Date: 2016-12-04
Type of information: Presentation of results at a congress
phase: 1
Announcement: presentation of results at the 58th American Society of Hematology (ASH) Annual Meeting
Company: Agios Pharmaceuticals (USA -MA)
Product: AG-519
Action
mechanism: pyruvate kinase activator. AG-519 is a pyruvate kinase activator.
Disease: pyruvate kinase deficiency, anemia
Therapeutic area: Hematological diseases
Country: UK
Trial
details: The purpose of the study is to investigate a drug called AG-519, which is being developed for the treatment of a disease called pyruvate kinase deficiency (also known as PK deficiency) and other forms of anemia. This study is a 5 part study with Part 1 enrolling healthy volunteers into single ascending dose (SAD) groups, Part 2 enrolling healthy volunteers into multiple ascending dose (MAD) groups and Part 3 enrolling healthy volunteers to investigate how much of the study drug is taken up by the body and how food affects the uptake of a prototype formulation of AG-519, Part 4 enrolling healthy volunteers of Japanese origin to compare to the results of subjects of non-Japanese origin, and Part 5 a non-randomized, open-label, multiple dose study enrolling healthy volunteers to further investigate how much of the study drug is taken up by the body when dosed over 14 days. (NCT02630927)
Latest
news: * On December 4, 2016, Agios Pharmaceuticals presented new data on AG-519, a PKR activator program, at the 2016 American Society of Hematology Annual Meeting and Exposition (ASH). AG-519 is being evaluated in an ongoing Phase 1 trial in healthy volunteers. Data were reported from four single ascending dose (SAD) cohorts of healthy volunteers (eight per group, 32 volunteers total) receiving daily doses of 50 mg, 250 mg, 750 mg or 1250 mg of AG-519 or placebo. Data were also reported from five multiple ascending dose (MAD) cohorts of healthy volunteers (eight per group, 40 volunteers total) dosed twice daily with 10 mg, 25 mg, 125 mg, 300 mg or 375 mg of AG-519 or placebo for 14 days. AEs from the SAD and MAD cohorts were mild or moderate (Grade 1 or 2) in severity, the most common being headache. * On June 9, 2016, Agios Pharmaceuticals announced the initial data from the Phase 1 integrated single ascending dose (SAD) and multiple ascending dose (MAD) clinical trial of AG-519 in healthy volunteers at the 21st Congress of the European Hematology Association (EHA) taking place June 9-12, 2016 in Copenhagen . These data provide early proof-of-mechanism for AG-519, a potent, oral, selective second pyruvate kinase-R (PKR) activator that is wholly owned by Agios. In this Phase 1 study, dosing of AG-519 over 14-days in healthy volunteers resulted in a dose-dependent increase in PKR activity as evidenced by a substantial increase in ATP (adenosine triphosphate) and decrease in 2,3-DPG (2,3-diphosphoglycerate) levels, which are important biomarkers of PKR activation in healthy volunteers. These data support the hypothesis that AG-519 enhances PKR activity and has the potential to correct the underlying defect of pyruvate kinase (PK) deficiency, a rare, potentially debilitating, congenital anemia.
A single case of Grade 2 thrombocytopenia was previously reported in a subject receiving 375 mg of AG-519 q12hr, which resolved spontaneously within seven days after the last dose.
After the data cut-off, one ongoing SAE of drug-related cholestatic hepatitis was reported in the bioavailability and food effect study after a dose of 300 mg. This event is being further evaluated.
Pharmacodynamic data from the MAD cohorts showed a mean decrease of up to 61% in blood 2,3-DPG levels and a mean increase of up to 63% in blood ATP levels from baseline. In contrast, healthy volunteers receiving placebo showed minimal changes in 2,3-DPG or ATP levels.
Volunteers treated with AG-519 exhibited no changes in sex steroids levels, consistent with a lack of aromatase enzyme inhibition.
The study is ongoing with final data not yet available for the bioavailability and food effect study and a Japanese volunteer cohort. The study allows for an optional additional open-label, multiple-dose cohort, which has not yet been initiated.
Results from the Completed SAD Portion of the Phase 1 Study: Four cohorts with doses of AG-519 ranging from 50 mg to 1250 mg were tested against placebo in 32 healthy volunteers.
AG-519 demonstrated a favorable safety profile in all doses tested. There were no serious adverse events (SAEs) reported, with all adverse events (AEs) being mild to moderate, and the most common being headache. In addition, there were no early discontinuations due to AG-519 and the maximum tolerated dose was not reached.
Mean decreases in blood 2,3-DPG levels up to 43 percent from baseline were observed in the SAD cohorts, reaching minimum levels after 24 hours. As expected, ATP levels did not change after a single dose of AG-519, consistent with SAD findings from AG-348. Healthy volunteers receiving placebo showed no changes in 2,3-DPG or ATP levels.
Preliminary Results from the Ongoing MAD Portion of the Phase 1 Study: The first two cohorts reported data from 16 healthy volunteers dosed twice daily with 125 mg or 375 mg of AG-519 or placebo for 14 days.
There were no SAEs reported, with all AEs being mild to moderate, and the most common being headache. One subject receiving AG-519 at the 375 mg dose experienced a low blood platelet count (Grade 2 thrombocytopenia) on Day 14. Platelet levels started to recover within five days of the last dose and returned to normal levels seven days after the last dose.
Pharmacodynamic data from these cohorts showed a mean decrease of up to 47 percent in blood 2,3-DPG levels and a mean increase of up to 62 percent in blood ATP levels from baseline. In contrast, healthy volunteers receiving placebo showed no changes in 2,3-DPG or ATP levels.
Subjects treated with AG-519 exhibited no significant changes in sex steroids levels, consistent with a lack of aromatase enzyme inhibition. Enrollment into additional MAD cohorts is ongoing.
