scholarly journals Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Liver‐Targeting Acetyl‐CoA Carboxylase Inhibitor (PF‐05221304): A Three‐Part Randomized Phase 1 Study

2020 ◽  
Vol 9 (4) ◽  
pp. 514-526 ◽  
Author(s):  
Arthur Bergman ◽  
Santos Carvajal‐Gonzalez ◽  
Sanela Tarabar ◽  
Aditi R. Saxena ◽  
William P. Esler ◽  
...  
Keyword(s):  
Phase 1 ◽  
Acetyl Coa Carboxylase ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Phase 1 Study ◽  
Acetyl Coa ◽  
Liver Targeting

scholarly journals Phase 1 study to access safety, tolerability, pharmacokinetics, and pharmacodynamics of kynurenine in healthy volunteers

2021 ◽  
Vol 9 (2) ◽  
Author(s):  
Mohammad Al‐Mahdi Al‐Karagholi ◽  
Jakob Møller Hansen ◽  
Dalia Abou‐Kassem ◽  
Anna Koldbro Hansted ◽  
Kumari Ubhayasekera ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Phase 1 ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Phase 1 Study

NDI-010976, A Potent, Liver-Directed, Oral Inhibitor of Acetyl Coa Carboxylase for Non-Alcoholic Steatohepatitis: A Phase 1 Single Ascending Dose Study in Healthy Volunteers

2016 ◽  
Vol 64 (2) ◽  
pp. S501-S502 ◽  
Author(s):  
W.F. Westlin ◽  
G. Harriman ◽  
H.J. Harwood ◽  
R. Kapeller ◽  
S. Lennon ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Phase 1 ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Alcoholic Steatohepatitis ◽  
Dose Study ◽  
Single Ascending Dose Study

The Novel, Investigational NEDD8-Activating Enzyme Inhibitor MLN4924 In Adult Patients with Acute Myeloid Leukemia (AML) or High-Grade Myelodysplastic Syndromes (MDS): A Phase 1 Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 658-658 ◽  
Author(s):  
Ronan T Swords ◽  
Harry P Erba ◽  
Daniel J DeAngelo ◽  
Peter G Smith ◽  
Michael D Pickard ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Febrile Neutropenia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Phase 1 ◽  
High Grade ◽  
The Novel ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Phase 1 Study ◽  
Acute Myeloid

Abstract Abstract 658 Background: NEDD8-activating enzyme (NAE) regulates the NEDD8 conjugation pathway, and is required for the activity of the cullin-RING E3 ligases (CRLs). CRLs control the timed degradation of several substrates involved in cell-cycle regulation, signal transduction, DNA replication, and stress response, including proteins important for the survival of AML cells. We evaluated the preclinical anti-leukemic activity of MLN4924, a novel, investigational, first-in-class small molecule inhibitor of NAE, and based on the activity of MLN4924 in preclinical AML models (Swords RT et al, Blood 2010) we conducted a phase 1 study to evaluate the safety and tolerability of this agent in patients with AML and advanced MDS. Methods: The primary objectives of this study were to evaluate the safety and tolerability of MLN4924, to establish the maximum tolerated dose (MTD), and to determine the recommended phase 2 dose of MLN4924 in patients with AML and high-grade MDS. Secondary objectives included a preliminary assessment of efficacy, and analysis of pharmacokinetics and pharmacodynamics (via NAE-regulated proteins in peripheral blood mononuclear cells). Patients aged ≥18 years, with ECOG performance status 0–2, who had AML or high-grade MDS, and who were not candidates for potentially curative therapy, were eligible. MLN4924 was administered as a 60-minute IV infusion on days 1, 3, and 5 of a 21-day cycle for up to 12 months or until documented disease progression. Dose escalation was commenced at 25 mg/m2 and proceeded using a standard 3+3′ escalation method until the MTD was established. Response assessment was based on recently published guidelines (Döhner H et al, Blood 2010) and adverse events (AEs) were graded per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events v3.0 (NCI Cancer Therapy Evaluation Program, 2006). Results: To date, 15 patients (9 males, 6 females; 14 AML, 1 high-grade MDS) have been enrolled and treated, including 3, 4, 3, 3, and 2 at dose levels of 25, 33, 44, 59, and 78 mg/m2, respectively. Median age was 62.3 years (range 29.3–84.0 years). By cytogenetics, 1 (7%), 5 (33%), and 7 (47%) patients had good-, intermediate-, and poor-risk disease (not available in 2). Prior antineoplastic therapies included cytarabine (n=7), azacitidine, daunorubicin (n=3 each), decitabine, etoposide, gemtuzumab, idarubicin, and mitoxantrone (n=2 each). To date, 3 patients have received ≥8 cycles; 6 remain on treatment. Two dose-limiting toxicities have been reported at the 78 mg/m2 dose level: one patient with multi-organ failure in Cycle 2, and one with reversible elevation of alanine aminotransferase in Cycle 1. The most common AEs were pneumonia (n=6), atelectasis, constipation, diarrhea, and febrile neutropenia (each n=4); most common grade ≥3 AEs were febrile neutropenia (n=4), elevated aspartate aminotransferase, and pneumonia (each n=3). Three patients have achieved a complete response (CR) to date. A 29-year-old woman with relapsed AML following allogeneic stem cell transplantation achieved a CR after cycle 1 at 25 mg/m2 before developing progressive disease at an extramedullary site during cycle 8. An 82-year-old man with history of high-risk MDS, which was unresponsive to azacitidine, that evolved into AML had a partial response in cycle 8 and a CR with incomplete recovery of blood counts (CRi) in cycle 10 at 33 mg/m2; the patient is currently in cycle 12 and has become transfusion-independent. A 71-year-old man with de-novo AML refractory to standard cytarabine plus daunorubicin induction achieved a CRi during cycle 1 at 44 mg/m2; although this was not maintained, the patient continued to benefit from treatment and is currently in cycle 11 with reduced transfusion dependence. Pharmacodynamic data are available for 9 patients; 7 show evidence of target inhibition in peripheral blood by changes in NAE-regulated proteins. Conclusion: The preliminary findings of this study indicate that the novel mechanism of action of MLN4924 through NAE inhibition results in observed activity in patients with relapsed or refractory AML, and suggest the successful translation of preclinical research in AML models into the clinic. Enrollment continues in expanded cohorts of AML and MDS patients at 59 mg/m2. Updated efficacy and safety data will be presented, together with data on MLN4924 pharmacokinetics and pharmacodynamics. Disclosures: Off Label Use: Investigational agent in clinical development for the treatment of acute myeloid leukemia or myelodysplastic syndromes. Erba:Millennium Pharmaceuticals, Inc.: Research Funding. DeAngelo:Deminimus: Consultancy. Smith:Millennium Pharmaceuticals, Inc.: Employment. Pickard:Millennium Pharmaceuticals, Inc.: Employment. Dezube:Millennium Pharmaceuticals: Employment, Equity Ownership. Giles:Millennium Pharmaceuticals, Inc.: Research Funding. Medeiros:Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding.

scholarly journals Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the MK2 Inhibitor ATI-450 in Healthy Subjects: A Placebo-Controlled, Randomized Phase 1 Study

2021 ◽  
Vol Volume 13 ◽  
pp. 123-134
Author(s):  
David Gordon ◽  
Edward T Hellriegel ◽  
Heidi Rath Hope ◽  
David Burt ◽  
Joseph B Monahan
Keyword(s):  
Healthy Subjects ◽  
Phase 1 ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Phase 1 Study

scholarly journals Pharmacokinetics and Pharmacodynamics of Garetosmab (Anti‐Activin A): Results From a First‐in‐Human Phase 1 Study

2020 ◽  
Vol 60 (11) ◽  
pp. 1424-1431 ◽  
Author(s):  
Frédéric Vanhoutte ◽  
Su Liang ◽  
Marcella Ruddy ◽  
An Zhao ◽  
Tiera Drewery ◽  
...  
Keyword(s):  
Phase 1 ◽  
Activin A ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Phase 1 Study

scholarly journals P3-012: PHASE 1 STUDY OF NDX-1017: SAFETY, PHARMACOKINETICS, AND PHARMACODYNAMICS IN HEALTHY YOUNG AND ELDERLY VOLUNTEERS

2019 ◽  
Vol 15 ◽  
pp. P929-P929
Author(s):  
Xue Hua ◽  
Kevin Church ◽  
William Walker ◽  
Philippe L'Hostis ◽  
Philippe Danjou ◽  
...  
Keyword(s):  
Phase 1 ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Phase 1 Study

scholarly journals A phase 1 study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-063, a selective PDE10A inhibitor

2016 ◽  
Vol 233 (21-22) ◽  
pp. 3787-3795 ◽  
Author(s):  
Max Tsai ◽  
Lambros Chrones ◽  
Jinhui Xie ◽  
Hakop Gevorkyan ◽  
Thomas A. Macek
Keyword(s):  
Phase 1 ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Phase 1 Study

scholarly journals Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of HBM9161, a novel FcRn inhibitor, in a Phase 1 Study for Healthy Chinese Volunteers

2021 ◽  
Author(s):  
Desmond Y.H. Yap ◽  
Jojo Hai ◽  
Paul C.H. Lee ◽  
Xueying Zhou ◽  
Michael Lee ◽  
...  
Keyword(s):  
Phase 1 ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Phase 1 Study ◽  
Healthy Chinese
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