scholarly journals Contact Activation Inhibitor and Factor XI Antibody, AB023, Produces Safe, Dose-Dependent Anticoagulation in a Phase 1 First-In-Human Trial

2019 ◽  
Vol 39 (4) ◽  
pp. 799-809 ◽  
Author(s):  
Christina U. Lorentz ◽  
Norah G. Verbout ◽  
Michael Wallisch ◽  
Matthew W. Hagen ◽  
Joseph J. Shatzel ◽  
...  
Keyword(s):  
Adverse Events ◽  
Healthy Adult ◽  
Thrombus Formation ◽  
Phase 1 ◽  
Human Study ◽  
Contact Activation ◽  
Factor Xi ◽  
Primate Model ◽  
Graft Thrombosis ◽  
Dose Dependent

Objective— Factor XI (FXI) contributes to thrombotic disease while playing a limited role in normal hemostasis. We generated a unique, humanized anti-FXI antibody, AB023, which blocks factor XIIa-mediated FXI activation without inhibiting FXI activation by thrombin or the procoagulant function of FXIa. We sought to confirm the antithrombotic activity of AB023 in a baboon thrombosis model and to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy adult subjects. Approach and Results— In a primate model of acute vascular graft thrombosis, AB023 reduced platelet and fibrin accumulation within the grafts by >75%. To evaluate the safety of AB023, we performed a first-in-human study in healthy adult volunteers without any serious adverse events. Overall, 10 of 21 (48%) subjects experienced 20 treatment-emergent adverse events, with 7 of 16 (44%) subjects following active treatment and 3 of 5 (60%) subjects following placebo. AB023 did not increase bleeding or prothrombin times. Anticoagulation was verified by a saturable ≈2-fold prolongation of the partial thromboplastin time for over 1 month after the highest dose. Conclusions— AB023, which inhibits contact activation-initiated blood coagulation in vitro and experimental thrombus formation in primates, produced a dose-dependent duration of limited anticoagulation without drug-related adverse effects in a phase 1 trial. When put in context with earlier observations suggesting that FXI contributes to venous thromboembolism and cardiovascular disease, although contributing minimally to hemostasis, our data further justify clinical evaluation of AB023 in conditions where contact-initiated FXI activation is suspected to have a pathogenic role. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT03097341.

SAT0196 A DOUBLE BLIND, PLACEBO CONTROLLED, SINGLE ASCENDING DOSE (SAD) AND MULTIPLE ASCENDING DOSE (MAD) STUDY OF ALPN-101, A FIRST-IN-CLASS DUAL ICOS/CD28 ANTAGONIST, IN HEALTHY VOLUNTEERS (HV)

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1040-1040
Author(s):  
J. Yang ◽  
J. Hillson ◽  
J. Lickliter ◽  
K. Manjarrez ◽  
A. Tercero ◽  
...  
Keyword(s):  
Adverse Events ◽  
Inflammatory Diseases ◽  
Phase 1 ◽  
Human Study ◽  
Keyhole Limpet Hemocyanin ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Expert Review ◽  
High Level ◽  
Dose Dependent

Background:ALPN-101 (ICOSL vIgD-Fc) is an Fc fusion protein of a human inducible T cell costimulatory ligand (ICOSL) variant immunoglobulin domain (vIgD™) designed to inhibit simultaneously the CD28 and ICOS inflammation pathways (1). ALPN-101 is effective in preclinical studies of lupus, arthritis, and Sjögren’s, and shows greater activity than single pathway inhibitors (2,3,4). It is in development for the treatment of multiple rheumatic and other inflammatory diseases.Objectives:To evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ALPN-101 in HVMethods:This was a first-in-human study of ALPN-101 (NCT03748836). 72 HV were allocated 4:2 to single intravenous (IV) or subcutaneous (SC) doses of ALPN-101: placebo at 0.001 – 10 mg/kg; 24 HV were allocated 6:2 to repeated IV doses of up to 1 mg/kg weekly x 4. Subjects were followed for 28 (SAD) or 49 (MAD) days to assess safety, PK, target saturation (TS) on T cells, circulating cytokines and PD, the latter based on suppression of IgG responses to keyhole limpet hemocyanin (KLH).Results:ALPN-101 was generally well-tolerated, with no treatment related serious adverse events, no cytokine release, no clinical immunogenicity, and no adverse trends in safety laboratories. Overall, adverse events were reported in 74.2% of subjects on ALPN-101 and 66.7% of subjects on placebo. All events were mild or moderate and resolved without sequelae. Dose-dependent increase in ALPN-101 exposure was observed from 0.012 to 10 mg/kg. The estimated t1/2was 2-8.6 days over 0.3 – 10 mg/kg. SC bioavailability was ~60% at 3 mg/kg. Minimal to modest accumulation was observed with repeat IV dosing. The TS at Cmaxincreased with dose between 0.001–0.03 mg/kg; thereafter the duration of high level TS (>95%) increased with dose (Figure 1). The duration of suppression of IgG anti-KLH response paralleled the duration of high level TS (Figure 2).Figure 1.Mean + SD Target Saturation of ALPN-101 on Circulating CD4+T LymphocytesFigure 2.Mean + SD Serum Anti-KLH IgG Change Relative to BaselineConclusion:ALPN-101 was well tolerated when administered as single doses up to 10 mg/kg or as repeated doses of up to 1 mg/kg weekly for 4 weeks, exhibiting dose-dependent PK, TS and PD including the inhibition of antibody responses to KLH immunization. These findings support future studies to evaluate the efficacy of ALPN-101 in multiple rheumatic and other inflammatory diseases.References:[1]Levin SD et al. Frontiers in Immunology 2020; 10:3086[2]Evans L et al. Arthritis and Rheumatology 2019:71: Supplement: Abstract 1531[3]Dillon S et al. Arthritis and Rheumatology 2018:70: Supplement: Abstract 136[4]Dillon S et al. Arthritis and Rheumatology 2019:71: Supplement: Abstract 2416Disclosure of Interests:Jing Yang Shareholder of: Alpine Immune Sciences, Inc., Employee of: Alpine Immune Sciences, Inc., Jan Hillson Shareholder of: Alpine Immune Sciences, Inc., Employee of: Alpine Immune Sciences, Inc., Jason Lickliter Consultant of: AUD 2500 from QBiotics for participation in an expert review panel for development of their oncology phase 1 trial (in Nov 2015), Kristi Manjarrez Shareholder of: Alpine Immune Sciences, Inc., Employee of: Alpine immune sciences, Inc., Almudena Tercero Shareholder of: Alpine Immune Sciences, Inc., Employee of: Alpine Immune Sciences, Inc., Jennifer Wiley Shareholder of: Alpine Immune Sciences, Inc., Employee of: Alpine Immune Sciences, Inc., Gary Means Shareholder of: Alpine Immune Sciences, Inc., Employee of: Alpine Immune Sciences, Inc., Russell Sanderson Shareholder of: Alpine Immune Sciences, Inc., Employee of: Alpine Immune Sciences, Inc., Kay Carley Shareholder of: Alpine Immune Sciences, Inc., Employee of: Alpine Immune Sciences, Inc., Stanford L. Peng Shareholder of: Alpine Immune Sciences, Inc., Employee of: CMO and President of Alpine Immune Sciences, Inc.

Abstract 56: Coagulation Factor XI Promotes Distal Platelet Activation and Single Platelet Consumption in the Bloodstream Under Shear Flow

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Jenya Zilberman-Rudenko ◽  
Chantal Wiesenekker ◽  
Asako Itakura ◽  
Owen J McCarty
Keyword(s):  
Shear Flow ◽  
Platelet Activation ◽  
Platelet Adhesion ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Coagulation Factor ◽  
Thrombin Inhibitor ◽  
Dependent Manner ◽  
Factor Xi ◽  
Primate Model

Objective: Coagulation factor XI (FXI) has been shown to contribute to thrombus formation on collagen or tissue factor (TF)-coated surfaces in vitro and in vivo by enhancing thrombin generation. Whether the role of the intrinsic pathway of coagulation is restricted to the local site of thrombus formation is unknown. This study was designed to determine whether FXI could promote both proximal and distal platelet activation and aggregate formation in the bloodstream. Approach and Results: Pharmacological blockade of FXI activation or thrombin activity in blood did not affect local platelet adhesion, yet reduced local platelet aggregation, thrombin localization and fibrin formation on immobilized collagen and TF under shear flow, ex vivo . Downstream of the thrombus formed on immobilized collagen or collagen and 10 pM TF, platelet CD62P expression and microaggregate formation and progressive platelet consumption were significantly reduced in the presence of FXI-function blocking antibodies or a thrombin inhibitor in a shear rate- and time-dependent manner. In a non-human primate model of thrombus formation, we found that inhibition of FXI reduced single platelet consumption in the bloodstream distal to a site of thrombus formation. Conclusions: This study demonstrates that the FXI-thrombin axis contributes to distal platelet activation and procoagulant microaggregate formation in the blood flow downstream of the site of thrombus formation. Our data highlights FXI as a novel therapeutic target for inhibiting distal platelet activation without affecting proximal platelet adhesion.

NE-180, a Novel glycoPEGylated Erythropoietin Demonstrates Dose-Dependent Activity in a Phase 1 Single Dose, Dose Escalating Study in Normal Human Volunteers (NHV).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1149-1149
Author(s):  
Bruce A. Wallin ◽  
Denise Ramjit ◽  
Michael Seiberling ◽  
David Zopf
Keyword(s):  
Adverse Events ◽  
Animal Studies ◽  
Phase 1 ◽  
Stopping Rules ◽  
Open Label ◽  
Serious Adverse Events ◽  
Maximal Increase ◽  
The Mean ◽  
Dose Dependent

Abstract NE-180 is a glycoPEGylated recombinant human erythropoietin that binds to and activates the erythropoietin (EPO) receptor. It has demonstrated in vitro activities comparable to EPO and an extended serum half-life in animal studies. This may allow less frequent dosing in patients being treated with chronic anemia. METHODS: A single center, open-label study of NE-180, administered as single escalating doses given by the SC or IV route, was conducted to assess the safety, tolerability, PK and PD. Subjects (male or female NHV) were planned to be assigned to one of 4 dose groups, 10 subjects per dose with 5 SC and 5 IV subjects per group: 0.5, 1.5, 3, or 4.5 mg/kg. Each dose group was planned to be initiated in an ascending, sequential fashion unless or until stopping rules were met. RESULTS: 25 NHV (16 females) were enrolled in the first two dose cohorts and have completed 56 day follow-up. The 1.5 mg/kg IV cohort met the protocol-specified Hb rate of rise stopping rule (change in Hb greater than 1 g/dL during any 14 day period). Injections were generally well tolerated with no discontinuations for adverse events or serious adverse events. Reticulocyte increases were dose proportional. Average reticulocyte count at baseline was 1.0±0.3%. The maximal increase occurred at day 7. The mean change from baseline for the 0.5 and 1.5 mg/kg SC group was: 0.9±0.4% and 2.2±0.9%, respectively. The mean change from baseline for the 0.5 and 1.5 mg/kg IV group was: 1.7±0.8% and 2.3±0.8%, respectively. PK data will be presented. CONCLUSIONS: Single doses up to 1.5 mg/kg of NE-180 administered to NHV were generally well tolerated and demonstrated potent dose-dependent erythropoietic activity.

scholarly journals First-in-Human Evaluation of the Safety, Tolerability, and Pharmacokinetics of SPR720, a Novel Oral Bacterial DNA Gyrase (GyrB) Inhibitor for Mycobacterial Infections

2021 ◽  
Author(s):  
Angela K. Talley ◽  
Archie Thurston ◽  
Grayson Moore ◽  
Vipul K. Gupta ◽  
Myriah Satterfield ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase 1 ◽  
Human Study ◽  
Dna Gyrase ◽  
Plasma Exposure ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Bacterial Dna ◽  
Elimination Pathway

SPR720 (phosphate pro-drug of SPR719) is a novel aminobenzimidazole bacterial DNA gyrase (GyrB) inhibitor in development for non-tuberculous mycobacterial pulmonary disease (NTM-PD) and pulmonary tuberculosis. SPR719 has demonstrated activity against clinically relevant mycobacteria in vitro and in murine and hollow fiber infection models. This Phase 1 randomized, double-blind, placebo-controlled, single ascending dose (SAD)/multiple ascending dose (MAD) trial evaluated the safety, tolerability, and pharmacokinetics of SPR720/SPR719. A total of 96 healthy volunteers (n=8/cohort, 3:1 randomization) received SPR720 (or placebo) as single oral doses ranging from 100 mg to 2000 mg, or repeat total daily doses ranging from 500 mg to 1500 mg for 7 or 14 days. SPR720 was well-tolerated at daily doses up to 1000 mg for up to 14 days. Across SAD/MAD cohorts, the most common adverse events (AEs) were gastrointestinal (nausea, vomiting and diarrhea) and headache, all of mild or moderate severity and dose dependent. No serious adverse events were reported. The median SPR719 T max ranged from 2.8 to 8.0 hours across cohorts, and the t 1/2 ranged from 2.9 to 4.5 hours and was shown to be dose-independent. Dosing with food decreased SPR719 plasma exposure by approximately 20%. In the MAD cohorts, SPR719 plasma exposure declined approximately 40% between Days 1 and 7, suggesting induction of an elimination pathway. However, plasma AUC 0-24 was comparable between Days 7 and 14. Results of this first-in-human study suggest that predicted therapeutic exposures of SPR719 can be attained with a once-daily oral administration of SPR720.

Safety, Tolerability, and Clinical Outcomes after Intraarticular Injection of a Recombinant Adeno-associated Vector Containing a Tumor Necrosis Factor Antagonist Gene: Results of a Phase 1/2 Study

2009 ◽  
Vol 37 (4) ◽  
pp. 692-703 ◽  
Author(s):  
PHILIP J. MEASE ◽  
NATHAN WEI ◽  
EDWARD J. FUDMAN ◽  
ALAN J. KIVITZ ◽  
JOY SCHECHTMAN ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Adverse Events ◽  
Clinical Outcomes ◽  
Tumor Necrosis ◽  
Phase 1 ◽  
Open Label ◽  
Disseminated Histoplasmosis ◽  
Patient Reported ◽  
Dose Dependent ◽  
Necrosis Factor

Objective.To assess safety and clinical outcomes in patients with inflammatory arthritis after intraarticular (IA) injection of rAAV2-TNFR:Fc, a recombinant adeno-associated viral vector containing the human tumor necrosis factor (TNF) receptor-immunoglobulin (IgG1) Fc fusion (TNFR:Fc) gene.Methods.In this phase 1/2 randomized study, adults with persistent moderate or severe inflammation in a target joint, being treated with or without systemic anti-TNF therapy, received a single IA injection of either rAAV2-TNFR:Fc (1 × 1011, 1 × 1012, or 1 × 1013DNase-resistant particles/ml joint volume) or placebo, followed by open-label rAAV2-TNFR:Fc 12–30 weeks later, depending on when the target joint met predetermined criteria for reinjection.Results.127 subjects received the first injection of blinded study drug; 95 subjects received open-label rAAV2-TNFR:Fc. Administration site reactions, consisting of transient mild to moderate increases in tenderness and swelling of the injected joint, occurred after 23/191 (12%) rAAV2-TNFR:Fc injections and were dose-dependent. Rates of other adverse events were not dose-dependent. Notable serious adverse events (SAE) included culture-negative septic arthritis in a subject receiving leflunomide and fatal disseminated histoplasmosis considered unrelated to rAAV2-TNFR:Fc in a subject receiving adalimumab. In the phase 2 portion of the study, a 30% decrease in target joint global visual analog scale was observed in 21/50 (42%) rAAV2-TNFR:Fc subjects and 3/16 (19%) placebo subjects 12 weeks after first injection (p = 0.14).Conclusion.IA rAAV2-TNFR:Fc resulted in administration site reactions after 12% of injections. A fatal SAE, disseminated histoplasmosis, was considered not related to study agent. Patient-reported outcome measures of clinical response showed greater improvement in treated patients than placebo patients.

New Insights Into Factor XI Function: From Biochemistry to Animal Models

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. SCI-20-SCI-20
Author(s):  
David Gailani
Keyword(s):  
Animal Models ◽  
Arterial Thrombosis ◽  
Conflicts Of Interest ◽  
Thrombus Formation ◽  
Anticoagulation Therapy ◽  
Factor Ix ◽  
Bleeding Complications ◽  
Contact Activation ◽  
Factor Xi ◽  
Deficient Mice

Abstract Abstract SCI-20 Factor XI (fXI) is the zymogen of an enzyme (fXIa) that contributes to blood coagulation through activation of factor IX (fIX). FXI has structural and mechanistic features that distinguish it from the vitamin K-dependent proteases of coagulation. The protein is a dimer of identical 80 kDa subunits, each containing four apple domains (A1-A4) that form a platform at the base of the trypsin-like protease domain. The apple domains contain binding sites for fIX, platelet receptors, and high molecular weight kininogen. FXI is converted to fXIa by cleavage of a single bond on each subunit, unmasking exosites required for fIX binding. Conversion of fXI to fXIa proceeds through an intermediate with only one activated subunit (1/2-fXIa). 1/2-fXIa, and monomeric forms of fXIa, activate fIX in a manner similar to fully activated fXIa, indicating each subunit functions as a complete enzyme. The importance of the dimeric structure of fXI is not clear at this point. It may facilitate activation, or allow fXIa to bind simultaneously to fIX and a surface (a platelet for example) at a wound site. Congenital fXI deficiency is associated with a variable propensity to bleed excessively after trauma to certain tissues. Symptoms are usually milder than in fIX deficiency (hemophilia B), and many affected individuals are asymptomatic. In the cascade-waterfall model of coagulation, fXI is activated by factor XIIa (fXIIa) during a process called contact activation. However, current models often omit contact activation, because fXII deficiency is not associated with abnormal hemostasis. Thrombin activates fXI, providing an explanation for normal hemostasis in fXII deficiency. In contrast to its modest role in hemostasis, fXI may serve an important role in thromboembolic diseases. High fXI levels are a risk factor for arterial and venous thrombosis in humans; and deficiency or inhibition of fXI confers resistance to thrombosis in animal models. FXI deficient mice are as resistant to arterial thrombosis as fIX deficient mice, or wild type mice treated with a supra-therapeutic dose of heparin. In arterial thrombosis models in mice, rabbits and baboons, lack of fXI activity results in instability of platelet rich thrombi, preventing vessel occlusion. FXI deficiency also prolongs survival and lessens the severity of disseminated intravascular coagulation in a mouse polymicrobial sepsis model. Interestingly, mice with combined deficiencies of fXI and fIX are more resistant to arterial thrombus formation than mice deficient in only one of these proteins, indicating fXIa has proteolytic targets other than fIX. The observation that fXII deficient mice are resistant to arterial thrombosis suggests that activation of fXI by contact activation, while unnecessary for hemostasis, contributes to thrombin generation in some pathologic processes. If the observations in mice apply to thromboembolism in humans, then fXIa and/or fXIIa may be excellent targets for novel antithrombotic strategies. In contrast to drugs such as heparin and warfarin, agents targeting fXIa or fXIIa would likely be associated with relatively few bleeding complications, and could be employed in clinical situations where anticoagulation therapy is currently contraindicated. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma

Blood ◽  
2012 ◽  
Vol 120 (3) ◽  
pp. 552-559 ◽  
Author(s):  
Jeffrey A. Zonder ◽  
Ann F. Mohrbacher ◽  
Seema Singhal ◽  
Frits van Rhee ◽  
William I. Bensinger ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Stable Disease ◽  
Plasma Cells ◽  
Phase 1 ◽  
Human Study ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose

Abstract This multicenter, first-in-human study evaluated the safety, tolerability, and pharmacokinetic and pharmacodynamic properties of the anti-CS1 monoclonal antibody elotuzumab. A standard 3 + 3 design was used to determine maximum tolerated dose; dose-limiting toxicities were assessed during cycle 1. Thirty-five patients with relapsed/refractory multiple myeloma were treated with intravenous elotuzumab at doses ranging from 0.5 to 20 mg/kg every 2 weeks. Patients who achieved at least stable disease after 4 treatments could receive another 4 treatments. No maximum tolerated dose was identified up to the maximum planned dose of 20 mg/kg. The most common adverse events, regardless of attribution, were cough, headache, back pain, fever, and chills. Adverse events were generally mild to moderate in severity, and adverse events attributed to study medication were primarily infusion-related. Plasma elotuzumab levels and terminal half-life increased with dose whereas clearance decreased, suggesting target-mediated clearance. CS1 on bone marrow–derived plasma cells was reliably saturated (≥ 95%) at the 10-mg/kg and 20-mg/kg dose levels. Using the European Group for Bone and Marrow Transplantation myeloma response criteria, 9 patients (26.5%) had stable disease. In summary, elotuzumab was generally well tolerated in this population, justifying further exploration of this agent in combination regimens.

scholarly journals Phase 1 Assessment of the Safety and Immunogenicity of an mRNA- Lipid Nanoparticle Vaccine Candidate Against SARS-CoV-2 in Human Volunteers

2020 ◽  
Author(s):  
Peter Kremsner ◽  
Philipp Mann ◽  
Jacobus Bosch ◽  
Rolf Fendel ◽  
Julian J. Gabor ◽  
...  
Keyword(s):  
Adverse Events ◽  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Clinical Investigation ◽  
Phase 1 ◽  
Fold Increase ◽  
Serious Adverse Events ◽  
S Protein ◽  
Human Volunteers ◽  
Dose Dependent

ABSTRACTThere is an urgent need for vaccines to counter the COVID-19 pandemic due to infections with severe acute respiratory syndrome coronavirus (SARS-CoV-2). Evidence from convalescent sera and preclinical studies has identified the viral Spike (S) protein as a key antigenic target for protective immune responses. We have applied an mRNA-based technology platform, RNActive®, to develop CVnCoV which contains sequence optimized mRNA coding for a stabilized form of S protein encapsulated in lipid nanoparticles (LNP). Following demonstration of protective immune responses against SARS-CoV-2 in animal models we performed a dose-escalation phase 1 study in healthy 18-60 year-old volunteers.This interim analysis shows that two doses of CVnCoV ranging from 2 μg to 12 μg per dose, administered 28 days apart were safe. No vaccine-related serious adverse events were reported. There were dose-dependent increases in frequency and severity of solicited systemic adverse events, and to a lesser extent of local reactions, but the majority were mild or moderate and transient in duration. Immune responses when measured as IgG antibodies against S protein or its receptor-binding domain (RBD) by ELISA, and SARS-CoV-2-virus neutralizing antibodies measured by micro-neutralization, displayed dose-dependent increases. Median titers measured in these assays two weeks after the second 12 μg dose were comparable to the median titers observed in convalescent sera from COVID-19 patients. Seroconversion (defined as a 4-fold increase over baseline titer) of virus neutralizing antibodies two weeks after the second vaccination occurred in all participants who received 12 μg doses.Preliminary results in the subset of subjects who were enrolled with known SARS-CoV-2 seropositivity at baseline show that CVnCoV is also safe and well tolerated in this population, and is able to boost the pre-existing immune response even at low dose levels.Based on these results, the 12 μg dose is selected for further clinical investigation, including a phase 2b/3 study that will investigate the efficacy, safety, and immunogenicity of the candidate vaccine CVnCoV.

Upregulation of Endogenous Erythropoietin (EPO) in Healthy Subjects by Inhibition of Hypoxia Inducible Factor (HIF) Prolyl Hydroxylase.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 174-174 ◽  
Author(s):  
P. Urquilla ◽  
A. Fong ◽  
S. Oksanen ◽  
S. Leigh ◽  
E. Turtle ◽  
...  
Keyword(s):  
Adverse Events ◽  
High Altitude ◽  
Phase 1 ◽  
Normal Subjects ◽  
Prolyl Hydroxylase ◽  
Serious Adverse Events ◽  
Endogenous Erythropoietin ◽  
Intermittent Exposure ◽  
Hif Prolyl Hydroxylase ◽  
Dose Dependent

Abstract High-altitude hypoxia stimulates erythropoiesis in anemic hemodialysis patients. Similarly, intermittent exposure to hypobaric hypoxia elevates EPO and stimulates erythropoiesis in normal subjects. HIF is a transcription factor that mediates the body’s response to hypoxia. The stability and activity of HIF are regulated by HIF Prolyl Hydroxylase (HIF-PH). Inhibition of HIF-PH results in the accumulation of HIF leading to the upregulation of erythropoietic genes. A FibroGen HIF-PH inhibitor, FG-2216, is an orally active small molecule with appropriate pharmacokinetic and pharmacodynamic activity for testing in humans. In animal studies, inhibitors of HIF-PH induce erythropoietic changes qualitatively similar to the effects of intermittent exposure to high altitude. Phase 1 studies were initiated in healthy male subjects to determine the safety, tolerability, pharmacokinetics, and biologic activity of FG-2216 dosed orally (0.3 to 20 mg/kg). Serum levels of FG-2216 increased in a dose-dependent fashion; its elimination was characterized by a half-life ~ of 14 hr. Dose-dependent elevation in serum EPO levels was observed with a minimum effective dose of 6 mg/kg. FG-2216 was subsequently administered using a schedule of 2 or 3 times a week for three weeks at doses of 10 and 20 mg/kg or placebo. Increased EPO was observed after each dose of FG-2216. There was no decrement in EPO response to subsequent doses, indicating a resetting of the EPO response during the dosing interval. An increase in reticulocytes and soluble transferrin receptor was accompanied by a modest increase in hematocrit and hemoglobin above normal values at baseline. A total of 54 subjects received FG-2216, which was well tolerated. There were no serious adverse events or dose-limiting toxicities. Adverse events possibly related to FG-2216 were mild and subsided with continued administration. The data provide first proof of concept for upregulation of endogenous EPO and erythropoietic responses in humans by a specific HIF-PH inhibitor.

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