2018: The Year's Best in Sickle Cell Disease

In 2018, Dr. Yutaka Niihara and colleagues published data that formed the basis of the U.S. Food and Drug Administration’s (FDA) approval of L-glutamine for the prevention of acute vaso-occlusive pain episodes in children and adults with sickle cell disease (SCD).¹  In a double-blind randomized controlled trial in children and adults with SCD, when compared to placebo, oral L-glutamine therapy taken twice daily for approximately a year was associated with decreased incidence rate of acute vaso-occlusive events.

The FDA approval of L-glutamine, only the second approved drug for sickle cell disease (SCD) in more than 20 years, has both symbolic and clinical importance. Conceptually, individuals with SCD and their families have new hope that after more than 30 years of participating in clinical trials sponsored by the National Institutes of Health (NIH), foundations, and industry, they have not been forgotten. The FDA’s recent approval provides tangible evidence that the research community is actively working to ameliorate intolerable acute pain episodes — the hallmark of the disease.

Scientifically, the results of the trial provide mounting evidence that novel therapies, other than those targeted at increasing levels of fetal hemoglobin, may decrease the severity of the disease. The primary basis for the trial is that red blood cells (RBCs) in individuals with SCD have increased concentrations of reactive oxygen species compared with normal RBCs. Consequently, glutathione levels are depleted within RBCs of individuals with SCD. Key substrates (cysteine, glutamate, glutamine, and glycine) of the glutathione cycle are increased. Prior research indicated that oral L-glutamine can significantly increase the NAD redox potential and NADH level in sickled RBCs,²  which led to a phase III trial of 238 individuals with SCD that were randomly allocated to 0.6 mg/kg daily of L-glutamine or placebo for six months.¹  The preliminary results were very promising and demonstrated a significant decrease in the incidence of vaso-occlusive events (3 vs. 4, p=0.005) and hospital days (6.5 vs. 11, p=0.0045) with no increase in adverse events when compared to placebo. Ultimately, Dr. Niihara and colleagues designed and successfully completed the phase III trial.

In the past year, multiple SCD trials have targeted anti-inflammatory therapies for the prevention of acute vaso-occlusive episodes. Crizanlizumab, a humanized, anti-P-selectin monoclonal antibody, was the therapeutic agent used in a randomized, double-blind, phase II, controlled trial, referred to as the Sustain Study.³  P-selectin, a cell adherence molecule expressed in sickled RBCs, endothelial cells, white blood cells, and activated platelets was the biological basis for the novel therapy. In the phase II trial, the investigators demonstrated that crizanlizumab at 5 mg/kg, 14 times during 52 weeks, when compared to placebo, significantly decreased incidence rates of vaso-occlusive pain episodes (1.63 vs. 2.98; p=0.01), and significantly delayed the median time to first vaso-occlusive pain episode (4.07 vs. 1.38 months; p=0.001). In a follow-up subgroup analysis of the same phase II trial, the investigators demonstrated that regardless of the number of acute vaso-occlusive pain events in the year prior to entering the trial, treatment with 5 mg/kg of crizanlizumab when compared to placebo was associated with a statistically significant lower hazard ratio of time to first vaso-occlusive event.⁴ 

In a 2017 phase II trial, Dr. Jeffrey Glassberg and colleagues demonstrated that in adults with SCD without asthma, once-daily mometasone furoate 220 μg dry powder inhalation, when compared to placebo throughout 16 weeks, had a higher reduction in daily pain score of 1.42 points (95% CI, 0.61-2.21; p=0.001).⁵  Collectively, the promising results of both phase II trials demonstrate that anti-inflammatory strategies could provide unique opportunities for combination therapy to decrease the incidence rate of acute vaso-occlusive events in children and adults with SCD.

The new phase II and phase III trials, the National Heart, Lung, and Blood–led Cure Sickle Cell Initiative, the development of the ASH Research Collaborative SCD clinical trials network, the open investigator-initiated and industry-sponsored gene therapy trials, and the two ongoing NIH-sponsored hematopoietic stem cell transplantation trials make the future look bright for patients with SCD. We look forward to future FDA-approved therapies for treating SCD symptoms, each one bringing us close to a day when the disease may routinely and safely be cured.