Decrease in the Severity of Painful Sickle Cell Crises with Oral Pglg

Background: Our earlier work suggested an enhancement of nicotinamide adenine dinucleotide (NAD) in sickled Red Blood Cells (sRBC) by administering a precursor of NAD, L-glutamine. We hypothesized that L-glutamine would decrease the incidence of painful sickle cell crises (PSCC). Small proof of concept studies led to the development of a multi-center Phase 2 placebo-controlled trial where oral pharmaceutical grade L-glutamine (PGLG) suggested benefit when measuring PSCC incidence at 24 weeks. A large multi-center Phase 3 trial further demonstrated that there was a reduction in the incidence of PSCC by administering PGLG compared to placebo. Additional analyses on the data from this trial were conducted and we are reporting our evaluation on the severity of crises between treatment arms.

Methods: A randomized (2:1), double-blind, placebo-controlled, parallel-group Phase 3 study was conducted at 31 sites in the United States. Subjects were stratified by hydroxyurea usage. This study included subjects 5 years of age and older that had at least 2 PSCC during the year prior to enrollment. The primary endpoint for the Phase 3 trial was the number of PSCC between treatment arms. Since PSCC events were adjudicated by a blinded third party committee and data were collected as an adverse event ranked as "None"(0), "Mild" (1), "Moderate" (2) and "Severe" (3), the difference in "Severity" of PSCC between treatment arms using Cochran Mantel Haenszel (CMH) Ranked Scores statistics was evaluated post-hoc. Each patient was counted only once at the highest level of severity.

Results; A total of 230 patients were enrolled; ages 5-58; 53.9 % female; 152 were assigned to PGLG and 78 to placebo; and the groups were well balanced for baseline clinical characteristics. The comparison of Severity for PGLG vs. Placebo indicated that at (0) was 24% vs. 10% respectively; at (1) was 6% vs. 8%; at (2) was 36% vs. 35%; and at (3) was 34% vs. 47%. Summary statistics for the cohort taken as a whole indicated a treatment difference benefit for the PGLG treatment (p = 0.0167). Other adverse events in the PGLG arm were similar to those observed in the placebo arm.

Conclusion: PGLG therapy may be providing clinical benefit over placebo in adult and pediatric patients with a history of two or more crises per year by reducing the "Severity" of painful crises. Difference appeared to be driven by (0) or "None" PSCC events and by a decrease in (3) "Severe" PSCC events. PGLG was administered without difficulty and did not require special monitoring.