Abstract

Hereditary Inclusion Body Myopathy (HIBM or GNE myopathy) is an autosomal recessive, non-inflammatory, neuromuscular disorder caused by a defect in the biosynthetic pathway for sialic acid (SA), which is required for the glycosylation of many proteins and lipids. There is no approved treatment for this disease. An extended release formulation of SA is currently being investigated for treatment of HIBM. A phase 1 study of orally administered Sialic Acid Extended Release (SA-ER) tablets was conducted to evaluate the safety and pharmacokinetics (PK) of single doses (650, 1950, 2925, 4875, and 6000mg) and 7-day repeat dosing (1950, 2925, 4875 and 6000mg/day) of SA-ER in 26 HIBM patients. Free SA in serum was measured by a validated liquid chromatography–tandem mass spectrometry assay. Administration of SA-ER did not cause any serious adverse events. The adverse events observed were all mild to moderate and showed no pattern or dose relationship. PK analyses showed that SA-ER is effectively absorbed in a dose dependent fashion and divided dosing three times per day over a 7day period provides steady, increased levels of free SA over the 24h cycle. Before treatment, HIBM patients had mean free serum SA level of 0.143 (SD=0.0094) μg/ml as compared with free serum SA levels of 0.203μg/ml (SD=0.047) in normal individuals. During the 7day repeat dosing phase, free SA levels were maintained about 3-fold above baseline and twice the normal levels in the two highest dose groups. The peak concentration time (Tmax) shifted later and the absorption curve broadened when drug was administered with food. The results suggest that administration of SA-ER tablets should achieve levels of free SA sufficient to support increased uptake and is expected to improve sialylation in the muscle of patients.

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