November-December 2018, Volume 15, Issue 6
A New Therapy for Sickle Cell Disease: FDA Approves Oral L-glutamine for Prevention of Acute Vaso-occlusive Events in Children and Adults
Published on: October 02, 2018
Niihara Y, Miller ST, Kanter J, et al. A phase 3 trial of L-glutamine in sickle cell disease. N Engl J Med. 2018;379:226-235.
Acute vaso-occlusive events (pain or acute chest syndrome) are the hallmark of sickle cell disease (SCD), resulting in a vast number of pain events for individuals affected with the disease and in millions of dollars per year of preventable health care expenditures. Until now, the U.S. Food and Drug Administration (FDA) has approved only one therapy for the prevention of acute vaso-occlusive pain events — hydroxyurea therapy. In 2017, the FDA approved L-glutamine (an amino acid) twice daily for preventing acute vaso-occlusive events in children and adults with SCD. This article presents the results that led to this approval.
Artful clinical research and two decades of translational perseverance provide the study background. Red blood cells (RBCs) in individuals with SCD have increased concentrations of reactive oxygen species compared with normal RBCs. Prior work demonstrated that homoserine, asparagine, and glutamine inhibited sickling of erythrocytes at room temperature.1 In 1998, Dr. Yutaka Niihara and colleagues conducted a small clinical study in seven participants with SCD and demonstrated a subjective improvement in symptoms after treatment with L-glutamine. Most importantly, the team demonstrated evidence to support their hypothesis — namely, that oral L-glutamine can significantly increase the NAD redox potential and NADH level in sickle RBCs.2 In 2005, Dr. Niihara and colleagues demonstrated that 30 g per day of L-glutamine reduced endothelial adhesion of sickle RBCs to human umbilical vein endothelial cells. Subsequently, in 2014, Dr. Niihara and colleagues conducted a phase II randomized double-blind placebo-controlled parallel-group multicenter study of 81 participants aged five years or older who were diagnosed with SCD or sickle β-thalassemia. The results were promising and demonstrated a significant decrease in the incidence of vaso-occlusive events (3 vs. 4 events; p=0.005) and hospital days (6.5 vs. 11 days; p=0.0045), with no increase in adverse events when compared with placebo.3
Finally, this phase III double-blind randomized controlled trial has been completed and published. A total of 230 participants with SCD or sickle β-thalassemia (age range, 5-58 years) were randomly assigned in a 2:1 ratio to receive L-glutamine (152 participants) or placebo (78 participants) for a total of 48 weeks. The trial medication (active therapy or placebo) was self-administered orally twice daily at approximately 0.3 g per kg of body weight per dose (10 g, 20 g, or 30 g [maximum dose] per day). Participants were given packets containing 5 g of white unflavored powder. The participants were expected to mix the contents of the packet with a nonheated drink or food and consumed immediately. To encourage adherence, participants received phone calls from research personnel. The participants in the L-glutamine group had significantly fewer pain episodes in the study period than those in the placebo group (p=0.005), with a median of 3.0 and 4.0 events, respectively, during the 11-month trial period. There were also fewer hospitalizations in the L-glutamine group versus the placebo group, with a median of 2.0 in the L-glutamine group and 3.0 in the placebo group (p=0.005). In both groups, hydroxyurea was prescribed in approximately two-thirds of the participants. Low-grade adverse events (nausea, noncardiac chest pain, fatigue, and musculoskeletal pain) were more common in the treatment group versus the placebo group.
Despite the success of the trial leading to an FDA-approved therapy, several questions linger about the results. The number of participants who completed the trial, designed to last 11 months, was significantly lower than expected. Only 63.8 percent and 75.6 percent in the treatment group and placebo group, respectively, completed all 11 months. Given the high dropout rate during the trial, imputation of the missing data was a key statistical approach to interpret the final clinical trial results. Furthermore, such a significant dropout rate in a clinical trial raises significant concerns about adherence outside of a clinical trial. Clearly, different strategies are required to improve adherence to this twice-a-day oral therapy. The trial excluded individuals with compound heterozygotes with SCD. Presumably, compound heterozygotes with SCD will be prescribed L-glutamine therapy, but the relative benefits are unclear, particularly given the anticipated lower rate of acute vaso-occlusive events in this population. Very likely, children and adults with SCD prescribed hydroxyurea therapy will receive dual therapy, and for those who cannot tolerate or refuse to take hydroxyurea, L-glutamine may become the initial therapy to attenuate the incidence rates of acute vaso-occlusive events.
Dr. Niihara, his colleagues, and the study participants and their families are to be congratulated on a job well done. The SCD community is grateful for completion of this trial and for establishing a new treatment option for children and adults with SCD. We look forward to the next iteration of research to better define other benefits of L-glutamine for SCD and to identify strategies for improved adherence to this therapy.
Rumen NM. Inhibition of sickling in erythrocytes by amino acids. Blood. 1975;45:45-48.
Niihara Y, Zerez CR, Akiyama DS, et al. Oral L-glutamine therapy for sickle cell anemia: I. Subjective clinical improvement and favorable change in red cell NAD redox potential. Am J Hematol. 1998;58:117-121.
Niihara Y, Macan H, Eckman JR, et al. L-glutamine therapy reduces hospitalization for sickle cell anemia and sickle β0-thalassemia patients at six months - a phase II randomized trial. Clin Pharmacol Biopharm. 2014;3:116.
Conflict of Interests
Dr. DeBaun indicated no relevant conflicts of interest.
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