INTRODUCTION: Pyruvate kinase deficiency (PKD) is an inborn error of metabolism affecting children and adults that results in lifelong hemolytic anemia and is associated with serious long-term comorbidities such as poor growth and development in children and chronic iron overload in adults. PKD is caused by a functional deficiency of the R-isoform of pyruvate kinase (PK-R) caused most often by a missense mutation. As a result of deficiency of this terminal enzyme in glycolysis, blood 2,3-DPG levels are elevated and ATP levels are low. AG-348 is a novel, first-in-class, small molecule allosteric activator of PK-R that directly targets the underlying metabolic defect in PKD. Preclinical studies demonstrated that AG-348 increases the activity of both wild type and various mutated PK-R enzymes. The key objectives of these first-in-human, Phase I, randomized, double-blind, placebo-controlled single (SAD) and multiple ascending dose (MAD) studies are to identify a safe and pharmacodynamically-active dose and schedule for AG-348 to be used in subsequent clinical studies in subjects with PKD [NCT02108106; NCT202149966].

METHODS: In the SAD, healthymen and women (non-childbearing potential) aged 18-60 years were randomized to receive a single oral dose of AG-348 or placebo (P). Six cohorts were evaluated, each containing 8 subjects (6 AG-348, 2 P), starting with 30 mg in cohort 1 followed by 120, 360, 700, 1400 and 2500 mg in cohorts 2-6, respectively. In the ongoing MAD, 2 cohorts (120 mg bid and 360 mg bid) of 8 subjects each (6 AG-348, 2 P) have completed 14 days of dosing and 2 weeks of follow-up. In both studies, safety assessments included adverse events (AEs), vital signs, ECG and clinical laboratory parameters. Serial blood samples are drawn for assessment of PK and PD parameters (2,3-DPG and ATP) pre-dose and at regular intervals thereafter at multiple doses in both the SAD and MAD studies. Preliminary results are reported here; final results will be available at the time of presentation.

RESULTS: In the SAD, all 48 subjects enrolled completed the study (47 males and 1 female; mean age 40 years). A preliminary analysis of safety data indicated that 19/48 (39%) subjects receiving AG-348 or placebo under fasted and/or fed conditions experienced at least 1 treatment-emergent AE during the study. All AEs were mild or moderate (Grade 1 and 2) in severity, and the most common were nausea (n=5; 10%) and headache (n=7; 14%). In the 2 completed MAD cohorts (13 males; 3 females; mean age 44 years), 8/16 (50%) of subjects receiving AG-348 or P experienced 11 AEs. All AEs were mild (n=10) or moderate (n=1) and the most frequent were venipuncture bruises. Frequency of AEs by treatment group will be presented. There were no serious AEs, discontinuations due to AEs, or dose-limiting toxicities in either study. Maximum tolerated dose was not reached in the SAD and dose escalation continues in the MAD. In SAD cohorts 1-6, exposure to single doses of AG-348 increased in a dose-proportional manner (mean plasma Cmax, AUC0-12hr and AUC0-72hr) (Figure 1 SAD study). Absorption was rapid, with a median Tmax of 0.75–4.0 h. Expected changes in pharmacodynamic markers including decrease in 2,3-DPG concentration (SAD [Figure 2] and MAD studies) and increase in ATP concentration (MAD study) were observed and will be presented in greater detail.

CONCLUSION: AG-348 had a favorable safety profile and was well tolerated in healthy subjects based on preliminary analysis of subjects receiving a single dose up to 2500 mg or multiple bid doses up to 360 mg for up to 14 days. AG-348 also demonstrated a desirable PK profile, with rapid absorption, low PK variability and dose-proportional exposure with PD effect as demonstrated on 2,3-DPG (Figure 2) and ATP.

Figure 1
Figure 1.
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Figure 2
Figure 2.
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Disclosures

Yang:Agios Pharmaceuticals: Employment, Stockholder Other. Merica:Agios Pharmaceuticals: Employment, Stockholder Other. Chen:Agios Pharmaceuticals: Employment, Stockholder Other. Cohen:Agios Pharmaceuticals: Consultancy. Goldwater:PAREXEL International: Employment. Hill:Agios Pharmaceuticals: Employment, Stockholder Other. Kim:Agios Pharmaceuticals: Employment, Stockholder Other. Kosinski:Agios Pharmaceuticals: Employment, Stockholder Other. Kung:Agios Pharmaceuticals: Employment, Stockholder Other. Silver:Agios Pharmaceuticals: Consultancy. Utley:Agios Pharmaceuticals: Employment, Stockholder Other. Agresta:Agios Pharmaceuticals: Employment, Stockholder Other.

Topics:
adverse event, contusions, enzymes, follow-up, headache, hemolytic anemia, inborn errors of metabolism, iron overload, maximum tolerated dose, multiple-dose regimen

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2014 by The American Society of Hematology
2014
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