MeMAGEN: A Phase IIa/IIb open-label trial of memantine testing safety and tolerability in sickle cell patients

Abstract

Administration of memantine, an antagonist of the N-methyl- d-aspartate receptor, prevents Ca²⁺ overload and dehydration of red blood cells (RBCs) in patients with sickle cell disease (SCD). The objectives of the 1-year dose-escalation Phase IIa/IIb Memantine trial (MeMAGEN - NCT03247218) with 17 SCD patients who were under stable hydroxycarbamide therapy were to test the drug's safety and tolerability. Daily memantine doses ranged from 5 to 15 mg for children/adolescents and from 5 to 20 mg for adults. Clinical and laboratory analysis showed that memantine was well tolerated. In children, a decrease in days spent in the hospital was observed. Safety was confirmed by laboratory tests, which were not, or were only minimally, altered during memantine therapy. In a subgroup of six patients whose RBCs presented with elevated K⁺ leakage before treatment, memantine therapy at its lowest dosage reduced this K⁺ loss and increased hemoglobin concentration. This study shows that memantine is safe and well tolerated by SCD patients, including children. Memantine has the potential to become a supportive and low-cost therapy in conjunction with hydroxycarbamide.

Figure 1

MeMAGEN study participants: flow chart, demographic data, treatment protocol, and memantine plasma concentration. (A) Flow chart of sickle cell patients' enrollment in the study. (B) Demographic data and brief clinical characteristics of all screened patients. Sβ(0), sickle cell β0 thalassemia; Sβ(+), sickle cell β+ thalassemia; SCD, sickle cell disease; Splx, splenectomy; SS, sickle cell homozygous. Note that data from patient #1001 were excluded from the overall calculations, as this patient did not intake memantine (as confirmed by minimal blood drug concentration, see methods). (C) Memantine treatment protocol. (D) Memantine concentration in plasma.

Figure 2

Clinical events before and during memantine treatment. Green lines: pretreatment period of −108 to 0 weeks; blue lines: treatment period of 0–60 weeks. Narrow blue lines represent 5–10 mg/day memantine for all participants, and wide blue lines represent 15 mg/day memantine in children or 15–20 mg/day memantine in adults. SCD, sickle cell disease.

Figure 3

Effect of daily doses of memantine on inflammation‐related blood markers. (A) Hemoglobin (Hb). (B) Fetal hemoglobin (HbF). (C) Reticulocytes. (D) White blood cells (WBC). (E) Ferritin. (F) C‐reactive protein (CRP). Data for the whole cohort are presented as median ± CI. A two‐tailed analysis of variance (ANOVA) test was performed as described in the Methods section, and P < 0.05 was considered statistically significant. 0, screening or pretreatment studies; 5/10, 5–10 mg/day memantine dose; 15/20, 15–20 mg/day memantine dose.

Figure 4

Impact of daily memantine on markers related to red blood cell (RBC) heterogeneity, morphology, and membrane permeability. (A) Hyperchromic RBC. (B) Side scatter. (C) Redistribution of RBCs in Percoll density gradient representative for a child and two adult patients on treatment with the following memantine daily doses: 0, 10, and 15 mg/day for the child and 0, 10, and 20 mg/day for adults. (D) Analysis of the localization of the main fraction within the Percoll gradient. The distance between the zero (0, solid line) point and the top (dotted line) and bottom (dashed line) borders of the main fraction of RBCs was measured using Image J software. Results of numeric analysis are presented as “distance to the top” and “distance to the bottom” panels. (E) Intracellular K⁺. (F) K⁺ loss. Data for the whole cohort are presented as median ± CI. 0, screening or pretreatment studies; 5/10, 5–10 mg/day memantine dose; 15/20, 15–20 mg/day memantine dose. AU, arbitrary units.