Image courtesy of NHLBI
The US Food and Drug Administration (FDA) has granted orphan drug designation to AG-348 for the treatment of pyruvate kinase deficiency (PKD), a rare form of hemolytic anemia.
AG-348 is a small molecule allosteric activator of pyruvate kinase-R enzymes that directly targets the underlying metabolic defect in PKD.
The orphan designation will provide Agios Pharmaceuticals, the company developing AG-348, with certain benefits. These include market exclusivity upon regulatory approval and exemption from FDA application fees and tax credits for qualified clinical trials.
According to Agios, AG-348 exhibited favorable safety and pharmacokinetic profiles in a pair of phase 1 studies conducted in healthy volunteers.
Study investigators also observed dose-dependent changes in adenosine triphosphate (ATP) and 2,3-DPG blood levels, which are consistent with increased activity of the glycolytic pathway, the expected pharmacodynamic effect of AG-348.
Results from both studies were presented in a poster at the 2014 ASH Annual Meeting (abstract 4007*). One of the studies was a single ascending dose (SAD) study, and the other was a multiple ascending dose (MAD) study.
SAD study
In this study, healthy volunteers were randomized to receive AG-348 (n=36) or placebo (n=12). Patients were divided into 6 dosing cohorts: 30 mg, 120 mg, 360 mg, 700 mg, 1400 mg, and 2500 mg.
The maximum-tolerated dose of AG-348 was not reached, and there were no serious adverse events (AEs) or early withdrawals among AG-348-treated subjects. Overall, the rate of AEs was 33.3% in the placebo arm and 44.4% in the AG-348 arm.
The rate of AEs that were considered possibly treatment-related was 16.7% in the placebo arm and 30.6% in the AG-348 arm. The most common treatment-related AEs were headache (occurring in 16.7% and 11.1% of patients, respectively), nausea (0% and 13.9%, respectively), and vomiting (0% and 5.6%, respectively).
Exposure to AG-348, as measured by area under the concentration × time curve (AUC), increased in a dose-proportional manner after a single dose. And absorption was rapid (median Tmax ranged from 0.77 to 4.07 hours), although Tmax increased and there was a less-than-proportional increase in Cmax at higher doses.
When AG-348 was administered from 30 mg to 360 mg, there was a dose-dependent decrease in blood 2,3-DPG levels over 24 hours—up to a 49% mean decrease. Increasing the dose beyond 360 mg did not result in additional decreases in 2,3-DPG levels. And levels returned to placebo levels after about 72 hours.
There were minimal increases in blood ATP levels after AG-348 treatment at any dose.
MAD study
At the time of the presentation, 2 cohorts of 8 subjects each (6 receiving AG-348 and 2 receiving placebo) had completed treatment in the MAD study. One cohort received drug or placebo at 120 mg BID, and the other received 360 mg BID.
The pharmacokinetic results for day 1 of this study were consistent with those of the SAD study. However, the Cmax and AUC0-Ʈ were lower on day 14 than day 1. Investigators said this suggests that multiple doses of AG-348 increase the rate of its own metabolism.
They also said the decrease in exposure observed on day 14 is consistent with preclinical data that suggest AG-348 is a moderate inducer of CYP3A4, which is the major route of the oxidative metabolism of AG-348.
As in the SAD study, the investigators observed decreases in 2,3-DPG blood levels after the first dose in cohorts 1 and 2—up to a 48% mean decrease from baseline for both doses. Concentrations returned to placebo levels between 48 and 72 hours after the last dose.
Unlike in the SAD study, patients in this study had increases in ATP—up to a 52% mean increase from baseline in both dosing cohorts. ATP levels remained elevated through 72 hours after the last dose.
The investigators said the results of these 2 studies have informed dose selection for the planned phase 2 study of AG-348 in PKD patients, which is expected to begin soon.
*Information in the abstract differs from that presented at the meeting.