueprint Medicines: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Novartis: Honoraria; BMS: Honoraria, Research Funding; Kartos Therapeutics: Honoraria, Research Funding; Promedior: Research Funding. Pemmaraju: Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Cellectis S.A. ADR: Other, Research Funding; Sager Strong Foundation: Other; CareDx, Inc.: Consultancy; Plexxicon: Other, Research Funding; Aptitude Health: Consultancy; DAVA Oncology: Consultancy; Celgene Corporation: Consultancy; MustangBio: Consultancy, Other; Roche Diagnostics: Consultancy; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; LFB Biotechnologies: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Samus: Other, Research Funding; Incyte: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Springer Science + Business Media: Other; Affymetrix: Consultancy, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Daver: Trovagene: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Glycomimetics: Research Funding; Novimmune: Research Funding; FATE Therapeutics: Research Funding; Astellas: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Hanmi: Research Funding; ImmunoGen: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Genentech: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Kadia: BMS: Other: Grant/research support; Amgen: Other: Grant/research support; Aglos: Consultancy; AbbVie: Consultancy, Other: Grant/research support; Novartis: Consultancy; AstraZeneca: Other; Astellas: Other; Genfleet: Other; Ascentage: Other; Jazz: Consultancy; Liberum: Consultancy; Dalichi Sankyo: Consultancy; Genentech: Consultancy, Other: Grant/research support; Cure: Speakers Bureau; Pfizer: Consultancy, Other; Pulmotech: Other; Sanofi-Aventis: Consultancy; Cellonkos: Other. Andreeff: Karyopharm: Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Glycomimetics: Consultancy; Syndax: Consultancy; ONO Pharmaceuticals: Research Funding; Novartis, Cancer UK; Leukemia & Lymphoma Society (LLS), German Research Council; NCI-RDCRN (Rare Disease Clin Network), CLL Foundation; Novartis: Membership on an entity's Board of Directors or advisory committees; Medicxi: Consultancy; AstraZeneca: Research Funding; Reata, Aptose, Eutropics, SentiBio; Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company; Aptose: Consultancy; Breast Cancer Research Foundation: Research Funding; Oxford Biomedica UK: Research Funding; Amgen: Research Funding; Senti-Bio: Consultancy. Cortes: Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sun Pharma: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Jain: ADC Therapeutics: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; Janssen: Honoraria; Fate Therapeutics: Research Funding; Beigene: Honoraria; Cellectis: Honoraria, Research Funding; TG Therapeutics: Honoraria; AstraZeneca: Honoraria, Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Genentech: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Servier: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Borthakur: Ryvu: Research Funding; Protagonist: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; University of Texas MD Anderson Cancer Center: Current Employment; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; ArgenX: Membership on an entity's Board of Directors or advisory committees. Alvarado: MEI Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; Sun Pharma: Consultancy, Research Funding; Daiichi-Sankyo: Research Funding; FibroGen: Research Funding; BerGenBio: Research Funding; CytomX Therapeutics: Consultancy; Jazz Pharmaceuticals: Research Funding. Huynh-Lu: Incyte Corporation: Speakers Bureau. Nguyen-Cao: Incyte Corporation: Speakers Bureau. Kantarjian: AbbVie: Honoraria, Research Funding; Jazz: Research Funding; Astellas Health: Honoraria; Precision Biosciences: Honoraria; NOVA Research: Honoraria; Taiho Pharmaceutical Canada: Honoraria; Immunogen: Research Funding; Ipsen Pharmaceuticals: Honoraria; Novartis: Honoraria, Research Funding; Ascentage: Research Funding; Daiichi-Sankyo: Research Funding; Aptitude Health: Honoraria; Astra Zeneca: Honoraria; Pfizer: Honoraria, Research Funding; BMS: Research Funding; KAHR Medical Ltd: Honoraria; Amgen: Honoraria, Research Funding. Verstovsek: NS Pharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; Promedior: Research Funding; PharmaEssentia: Research Funding; AstraZeneca: Research Funding; Blueprint Medicines Corp: Research Funding; Genentech: Research Funding; Ital Pharma: Research Funding; Gilead: Research Funding; Roche: Research Funding; Protagonist Therapeutics: Research Funding; Celgene: Consultancy, Research Funding; CTI BioPharma: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. OffLabel Disclosure: Sotatercept is an activin receptor ligand trap. This trial evaluates sotatercept for the treatment of anemia in patients with MPN-associated myelofibrosis.
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Borgstein, Niels. "ACE-011, a Soluble Activin Receptor Type IIA IgG-Fc Fusion Protein, Increases BMD in Postmenopausal Healthy Women." Journal of Clinical Densitometry 12, no. 3 (July 2009): 388. http://dx.doi.org/10.1016/j.jocd.2009.03.051.

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Chen, Nianhang, Adberrahmane Laadem, Matthew L. Sherman, Simon Zhou, Victoria Sung, Maria Palmisano, and Rajesh Chopra. "Exposures and Erythropoietic Responses to Sotatercept (ACE-011) in Healthy Volunteers and Cancer Patients: Implications for Mechanism of Action." Blood 120, no. 21 (November 16, 2012): 3454. http://dx.doi.org/10.1182/blood.v120.21.3454.3454.

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Abstract Abstract 3454 Introduction: Sotatercept (ACE-011), a recombinant fusion protein consisting of the extracellular domain of the human activin receptor type IIA linked to the human IgG1 Fc domain, is a ligand trap for multiple TGF-β super family ligands including activin A/B and growth differentiation factor-11 (GDF-11). Data from in vitro studies and animal models suggest that sotatercept may act on late erythroblasts to promote erythropoiesis. The relationship between serum sotatercept exposure and erythropoietic responses was studied in healthy postmenopausal women (HPMW) and cancer patients (pts). Methods: Data were obtained from a total of 157 subjects in 5 clinical studies, including79 HPMW, 30 pts with multiple myeloma (46% were anemic, hemoglobin [Hgb] < 11 g/dL), and 48 anemic pts with solid tumors. In HPMW, sotatercept was given as either a single intravenous (IV) infusion over 60 min (0.01 to 3 mg/kg), or as multiple subcutaneous (SC) injections (0.03 to 1 mg/kg Q4W). In pts, sotatercept was given at 0.1 to 0.5 mg/kg Q4Wor 15 and 30 mg Q6W. Serial blood samples for pharmacokinetic analysis were collected for up to 24 weeks (wks) after the first dose. Hgb was monitored weekly or more frequently in most studies. The magnitude of the initial Hgb response was defined as the maximum Hgb increase (g/dL) from baseline within 4 wks of Dose 1. Erythropoietin (EPO) and reticulocyte data were obtained mainly from HPMW. Results: Increases in the maximum serum concentration (Cmax) and area under concentration-time curve over 28 days (AUC28d) of sotatercept were proportional to dose for both IV and SC administration. The half-life in serum was 3 to 4 wks, independent of the dosing route or study population. Cmax was ∼3-fold higher for IV doses than for the same SC doses, and it occurred at the end of IV infusion as compared to ∼7 days after SC injection. Body weight and gender were not found to significantly affect sotatercept exposure. In HPMW, a rapid initial Hgb increase was observed near the time of sotatercept Cmax (Tmax). With single IV doses, a rise in Hgb was evident on Day 2 (mean increase = 0.46 g/dL at 0.1 mg/kg and 0.56–0.84 g/dL at 0.3 to 3 mg/kg). With SC doses, a rise in Hgb was evident 1 wk after Dose 1 (mean increase ≥ 0.68 g/dL at 0.1 to 1 mg/kg). AUC28d and Cmax correlated with the magnitude of initial Hgb response up to 200 day•μg/mL and 10 μg/mL, respectively. Increasing Cmax from 10 to 100 μg/mLwith single IV doses did not further elevate the initial Hgb increase, but it prolonged the duration of Hgb increase (≥1 g/dL) from ∼8 to >16 wks. A concentration-dependent increase in serum EPO was observed in HPMW, with the peak level ranging from 25 to 67 mIU/mL at the SC dose of 1 mg/kg (baseline EPO = 11 to 23 mIU/mL). An increase in reticulocytes was also observed at ≥ 1 mg/kg, reaching the peak 1–2 wks postdose, consistent with the time for the formation of reticulocytes from early erythroid progenitors. The effect of sotatercept on reticulocytes was more evident with IV doses (∼2-fold higher than the baseline), suggesting this effect may be related to Cmax. EPO and reticulocytes responses were not apparent at lower SC doses or concentrations of sotatercept (≤ 0.3 mg/kg or < 5 μg/mL), though these doses induced an initial rapid Hgb increase. A rapid rise in Hgb was also observed in cancer pts at all studied doses, again with the peak increase occurring ∼1 wk postdose (near Tmax). Exposure-response analysis suggests that the magnitude of the initial Hgb increase in cancer pts was comparable to that in HPMW. However, the duration of Hgb response was less sustained in cancer pts receiving chemotherapy, likely due to lower exposure levels studied and myelosuppression. Alternative dosing regimens to increase exposure by increasing dose or shortening dosing interval are currently being explored. Conclusion: The clinical data suggests that sotatercept acts through a mechanism distinct from that of EPO. The rapid Hgb increase at all dose levels supports the hypothesis that sotatercept acts essentially at a late stage of erythropoiesis to induce erythroid maturation. High concentrations of sotatercept are also associated with EPO release, reticulocyte production and sustained Hgb increase, possibly through influencing earlier stages of erythropoiesis. These findings define a relationship between inhibition of TGF-β superfamily ligands and erythropoiesis in humans and support the development of sotatercept in anemia and diseases of ineffective erythropoiesis. Disclosures: Chen: Celgene: Employment. Laadem:Celgene: Employment. Sherman:Acceleron Pharma: Employment, Equity Ownership. Zhou:Celgene Corporation: Employment. Sung:Celgene: Employment, Equity Ownership. Palmisano:Celgene: Employment, Equity Ownership. Chopra:Celgene Corporation: Employment, Equity Ownership.
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Carrancio, Soraya, Jennifer A. Markovics, Piu Wong, Jim Leisten, Matthew C. Groza, Heather K. Raymon, Carla Heise, Rajesh Chopra, Tom O. Daniel, and Victoria Sung. "Sotatercept, an Activin Receptor IIa Ligand Trap, Acts Through Bone Marrow Accessory Cells to Promote Late-Stage Erythropoiesis and a Rapid Induction of Red Blood Cell Number and Hemoglobin." Blood 120, no. 21 (November 16, 2012): 372. http://dx.doi.org/10.1182/blood.v120.21.372.372.

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Abstract Abstract 372 The regulation of erythropoiesis requires stem cell factor and erythropoietin (EPO) for the proliferation and survival of erythroid progenitor and early precursor cells. While recombinant EPO is widely used for treating various types of anemia, it often lacks efficacy in cases of anemia due to ineffective erythropoiesis in which immature erythroid precursors undergo apoptosis. Thus, there is an need for new therapies to treat the later stages of erythropoiesis. Members of the transforming growth factor beta (TGFβ) superfamily have been studied as potential regulators of erythropoiesis, iron regulation and globin expression. Sotatercept (ACE-011), a recombinant fusion protein consisting of the extracellular domain of the human activin receptor IIA (ActRIIA) linked to the human immunoglobulin G1 (IgG1) Fc domain, is a ligand trap which binds a number of TGFβ superfamily ligands including activin A, activin B, growth differentiation factor-11 (GDF-11) and bone morphogenetic protein-10 (BMP-10). Administration of sotatercept led to substantial increases in red cell number and hemoglobin in human subjects, but the mechanism is not fully understood. We utilized both mouse in vivo and human in vitro models to investigate the mechanism of sotatercept in promoting erythropoiesis. In order to compare the effects of RAP-011 (the murine version of sotatercept) to EPO on red blood cell (RBC) parameters, C57/Bl mice were dosed with RAP-011, EPO or control vehicle. RAP-011-treated mice had a rapid and statistically significant increase in hematocrit, hemoglobin, and RBC number in less than 72-hours. As rapidly as 24 hours after treatment, RAP-011 induced a significant increase in RNA-negative, enucleated cells in the bone marrow (BM). RAP-011 also rapidly increased BM BFU-e and CFU-e erythroid progenitors, while EPO was more effective on spleen-derived progenitors. These data suggest that RAP-011 acts primarily on both bone marrow progenitor cells and late erythroblasts to promote erythropoiesis. In order to investigate the cellular mechanism by which RAP-011 increases red blood cell parameters, we conducted a series of in vitro experiments and found no evidence to support direct effects of RAP-011 on human CD34+ cells assessed in colony formation assays and in erythroid differentiation in liquid culture. As both clinical and pharmacological findings point to a clear role for RAP-011 in stimulating RBC parameters, we hypothesized that RAP-011 effects may be mediated by accessory cells in the BM microenvironment. Human CD36+ cells, which are highly enriched for erythroid progenitors, were co-cultured with long-term BM cultures and erythroid differentiation was assessed following 6 days of culture in EPO (2U/mL)-supplemented media. At day 6 the output of these cultures was predominantly characterized as EryA (∼basophilic erythroblast) but with the addition of RAP-011 (50μM), a significant fraction of CD36+ cells matured into EryB/C cells (polychromatic/orthochromatic erythroblasts), suggesting that factors produced by BM accessory cells mediate RAP-011 erythropoietic effects and that, in contrast to EPO, RAP-011 may play a role in the latter stages of erythroblast maturation. To identify cytokines that may mediate RAP-011 effects, CD36+ cells were treated with several activin receptor IIA ligands. GDF-11 treatment significantly decreased proliferation of GPA+ cells during the differentiation process and RAP-011 effectively reversed this effect, but had no consequence on untreated cells. These data suggest that GDF-11 may mediate the erythroipoietic stimulatory effects of RAP-011. In summary, RAP-011 induced a rapid increase in RBC parameters in mice (reflected in the number of enucleated cells found in the bone marrow), likely mediated by BM accessory cells. Our data also suggest that effects of sotatercept may be mediated at least partly by GDF-11, acting as a potential negative regulator of the terminal stages of erythropoiesis. The ability of sotatercept to reverse this inhibition would lead to a rapid release of terminal erythroid cells into the circulation. These data support the rationale to develop sotatercept for the treatment of anemia and ineffective erythropoiesis, especially in patients who may not respond to EPO. Disclosures: Carrancio: Celgene Corporation: Employment. Markovics:Celgene Corporation: Employment. Wong:Celgene Corporation: Employment. Leisten:Celgene Corporation: Employment. Groza:Celgene Corporation: Employment. Raymon:Celgene Corporation: Employment. Heise:Celgene Corporation: Employment. Chopra:Celgene Corp: Employment, Equity Ownership. Daniel:Celgene Corporation: Employment. Sung:Celgene Corporation: Employment.
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Iancu-Rubin, Camelia, Goar Mosoyan, Jiapeng Wang, Thomas Kraus, Victoria Sung, and Ronald Hoffman. "Stromal cell-mediated inhibition of erythropoiesis can be attenuated by Sotatercept (ACE-011), an activin receptor type II ligand trap." Experimental Hematology 41, no. 2 (February 2013): 155–66. http://dx.doi.org/10.1016/j.exphem.2012.12.002.

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Mulivor, Aaron W., Denise Barbosa, Ravi Kumar, Matthew Leigh Sherman, Jas Seehra, and R. Scott Pearsall. "RAP-011, a Soluble Activin Receptor Type IIa Murine IgG-Fc Fusion Protein, Prevents Chemotherapy Induced Anemia." Blood 114, no. 22 (November 20, 2009): 161. http://dx.doi.org/10.1182/blood.v114.22.161.161.

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Abstract Abstract 161 Anemia is a common and often severe side-effect of chemotherapy treatment that can alter treatment regimens and can frequently require patients to receive blood transfusions. The majority of therapies approved for anemia target the erythropoietin (EPO) pathway. However, recent studies suggest an increased risk of mortality associated with recombinant erythropoietin (EPO) and its derivatives, which may stimulate tumor progression and increase the occurrence of thromboembolic events. The TGF-β superfamily of proteins has been reported to play a role in red blood cell (RBC) development, but works via a different pathway from EPO. RAP-011 is a murine fusion protein based on the activin receptor type IIA (ActRIIA) that binds to and prevents signaling of certain members of the TGF-β superfamily through the ActRIIA receptor. The purpose of the current study is to evaluate the effect of RAP-011 on chemotherapy induced anemia (CIA) in a mouse model. To investigate the ability of RAP-011 to prevent anemia, six week old C57BL/6 mice (30/dose group) were treated with Vehicle (VEH), or RAP-011 (1 mg/kg, 10 mg/kg, 30 mg/kg) 7 days prior to chemotherapy (Day -7). On Day 0, the mice received a single dose of paclitaxel (25 mg/kg) to induce CIA. 10 mice from each treatment group were sacrificed on Days 0, 3 and 7 and blood was collected for complete blood cell counts. On study day 0, immediately prior to CIA induction, VEH treated mice had an average hematocrit of 41.6% and RAP-011 treated mice had significantly increased hematocrits compared to the VEH cohort (1 mg/kg 43.4%, P<0.001; 10 mg/kg 42.7%, P<0.001; 30 mg/kg 43.59%, P<0.001). Similarly, VEH treated mice had an average hemoglobin level of 154.4 g/l and RAP-011 treated mice had significantly increased levels compared to the VEH cohort (1 mg/kg 167.2 g/l, P<0.001; 10 mg/kg 167.1 g/l, P<0.001; 30 mg/kg 170.1 g/l, P<0.001). 3 days following CIA the hematocrit in VEH treated mice was decreased to 38.3%. The hematocrit in RAP-011 treated groups decreased as well, but was significantly greater than VEH controls (1 mg/kg 41.0%, P<0.001; 10 mg/kg 42.9%, P<0.001; 30 mg/kg 42.3%, P<0.001). Hemoglobin measurements followed a similar pattern with VEH treated mice being decreased (137.0 g/l) whereas all of the RAP-011 treated cohorts were decreased but were significantly greater than the VEH cohort (1 mg/kg 150.8 g/l, P<0.001; 10 mg/kg 154.3 g/l, P<0.001; 30 mg/kg 151.2 g/l, P<0.001). One week following CIA the hematocrit in VEH treated mice was still decreased compared to the baseline measurements (40.7%, P<0.001). The lowest dose RAP-011 treated group was decreased as well (1 mg/kg 42.9%, P<0.001). However, the higher RAP-011 dosed cohorts had returned to their baseline values and were significantly higher than the VEH treated cohort (10 mg/kg 44.6%, P<0.001; 30 mg/kg 43.8%, P<0.001). Hemoglobin levels in the VEH cohort returned to baseline levels (150.5 g/l) and all of the RAP-011 treated cohorts were significantly increased compared to VEH (1 mg/kg 161.4 g/l, P<0.05; 10 mg/kg 171.7 g/l, P<0.001; 30 mg/kg 167.2 g/l, P<0.001). These data suggest that altering signaling in the TGFβ superfamily by use of a soluble ActRIIA receptor might act as a novel anemia therapy in patients receiving chemotherapy. Towards this end, ACE-011, the human analog of RAP-011, is currently in clinical development for the treatment of chemotherapy induced anemia. Disclosures: Mulivor: Acceleron Pharma: Employment. Barbosa:Acceleron Pharma: Employment. Kumar:Acceleron Pharma: Employment. Sherman:Acceleron: Employment, Equity Ownership. Seehra:Acceleron Pharma: Employment. Pearsall:Acceleron Pharma: Employment.
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Iancu-Rubin, Camelia, Goar Mosoyan, Jiapeng Wang, Thomas Kraus, and Ronald Hoffman. "Stromal Cells-Mediated Inhibition of Erythropoiesis Can Be Counteracted by Sotatercept (ACE-011), an Activin Receptor Type II (ActRIIA) Fusion Protein." Blood 120, no. 21 (November 16, 2012): 1254. http://dx.doi.org/10.1182/blood.v120.21.1254.1254.

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Abstract Abstract 1254 Sotatercept (ACE-011) is an activin type IIA receptor (ActRIIA) fusion protein which antagonizes activin and is currently being evaluated in clinical trials for the treatment of cancer-related bone loss and anemia. Administration of sotatercept has been associated with an increase in the hemoglobin (Hb) and hematocrit (Ht) levels in preclinical and clinical studies, yet the mechanisms underlying the effects of this drug on erythropoiesis remain unknown. We, therefore, addressed the potential mechanisms underlying the effects of sotatercept on erythroid lineage by investigating its direct and indirect influences on in vitro erythropoiesis. The direct effects of sotatercept on the ability of human primary CD34+ cells to form erythroid (Ery) colonies and to generate Ery cells in liquid cultures was examined. Neither the number, the size nor the morphology of BFU and CFU-E colonies were affected by sotatercept treatment. Likewise, the percentage of CD36+/Glycophorin (GPA)+ cells generated in liquid cultures treated with sotatercept was similar to that observed in control cultures. We further showed that treatment with activin induced Ery differentiation of K562 erythroleukemic cells and this effect was counteracted by sotatercept, which is in agreement with its function as activin trap. By contrast, activin alone or in combination with sotatercept did not stimulate Ery differentiation of primary CD34+ cells, suggesting that sotatercept does not affect in vitro erythropoiesis directly or through its interaction with activin. Since stromal cells (SC) are both a major source of activin and important players in the regulation of hematopoiesis we next examined if sotatercept might influence the ability of BM-derived SC to affect erythropoiesis. Conditioned media (CM) produced by a heterogeneous population of SC inhibited Ery differentiation of CD34+ cells (i.e. the percentage of CD36+/GPA+ cells was 5-fold lower in cultures containing SC-CM as compared to control) and skewed their phenotype towards the myeloid lineage. SC-mediated inhibition of erythropoiesis was associated with the maintenance of a CD34+ cells phenotype (i.e. twice as many cells were CD34+in cultures differentiated in the presence of SC-CM as compared to control) and with the abrogation of the Ery gene signature, including a drastic suppression of most Hb and glycophorin encoding genes as well as genes involved in Hb stabilization and heme metabolism. When identical experiments were performed in the presence of CM produced by SC treated with sotatercept, the ability of SC-derived CM to inhibit erythropoiesis was significantly diminished. CD34+ cells differentiated in media conditioned by sotatercept-treated SC, generated 1.7-fold more CD36+/GPA+ Ery progenitors (p value ≤ 0.005) and 1.3-fold more mature GPA+ eryrthroblasts (p value ≤ 0.05) as compared to those generated in the presence of CM from untreated SC. In addition, they formed 1.4 times greater number of BFU-E colonies than that observed in the presence of CM derived from untreated SC. Importantly, CM from sotatercept-treated SC did not affect other hematopoietic lineages (e.g. expression of CD33, CD14 or CD61). These observations indicated that treatment with sotatercept modulated SC function to create a milieu of soluble factors which are more permissive for erythropoiesis. To indentify these potential factors we performed gene expression profiling of SC cultured in the presence or absence of sotatercept. The number of genes significantly affected by the drug was relatively small, but included genes encoding proteins which are known for their erythropoiesis-stimulatory roles (e.g. Angiotensin II, SDF1, BMP6 and IGFBP2), proteins which are potent inhibitors erythropoiesis (e.g. VEGF) and proteins with less well defined effects on erythroid lineage (e.g. BMP2, Oncostatin and Il-6). We validated these findings by measuring the levels of these secreted proteins, as well as of activin levels in the SC-CM, and demonstrated that sotatercept modifies the secretory profile of SC. We propose that SC-derived negative signals may represent an important component which contributes to the regulation of erythropoiesis. The stimulatory effects of sotatercept on red cell production, therefore, appear to be a consequence of its ability to counteract such inhibitory signals and to induce the production of a variety of Ery-promoting factors by the BM microenvironment. Disclosures: Iancu-Rubin: Celgene: Research Funding. Hoffman:Celgene: Research Funding.
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Walpurgis, Katja, Andreas Thomas, Matthias Vogel, Christian Reichel, Hans Geyer, Wilhelm Schänzer, and Mario Thevis. "Testing for the erythropoiesis-stimulating agent Sotatercept/ACE-011 (ActRIIA-Fc) in serum by means of Western blotting and LC-HRMS." Drug Testing and Analysis 8, no. 11-12 (October 13, 2016): 1152–61. http://dx.doi.org/10.1002/dta.2093.

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Lotinun, Sutada, R. Scott Pearsall, Monique V. Davies, Tod H. Marvell, Travis E. Monnell, Jeffrey Ucran, Roberto J. Fajardo, et al. "A soluble activin receptor Type IIA fusion protein (ACE-011) increases bone mass via a dual anabolic-antiresorptive effect in Cynomolgus monkeys." Bone 46, no. 4 (April 2010): 1082–88. http://dx.doi.org/10.1016/j.bone.2010.01.370.

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Vallet, Sonia, Siddhartha Mukherjee, Nileshwari Vaghela, Samantha Pozzi, Loredana Santo, Diana Cirstea, Mariateresa Fulciniti, et al. "Restoration of Bone Balance Via Activin a Inhibition Results in Anti-Myeloma Activity." Blood 112, no. 11 (November 16, 2008): 645. http://dx.doi.org/10.1182/blood.v112.11.645.645.

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Abstract A distinct feature of multiple myeloma (MM) is the tight interaction between malignant plasma cells and their bone microenvironment, creating a niche suitable for MM growth. In particular, MM cells inhibit osteoblast (OB) differentiation and stimulate osteoclast (OC) function, resulting in imbalanced bone remodeling and osteolytic bone disease. Here we studied a novel cytokine, activin A, identified from a broad range of cytokines, in the development of MM bone disease. We next asked whether activin A inhibition could restore bone balance and suppress tumor growth. Activin, a member of the TNF-α superfamily, is a pleiotropic cytokine involved in bone remodeling. Here, we observed, that MM patients with multiple osteolytic lesions had a 4-fold increase in activin A expression levels in bone marrow plasma compared to MM patients with one or less osteolytic lesions and non-MM patients (average 123.6 ± 136 vs 26.4 ± 21.4 vs 30.6 ± 25.1 pg/ml respectively, p<0.05). Interestingly, our data demonstrate that the main source of activin in the MM niche are bone marrow stromal cells (BMSCs), followed by OCs, and OBs (average levels in 72h culture supernatant are 1884, 1300, 299 pg/ml, respectively). In contrast, MM cells did not secrete activin, but stimulated its secretion in coculture by BMSC (by 1.3 to 2 fold increase). Activin A stimulated OC differentiation in synergy with RANKL and M-CSF via induction of a three-fold increase in precursor cell proliferation. Moreover, activin A had a potent inhibitory effect on OB differentiation as verified by ALP activity (reduced by 30% compared to control, p<0.05) and OB function, assessed with alizarin red (80% inhibition, p< 0.01). To test the role of targeting activin A with therapeutic intent, we used both a neutralizing antibody and a soluble receptor fusion, RAP-011 (Acceleron Pharma Inc., Cambridge). In effect, both strategies enhanced OB differentiation and activity (5 fold increase in calcium deposition at day 21, p<0.05). This was confirmed by quantitative-PCR analysis of ALP and osteocalcin gene expression. Importantly, RAP-011 promoted OB differentiation even in the presence of INA6 MM cells and reversed the inhibitory effects of the stroma-dependent MOLP5 MM cells as well as patient derived MM cells on OB. Enhanced OB differentiation by RAP-011 resulted in inhibition of MM cell proliferation compared to BMSCs and mature OB. These data thus suggest that manipulating the bone niche may result in reduced tumor growth. To further verify if these results translated in reduced tumor growth in vivo, we used the SCID-hu mouse model consisting of INA6 MM cells injected in a subcutaneously implanted fetal human bone. RAP-011 treatment resulted in a decrease in the number of osteolytic lesions assessed by CT imaging accompanied by improved bone density. These effects translated in reduced MM cell growth, analyzed by soluble human IL6 receptor levels, in the treated group compared to the control (p<0.02). These data therefore suggest that activin A is involved in development of MM bone disease and can be effectively targeted by a novel clinical grade compound. RAP-011 demonstrated bone-anabolic effects via inhibition of OC formation and stimulation of OB differentiation resulting in restoration of bone balance within the MM niche, which translated in in-vivo inhibition of MM cell growth. These effects of RAP-011 support the use of the human ACE-011 as an attractive approach for the treatment of MM.
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22

Yee, Andrew J., Jacob P. Laubach, Ajay K. Nooka, Elizabeth K. O'Donnell, Edie A. Weller, Nicole R. Couture, Ellen E. Wallace, et al. "Phase 1 Dose-Escalation Study of Sotatercept (ACE-011) in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma." Blood 126, no. 23 (December 3, 2015): 4241. http://dx.doi.org/10.1182/blood.v126.23.4241.4241.

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Abstract Introduction Anemia and bone disease are hallmarks of multiple myeloma (MM). Sotatercept (ACE-011) is a novel, first-in-class activin type IIA receptor fusion protein that binds with high affinity to activin A and GDF11, and it acts during late-stage erythropoiesis to increase the production of mature erythrocytes through a mechanism independent of erythropoietin. Sotatercept has shown promising activity in clinical trials for anemia in myelodysplastic syndromes (Komrokji et al., ASH 2014) and in thalassemia (Cappellini et al., EHA 2015). Additionally, we have shown that targeting activin A through an analog of sotatercept reverses osteoblast inhibition and improves MM bone disease in a mouse model (Vallet et al., PNAS 2010). Lenalidomide increases activin A secretion with consequent inhibition of osteoblastogeneis, and this can be abrogated by treatment with an activin A neutralizing antibody (Scullen et al., Leukemia 2013). Sotatercept has been previously studied with melphalan, prednisolone, and thalidomide in MM (Abdulkadyrov et al., Br J Haematol 2014). Based on these findings, we evaluated sotatercept in combination with lenalidomide and dexamethasone in MM (NCT01562405). Methods Patient with relapsed and/or refractory MM with at least one prior line of therapy, anemia with hemoglobin <13 g/dL, lytic bone disease, and otherwise adequate organ function were eligible to participate. Sotatercept 10, 15, 30, or 45 mg was given s.c. q28 days along with lenalidomide and weekly dexamethasone on a standard 28 day schedule, with dose escalation following a 3 + 3 design. Sotatercept was held for hemoglobin ≥13 g/dL or for ≥ grade 3 hypertension. Bone mineral density by DEXA was assessed after four cycles. Bisphosphonates were not permitted during the study; prior bisphosphonate therapy was allowed. Results Thirteen patients with a median age of 62 years (range 49-77) and a median of 2 prior lines (range 1-5) of therapy have been enrolled to date (July 31, 2015). Median duration of treatment is 8.1 months (range 0.5, 27 months); five patients continue on study. The MTD has not been reached, and the current dosing level is sotatercept 45 mg with lenalidomide 25 mg. Grade 3-4 adverse events included anemia (38%), diarrhea (15%), fatigue (15%), hypophosphatemia (15%), and thrombocytopenia (38%). Grade 3 hypertension occurred in one patient receiving sotatercept 15 mg (hemoglobin at the time, 11.5 g/dL). There was one death on study that was unrelated to treatment. In patients who completed at least two cycles of treatment, there was a significant mean increase in hemoglobin on study of 0.94 g/dL (N = 10, p = 0.0048) from a mean starting hemoglobin 10.27 g/dL (range 8.6, 12.2). Mean maximal increase in hemoglobin was 2.11 g/dL (range 1.1, 4). Bone density by DEXA was assessed after four cycles. In patients who received a cumulative dose of sotatercept over 45 mg (N = 6), total lumbar spine BMD increased by a mean of 2.0% after four cycles; 83% had increase in BMD. ORR for this combination was 60% (CR = 1, VGPR = 1, PR = 4, SD = 4) in patients evaluable for response. Conclusion Sotatercept in combination with lenalidomide and dexamethasone is well tolerated with expected toxicities related to lenalidomide in MM. Preliminary data from this ongoing study suggest that sotatercept leads to early increases in both hemoglobin and bone mineral density, and it is the first agent that may address both of these significant causes of morbidity in MM. Disclosures Laubach: Novartis: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Millennium: Research Funding. Nooka:Onyx Pharmaceuticals: Consultancy; Spectrum Pharmaceuticals: Consultancy. O'Donnell:Millennium: Consultancy. Puccio-Pick:Celgene Corp.: Employment. Laadem:Celgene Corporation: Employment. Sherman:Acceleron Pharma: Employment. Raje:Acetylon: Research Funding; AstraZeneca: Research Funding; Onyx: Consultancy; Takeda: Consultancy; Eli Lilly: Research Funding; Millenium: Consultancy; Novartis: Consultancy; Amgen: Consultancy; BMS: Consultancy; Celgene Corporation: Consultancy.
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Smith, William T., John Havill, Nelson Kopyt, Jeffrey Kaupke, Daniel Aversa, and Nianhang Chen. "FP661LONG-TERM EFFECTS OF 3 DOSE LEVELS OF SOTATERCEPT COMPARED WITH PLACEBO FOR CORRECTION OF ANEMIA IN HEMODIALYSIS SUBJECTS: INTERIM ANALYSIS OF ACE-011-REN-001." Nephrology Dialysis Transplantation 30, suppl_3 (May 2015): iii295. http://dx.doi.org/10.1093/ndt/gfv182.09.

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24

Cappellini, Maria-Domenica, John Porter, Raffaella Origa, Gian Luca Forni, Adberrahmane Laadem, Frédéric Galacteros, Dimana Miteva, et al. "A Phase 2a, Open-Label, Dose-Finding Study To Determine The Safety and Tolerability Of Sotatercept (ACE-011) In Adults With Beta (β)-Thalassemia: Interim Results." Blood 122, no. 21 (November 15, 2013): 3448. http://dx.doi.org/10.1182/blood.v122.21.3448.3448.

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Abstract Background Beta (β)-thalassemia is characterized by ineffective erythropoiesis leading to anemia, bone marrow erythroid hyperplasia, iron overload, and organ failure. Sotatercept (ACE-011) is a novel and first-in-class activin type IIA receptor (ActRIIA) fusion protein that increases the release of mature erythrocytes into circulation by acting mainly on late-stage erythropoiesis (Carrancio S, et al. Blood. 2012;120:abstract 372). Clinical data in healthy volunteers have shown that treatment with sotatercept results in increased red blood cell (RBC) parameters, including hemoglobin level (Ruckle J, et al. J Bone Miner Res. 2009;24:744-52). RAP-011, a murine ortholog of sotatercept, was efficacious in a mouse model of β-thalassemia intermedia, reducing ineffective erythropoiesis as well as significantly improving anemia and decreasing bilirubin levels, supporting the clinical development of sotatercept (Dussiot M et al. Blood 2012;120:abstract 247). Methods This is an ongoing phase 2a, multicenter, open-label, dose-finding study to determine a safe and active dose level of sotatercept in adult patients with RBC-transfusion dependent (TD) β-thalassemia major or patients with β-thalassemia intermedia who are either TD or non-transfusion dependent (NTD). The dose levels of sotatercept studied to date are 0.1, 0.3, and 0.5 mg/kg, given subcutaneously once every 3 weeks. Safety is assessed according to NCI-CTC grading. Efficacy is assessed by hemoglobin increase from baseline and/or reduction in transfusion burden. Secondary endpoints include assessment of biomarkers for erythropoiesis, hemolysis, iron metabolism, and bone metabolism, as well as in vitro dyserythropoiesis. Dose escalation to higher dose levels is planned contingent on data review and favorable safety profile as determined by the Steering Committee. Results Patient demographics. A total of 25 patients have been enrolled as of July 26, 2013; 8 in the 0.1 mg/kg cohort, 9 in the 0.3 mg/kg cohort, and 8 in the 0.5 mg/kg cohort. Treatment and analysis for the 0.5 mg/kg cohort is underway and will be updated and presented. In the 0.1 and 0.3 mg/kg cohorts, 3 (18%) patients had β-thalassemia major and 14 (82%) had β-thalassemia intermedia (12 of whom were NTD and 2 of whom were TD). Of the 12 NTD β-thalassemia intermedia patients, 6 were treated at the 0.1 mg/kg dose level and 6 at the 0.3 mg/kg dose level. Median baseline hemoglobin for these NTD patients was 8.6 g/dL (range 5.8 to 10.7 g/dL). Median number of sotatercept doses administered was 4 (range 2 to 7) in the 0.1 mg/kg cohort and 8 (range 3 to 9) in the 0.3 mg/kg cohort; 13/17 (76%) patients remained on treatment. Safety.Sotatercept was generally well tolerated. There were no dose-limiting toxicities reported. Two serious adverse events were reported in the 0.1 mg/kg cohort: a grade 2 phlebitis in an NTD patient with a history of high D-dimer at baseline, and a worsening grade 3 bone pain in a TD β-thalassemia major patient with a history of osteoporosis; both were considered possibly study drug-related. Hemoglobin levels/transfusion requirements. Among NTD patients, preliminary data showed that 1 (17%) patient in the 0.1 mg/kg cohort and all 6 (100%) patients in the 0.3 mg/kg cohort had at least a 1 g/dL increase in hemoglobin level from baseline; among these, 1 patient treated with sotatercept 0.3 mg/kg showed a 2 g/dL hemoglobin level increase from baseline as well as a decrease in total bilirubin level from 2.7 × upper limit of normal (ULN) at baseline to 1.8 × ULN. No other relevant decrease in total bilirubin level was reported at the lower dose levels (0.1 mg/kg or 0.3 mg/kg). Three TD patients were still receiving treatment (2 β-thalassemia intermedia and 1 β-thalassemia major). There had been no appreciable reduction in transfusion burden in the 0.1 and 0.3 mg/kg cohorts to date; however further follow up is warranted and an update will be presented. Conclusion Based on these preliminary data, sotatercept administered subcutaneously every 3 weeks may improve anemia via a novel mechanism of action with a favorable safety profile, thereby addressing a significant unmet medical need for patients with NTD β-thalassemia intermedia. The current data suggest a dose-dependent response that supports further evaluation of the exposure–effect relationship of sotatercept in patients with NTD β-thalassemia intermedia. The first, second, and last authors contributed equally to this abstract. Disclosures: Cappellini: Genzyme: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Off Label Use: Sotatercept is an investigational agent that is being assessed for efficacy and safety in beta-thalassemia. Porter:Novartis: Consultancy, Research Funding; Shire: Consultancy; Celgene: Honoraria. Forni:Celgene: Research Funding; Shire: Research Funding; Novartis Pharma: Research Funding. Laadem:Celgene Corp.: Employment, Equity Ownership. Galacteros:Celgene: Consultancy. Miteva:Celgene Corp.: Employment. Sung:Celgene Corp.: Employment, Equity Ownership. Chopra:Celgene Corp.: Employment, Equity Ownership. Klesczewski:Celgene Corp.: Employment. Attie:Acceleron Pharma: Employment. Hermine:Celgene Corporation: Consultancy, Research Funding.
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Smith, William, Hartmut Malluche, and Keith Hruska. "SP645QUANTITATIVE COMPUTED TOMOGRAPHY RESULTS FOR BONE MASS AND ABDOMINAL AORTIC VASCULAR CALCIFICATION IN HEMODIALYSIS SUBJECTS TREATED WITH ESCALATING DOSE LEVELS OF SOTATERCEPT: INTERIM ANALYSIS OF ACE-011-REN-001." Nephrology Dialysis Transplantation 30, suppl_3 (May 2015): iii591. http://dx.doi.org/10.1093/ndt/gfv199.11.

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Klotz, B., L. Seefried, R. Ebert, and F. Jakob. "Activin-Antagonisten in der Therapie der Osteoporose." Osteologie 20, no. 03 (2011): 217–21. http://dx.doi.org/10.1055/s-0037-1619996.

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ZusammenfassungActivin A ist ein Polypeptid mit vielfältigen biologischen Wirkungen auf die Regulation der Fertilität, die Pluripotenz und Differenzierung von Stammzellen, die Differenzierung von Neuronen, Inselzellen und Immunzellen und die Regulation des Stoffwechsels. Activin gehört zu den Liganden der Familie der TGFβ- Superfamilie. Die Activine A, B und C binden an die Typ-II-BMP-Rezeptoren (Activin-Rezeptor IIA [ActRIIA] und IIB [ActRIIB]) und rekrutieren spezifische Typ-I-Rezeptoren (activin receptor-like kinase 2 [ALK2], 4 [ALK4] und 7 ]ALK7]). Da der ActRIIB auch andere Faktoren wie z. B. Myostatin (GDF8) und die Bone Morphogenetic Proteins 7 und 2 (BMP-7, BMP-2) bindet, konkurrieren diese Liganden um den Rezeptor. Im Alter findet man erhöhte Activin- Spiegel im Serum. Activin-Antagonisten verändern die Balance zwischen den verschiedenen Liganden und verursachen eine veränderte Genregulation an allen Zellen, die entsprechende Signalsysteme exprimieren. Ein ACTIIIGG- Fusionsprotein mit Activin-antagonistischer Wirkung wird unter dem Namen Sotatercept (ACE-011) bereits klinisch als Medikament gegen die Tumor-induzierte und die Chemotherapie- induzierte Anämie erprobt und präklinisch für die Therapie der Osteoporose entwickelt. Am Knochen entfaltet der Antagonist eine duale Wirkung, er zeigt ausgeprägte anabole Effekte und verringert die Knochenresorption. In einem Mausmodell der Androgendefizienz werden zudem eine anabole Wirkung am Muskel und eine Verringerung des Fettgewebes beschrieben. Weitere Studien sind auf dem Weg, um sicherzustellen, dass das vielversprechende Medikament bei der Anwendung am Menschen neben der Effizienz auch ein gutes Sicherheits- und Nebenwirkungsprofil besitzt. Wenn es die Klinikreife erreicht, wird es unser therapeutisches Arsenal zur Behandlung der Osteoporose und möglicherweise auch der Sarkopenie wesentlich bereichern.
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Komrokji, R., G. Garcia-Manero, L. Ades, A. Laadem, B. Vo, T. Prebet, A. Stamatoullas, et al. "14 A PHASE 2, DOSE-FINDING STUDY OF SOTATERCEPT (ACE-011) IN PATIENTS WITH LOWER-RISK MYELODYSPLASTIC SYNDROMES (MDS) OR NON-PROLIFERATIVE CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) AND ANEMIA REQUIRING TRANSFUSION." Leukemia Research 39 (April 2015): S5—S6. http://dx.doi.org/10.1016/s0145-2126(15)30015-1.

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Vecchio, Lucia Del, and Francesco Locatelli. "New Treatment Approaches in Chronic Kidney Disease-associated Anaemia." European Oncology & Haematology 07, no. 02 (2011): 132. http://dx.doi.org/10.17925/eoh.2011.07.02.132.

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Recombinant human erythropoietin (rHuEPO) is an effective agent for the treatment of anaemia in patients with chronic kidney disease. However, given its relatively short half-life, it requires a relatively frequent administration schedule. Moreover, it can be administered only subcutaneously or intravenously and is unstable at room temperature, making a strict cold chain control necessary. Pharmacological research has focused on the development of new agents to circumvent these relative disadvantages. Some long-acting erythropoietin-stimulating agents (ESAs) are already available for clinical use that require a less-frequent administration schedule. Peginesatide (Hematide™), which is a small dimeric peptide with a chemical structure unrelated to EPO, has recently ended phase III clinical trials. Other new molecules undergoing clinical development are CNTO 530 and CNTO 528, ACE-011 and hypoxia-inducible transcription factor stabilisers. The latter have the advantage that they can be administered orally but their clinical development faces a significant hurdle following a case of fatal hepatitis. Newer molecules in this class are undergoing clinical evaluation. Other strategies, such as EPO fusion proteins, agonistic antibodies targeting the EPO receptor and gene therapy have only been tested in animal models or are undergoing pre-clinical evaluations. Before clinical approval, all these new strategies need to address safety concerns raised recently about the use of ESAs regarding possible increased cardiovascular risks following targeting to high haemoglobin levels and/or exposure to excessive doses without reaching a target in both higher and lower haemoglobin groups, and reduced survival and tumour control in the oncology setting. Many of these molecules will also need careful evaluation for possible immunogenicity.
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Raftopoulos, H., A. Laadem, M. Puccio, and R. D. Knight. "A phase II/III study of sotatercept (ACE-011), an activin antagonist, for chemotherapy-induced anemia in patients with metastatic non-small cell lung cancer treated with first-line platinum-based chemotherapy." Journal of Clinical Oncology 29, no. 15_suppl (May 20, 2011): TPS235. http://dx.doi.org/10.1200/jco.2011.29.15_suppl.tps235.

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Raftopoulos, Haralambos, Abderrahmane Laadem, Paul J. Hesketh, Jerome Goldschmidt, Nashat Gabrail, Cynthia Osborne, Muhammad Ali, et al. "Sotatercept (ACE-011) for the treatment of chemotherapy-induced anemia in patients with metastatic breast cancer or advanced or metastatic solid tumors treated with platinum-based chemotherapeutic regimens: results from two phase 2 studies." Supportive Care in Cancer 24, no. 4 (September 14, 2015): 1517–25. http://dx.doi.org/10.1007/s00520-015-2929-9.

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Komrokji, Rami S., Guillermo Garcia-Manero, Lionel Ades, Abderrahmane Laadem, Bond Vo, Thomas Prebet, Aspasia Stamatoullas, et al. "An Open-Label, Phase 2, Dose-Finding Study of Sotatercept (ACE-011) in Patients with Low or Intermediate-1 (Int-1)-Risk Myelodysplastic Syndromes (MDS) or Non-Proliferative Chronic Myelomonocytic Leukemia (CMML) and Anemia Requiring Transfusion." Blood 124, no. 21 (December 6, 2014): 3251. http://dx.doi.org/10.1182/blood.v124.21.3251.3251.

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Abstract Introduction: Anemia, a hallmark of MDS, is challenging to treat, particularly after failure of erythropoiesis-stimulating agents (ESAs). Sotatercept (ACE-011) is a novel and first-in-class activin type IIA receptor fusion protein that acts on late-stage erythropoiesis to increase mature erythrocyte release into the circulation (Carrancio et al. Br J Haematol 2014;165:870-82). Treatment with sotatercept stimulated erythropoiesis and significantly increased hemoglobin (Hb) levels in healthy volunteers (Sherman et al. J Clin Pharmacol 2013;53:1121-30), supporting its clinical development for the treatment of anemia in patients (pts) with lower-risk MDS. Methods: The primary objective of this phase 2, open-label, dose-finding study is to determine a safe, tolerable, and effective dose of sotatercept resulting in erythroid hematological improvement (HI-E; modified IWG 2006 criteria) in pts with anemia and IPSS-defined Low or Int-1-risk MDS or non-proliferative CMML (white blood cells < 13,000/µL). Secondary objectives include rate of RBC-transfusion independence (RBC-TI) ≥ 8 weeks. Eligible pts had anemia (≥ 2 RBC units transfusion requirement in the 12 weeks prior to enrollment for Hb ≤ 9.0 g/dL) with no response, loss of response, or low chance of response to ESAs (serum erythropoietin [EPO] > 500 mIU/mL). Pts received subcutaneous sotatercept at dose levels of 0.1, 0.3, 0.5, or 1.0 mg/kg once every 3 weeks. ClinicalTrials.gov identifier: NCT01736683. Results: As of May 22, 2014, a total of 54 MDS pts were enrolled: 7, 6, 21, and 20 in the sotatercept 0.1, 0.3, 0.5, and 1.0 mg/kg dose groups, respectively. Median age was 71 years (range 56–86) and median time from diagnosis was 4 years (range 0–31); most pts were male (70%). Pts received a median of 6 RBC units (range 0–18) in the 8 weeks prior to treatment start. Forty-five pts (83%) received ≥ 4 RBC units in the 8 weeks prior to treatment start (high transfusion burden; HTB), and 9 pts (17%) received < 4 units in the 8 weeks prior to treatment start (low transfusion burden; LTB). Nineteen pts (35%) had IPSS Low and 34 pts (63%) had IPSS Int-1-risk MDS; IPSS risk data were missing for 1 pt. Fifty-one pts (94%) had prior treatment with ESAs, 30 (56%) with hypomethylating agents, 26 (48%) with lenalidomide, and 26 (48%) with other MDS treatments; 15 pts (28%) had serum EPO > 500 mIU/mL. Of the 53 pts evaluable for efficacy, HI-E was observed in 21 pts (40%) overall: 0, 4 (67%), 8 (40%), and 9 pts (45%) in the sotatercept 0.1, 0.3, 0.5, and 1.0 mg/kg dose groups, respectively. Nineteen of 44 HTB pts responded with a ≥ 4 RBC units/8 weeks transfusion burden reduction; duration of transfusion response appeared to be dose-dependent. Five HTB pts achieved RBC-TI ≥ 8 weeks, with RBC-TI duration ranging from 59–345+ days. Eight of 9 LTB pts showed Hb increases, not influenced by transfusion, ranging from 1.3–3.8 g/dL. Of these, 2 pts had a Hb increase ≥ 1.5 g/dL sustained for ≥ 8 weeks. Pts with Hb > 11.0 g/dL were subject to dose delay per protocol, which may have impacted Hb increase sustainability. RBC-TI ≥ 8 weeks was achieved in 6 LTB pts. Increases in platelet and neutrophil levels were seen in pts with baseline thrombocytopenia and pts with baseline neutropenia, respectively. Sotatercept was generally well tolerated. Twenty pts (37%) reported ≥ 1 suspected treatment-related adverse event (AE); fatigue (11%), headache (9.3%), decreased appetite (7.4%), and nausea (7.4%) were the most common. Of 35 pts (65%) who discontinued treatment, 28 discontinued due to lack of therapeutic effect and 4 due to AEs. Of those AEs leading to discontinuation, 3 were suspected to be treatment-related: 1 pt with grade 2 hemolytic anemia, 1 pt with grade 3 hypertension, and 1 pt with grade 2 muscular weakness in the sotatercept 0.3, 0.5, and 1.0 mg/kg dose groups, respectively. Other reasons for discontinuation were withdrawal of consent (n = 2; 4%) and pt decision (n = 1; 2%). Conclusions: Sotatercept was well tolerated in lower-risk MDS pts at the dose levels tested, with promising evidence of clinical activity in this largely HTB cohort of ESA-refractory, anemic, lower-risk MDS pts. Further exploration of higher sotatercept dose levels and longer-term treatment is planned. PF and AFL contributed equally to this abstract as senior co-authors. Disclosures Komrokji: Celgene Corporation: Consultancy, Research Funding. Off Label Use: Sotatercept (ACE-011) is an investigational agent that is being assessed for efficacy and safety in myelodysplastic syndromes.. Garcia-Manero:Celgene Corporation: Research Funding. Ades:Novartis: Research Funding; Celgene Corporation: Research Funding. Laadem:Celgene Corporation: Employment, Equity Ownership. Vo:Celgene Corporation: Employment. Prebet:Celgene Corporation: Honoraria. Boyd:US Oncology: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen Corporation: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim Corporation: Membership on an entity's Board of Directors or advisory committees. Beyne-Rauzy:Novartis: Research Funding; Celgene: Research Funding. Zou:Celgene: Employment. Attie:Acceleron Pharma: Employment. Sherman:Acceleron Pharma: Employment, Equity Ownership. Fenaux:Novartis: Research Funding; Janssen: Research Funding; Celgene: Research Funding. List:Celgene: Consultancy.
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Vasekar, Monali, and Timothy J. Craig. "ACE Inhibitor–Induced Angioedema." Current Allergy and Asthma Reports 12, no. 1 (November 30, 2011): 72–78. http://dx.doi.org/10.1007/s11882-011-0238-z.

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Maurin, Corantin, Zhiguo He, Marielle Mentek, Paul Verhoeven, Sylvie Pillet, Thomas Bourlet, Françoise Rogues, et al. "Exploration of the ocular surface infection by SARS-CoV-2 and implications for corneal donation: An ex vivo study." PLOS Medicine 19, no. 3 (March 1, 2022): e1003922. http://dx.doi.org/10.1371/journal.pmed.1003922.

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Background The risk of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) transmission through corneal graft is an ongoing debate and leads to strict restrictions in corneas procurement, leading to a major decrease in eye banking activity. The aims of this study are to specifically assess the capacity of human cornea to be infected by SARS-CoV-2 and promote its replication ex vivo, and to evaluate the real-life risk of corneal contamination by detecting SARS-CoV-2 RNA in corneas retrieved in donors diagnosed with Coronavirus Disease 2019 (COVID-19) and nonaffected donors. Methods and findings To assess the capacity of human cornea to be infected by SARS-CoV-2, the expression pattern of SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE-2) and activators TMPRSS2 and Cathepsins B and L in ocular surface tissues from nonaffected donors was explored by immunohistochemistry (n = 10 corneas, 78 ± 11 years, 40% female) and qPCR (n = 5 corneas, 80 ± 12 years, 40% female). Additionally, 5 freshly excised corneas (80 ± 12 years, 40% female) were infected ex vivo with highly concentrated SARS-CoV-2 solution (106 median tissue culture infectious dose (TCID50)/mL). Viral RNA was extracted from tissues and culture media and quantified by reverse transcription quantitative PCR (RT-qPCR) (viral RNA copies) 30 minutes (H0) and 24 hours (H24) after infection. To assess the risk of corneal contamination by SARS-CoV-2, viral RNA was tested by RT-qPCR (Ct value) in both corneas and organ culture media from 14 donors diagnosed with COVID-19 (74 ± 10 years, 29% female) and 26 healthy donors (79 ± 13 years, 57% female), and in organ culture media only from 133 consecutive nonaffected donors from 2 eye banks (73 ± 13 years, 29% female). The expression of receptor and activators was variable among samples at both protein and mRNA level. Based on immunohistochemistry findings, ACE-2 was localized mainly in the most superficial epithelial cells of peripheral cornea, limbus, and conjunctiva, whereas TMPRSS2 was mostly expressed in all layers of bulbar conjunctiva. A significant increase in total and positive strands of IP4 RNA sequence (RdRp viral gene) was observed from 30 minutes to 24 hours postinfection in central cornea (1.1 × 108 [95% CI: 6.4 × 107 to 2.4 × 108] to 3.0 × 109 [1.4 × 109 to 5.3 × 109], p = 0.0039 and 2.2 × 107 [1.4 × 107 to 3.6 × 107] to 5.1 × 107 [2.9 × 107 to 7.5 × 107], p = 0.0117, respectively) and in corneoscleral rim (4.5 × 109 [2.7 × 109 to 9.6 × 109] to 3.9 × 1010 [2.6 × 1010 to 4.4 × 1010], p = 0.0039 and 3.1 × 108 [1.2 × 108 to 5.3 × 108] to 7.8 × 108 [3.9 × 108 to 9.9 × 108], p = 0.0391, respectively). Viral RNA copies in ex vivo corneas were highly variable from one donor to another. Finally, viral RNA was detected in 3 out of 28 corneas (11%) from donors diagnosed with COVID-19. All samples from the 159 nonaffected donors were negative for SARS-CoV-2 RNA. The main limitation of this study relates to the limited sample size, due to limited access to donors diagnosed with COVID-19 and concomitant decrease in the procurement corneas from nonaffected donors. Conclusions In this study, we observed the expression of SARS-CoV-2 receptors and activators at the human ocular surface and a variable increase in viral RNA copies 24 hours after experimental infection of freshly excised human corneas. We also found viral RNA only in a very limited percentage of donors with positive nasopharyngeal PCR. The low rate of positivity in donors diagnosed with COVID-19 calls into question the utility of donor selection algorithms. Trial registration Agence de la Biomédecine, PFS-20-011 https://www.agence-biomedecine.fr/.
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Nawaz, Syed Kashif, and Shahida Hasnain. "Association of ACE ID and ACE G2350A polymorphism with increased blood pressure in persons exposed to different sound levels in Pakistan." International Archives of Occupational and Environmental Health 84, no. 4 (February 9, 2011): 355–60. http://dx.doi.org/10.1007/s00420-011-0619-6.

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Nguyen, V. M., T. T. Tran, and H. N. Vo. "The study of angiotensin converting enzyme isolation from crossbred rabbit lung and enzyme storage capacity in frozen conditions." Food Research 4, no. 4 (March 26, 2020): 1082–88. http://dx.doi.org/10.26656/fr.2017.4(4).011.

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The study was carried out to obtain angiotensin converting enzyme (ACE) with high specific activity and to evaluate the ability to maintain enzyme activity in extract products as well as in rabbit lungs using frozen condition. In the scope of the content, the study conducted an evaluation to select the appropriate extraction solvent of four solvents including acetone, ethanol, Tris-HCl and distilled water. Initially, the research results have helped determine distilled water as the suitable extraction solvent and the difference is not statistically significant compared to Tris-HCl solvent. Angiotensin converting enzyme extract that was obtained by distilled water solvent has a specific activity of 10.35 U/g protein. In addition, the study investigated the ability to maintain angiotensin converting enzyme activity in rabbit lung and crude enzyme product during frozen storage (-18±2°C). The results of the study showed that angiotensin converting enzyme activity could be maintained for 3 months in rabbit lungs and 4 months in the crude product. Besides, the study also used ammonium sulfate with different concentrations to conduct angiotensin converting enzyme collection from extract product. The results of this content help determine the use of saturated ammonium sulfate with concentrations of 50% to 60% for the highest efficiency. The precipitation process helped obtain ACE products with a purity of 4.22 times, the specific activity of 42.64 U/g protein and the recovery rate of ACE up to 29.37%.
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Kim, Young Ree, Hyun Ju Kim, Mi Hee Kong, Keun Hwa Lee, Sun Hyung Kim, Sung Ha Kang, and Seung Ho Hong. "The ACE polymorphism is associated with BMI in patients with metabolic syndrome." Genes & Genomics 33, no. 4 (August 2011): 343–48. http://dx.doi.org/10.1007/s13258-011-0054-9.

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Garatachea, Nuria, Carmen Fiuza-Luces, Gema Torres-Luque, Thomas Yvert, Catalina Santiago, Félix Gómez-Gallego, Jonatan R. Ruiz, and Alejandro Lucia. "Single and combined influence of ACE and ACTN3 genotypes on muscle phenotypes in octogenarians." European Journal of Applied Physiology 112, no. 7 (November 2, 2011): 2409–20. http://dx.doi.org/10.1007/s00421-011-2217-4.

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Murry, Benrithung, Neikethono Vakha, Nongthombam Achoubi, M. P. Sachdeva, and K. N. Saraswathy. "APOE, MTHFR, LDLR and ACE Polymorphisms Among Angami and Lotha Naga Populations of Nagaland, India." Journal of Community Health 36, no. 6 (April 3, 2011): 975–85. http://dx.doi.org/10.1007/s10900-011-9397-z.

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Misra, Usha K., Jayantee Kalita, Bindu I. Somarajan, Bishwanath Kumar, Moromi Das, and Balraj Mittal. "Do ACE (rs4646994) and αADDUCIN (rs4961) gene polymorphisms predict the recurrence of hypertensive intracerebral hemorrhage?" Neurological Sciences 33, no. 5 (December 24, 2011): 1071–77. http://dx.doi.org/10.1007/s10072-011-0903-y.

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Kwok, T., J. Leung, Y. F. Zhang, D. Bauer, K. E. Ensrud, E. Barrett-Connor, and P. C. Leung. "Does the use of ACE inhibitors or angiotensin receptor blockers affect bone loss in older men?" Osteoporosis International 23, no. 8 (November 12, 2011): 2159–67. http://dx.doi.org/10.1007/s00198-011-1831-7.

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Kim, Wook, Hyun Ik Cho, Ki Cheol Kim, Young Ho So, and Jang Gun Oh. "Relationships between digit ratio (2D:4D), ACE gene polymorphism, and physical performance in the Korean population." Genes & Genomics 33, no. 4 (August 2011): 407–12. http://dx.doi.org/10.1007/s13258-011-0039-8.

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Ko, Seok-Chun, Min Cheol Kang, Jung-Kwon Lee, Hee-Guk Byun, Se-Kwon Kim, Seung-Cheol Lee, Byong-Tae Jeon, Pyo-Jam Park, Won-Kyo Jung, and You-Jin Jeon. "Effect of angiotensin I-converting enzyme (ACE) inhibitory peptide purified from enzymatic hydrolysates of Styela plicata." European Food Research and Technology 233, no. 6 (October 4, 2011): 915–22. http://dx.doi.org/10.1007/s00217-011-1585-7.

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Valika, Ali A., and Mihai Gheorghiade. "Ace inhibitor therapy for heart failure in patients with impaired renal function: a review of the literature." Heart Failure Reviews 18, no. 2 (January 3, 2012): 135–40. http://dx.doi.org/10.1007/s10741-011-9295-6.

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Kerkaert, Barbara, Frédéric Mestdagh, Tatiana Cucu, Kshitij Shrestha, John Van Camp, and Bruno De Meulenaer. "The impact of photo-induced molecular changes of dairy proteins on their ACE-inhibitory peptides and activity." Amino Acids 43, no. 2 (November 25, 2011): 951–62. http://dx.doi.org/10.1007/s00726-011-1157-y.

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Cacciatore, Francesco, Giuseppe Bruzzese, Dino Franco Vitale, Antonio Liguori, Filomena de Nigris, Carmela Fiorito, Teresa Infante, et al. "Effects of ACE inhibition on circulating endothelial progenitor cells, vascular damage, and oxidative stress in hypertensive patients." European Journal of Clinical Pharmacology 67, no. 9 (March 29, 2011): 877–83. http://dx.doi.org/10.1007/s00228-011-1029-0.

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Sun, Yuanxia, Shigeru Hayakawa, Masahiro Ogawa, Supaporn Naknukool, Yupin Guan, and Yoshiyuki Matsumoto. "Evaluation of angiotensin I-converting enzyme (ACE) inhibitory activities of hydrolysates generated from byproducts of freshwater clam." Food Science and Biotechnology 20, no. 2 (April 2011): 303–10. http://dx.doi.org/10.1007/s10068-011-0043-4.

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Lee, Seung-Ju, Dong Sup Lee, Hyun-Sop Choe, Dong Choon Park, and Yong-Hyun Cho. "Evaluation of Seeplex® STD6 ACE Detection kit for the diagnosis of six bacterial sexually transmitted infections." Journal of Infection and Chemotherapy 18, no. 4 (2012): 494–500. http://dx.doi.org/10.1007/s10156-011-0362-7.

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Masud, Rizwan, and Irfan Zia Qureshi. "Tetra primer ARMS-PCR relates folate/homocysteine pathway genes and ACE gene polymorphism with coronary artery disease." Molecular and Cellular Biochemistry 355, no. 1-2 (May 13, 2011): 289–97. http://dx.doi.org/10.1007/s11010-011-0866-6.

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49

Wang, Hui, Yongyu Li, Yongqiang Cheng, Lijun Yin, and Lite Li. "Effect of the Maillard Reaction on Angiotensin I-Converting Enzyme (ACE)-Inhibitory Activity of Douchi During Fermentation." Food and Bioprocess Technology 6, no. 1 (May 27, 2011): 297–301. http://dx.doi.org/10.1007/s11947-011-0596-5.

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50

Gandhi, Gunjan Y., and William L. Isley. "Review: ACE inhibitors and angiotensin-receptor blockers reduce diabetes in hypertension and other CV risk factors." ACP Journal Club 146, no. 1 (January 1, 2007): 11. http://dx.doi.org/10.7326/acpjc-2007-146-1-011.

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