Sickle Cell Disease (SCD)

Progress in sickle cell disease (SCD) was stifled for almost 2 decades prior to the US Food and Drug Administration (FDA) approval of Endari™ (L-glutamine oral powder) in 2017. It is the second drug to gain FDA approval for patients with SCD and the first new drug to enter the arena in almost 20 years.¹ It is approved for use in patients aged 5 years and older for the reduction of acute complications associated with SCD.²

Endari is a powdered amino acid (L-glutamine) that comes in 5-g packets. Dose is based on patient weight, with a recommended dose of 1, 2, and 3 packets per day for patients who weigh <30 kg, 30 to 65 kg and >65 kg, respectively. The packets should be dissolved in cold liquid or cold food such as yogurt immediately before ingestion. Complete dissolution is not required.² 

Get full prescribing information for Endari on MPR’s monograph page.

Mechanism of Action

The precise mechanism of action is not known, and the rationale for the use of L-glutamine is based on theoretical principles. It is theorized that by reducing the increased oxidative stress experienced by erythrocytes in patients with SCD, a reduction in hemolysis and vaso-occlusive crises would be expected. L-glutamine, in theory, potentiates the nicotinamide adenine dinucleotide (NAD) redox potential and, in turn, alleviates oxidative stress and leads to lower levels of hemolysis and vaso-occlusive events.² 

Efficacy in Clinical Trials

The efficacy of Endari was evaluated in a randomized, double-blind, placebo-controlled, multicenter clinical trial including 230 patients aged 5 to 58 years with sickle cell anemia or sickle β⁰-thalassemia. At the end of the 48-week intervention period, patients in the Endari group demonstrated a decreased median number of sickle cell crises (n=3) compared to the placebo group (n=4). In both groups, the range was 0 to 15 crises during the study period.  Recurrent crisis event time analysis yielded an intensity rate ratio (IRR) value of 0.75 in favor of Endari, suggesting that over the entire 48-week period, the average cumulative crisis count was reduced by 25% from the Endari group over the placebo group.²

The strength of this data is questionable (see Limitations).

Safety 

Endari has a good safety profile. Common adverse reactions include constipation, nausea, headache, abdominal pain, cough, pain in extremities, back pain, and chest pain. There are no reported contraindications listed for Endari to date.² 

There is insufficient data to recommend Endari for pregnant or breastfeeding patients. Endari has not been evaluated in children under 5 years of age.² 

Limitations

No P values are available for the submitted study, potentially due to a lack of statistical significance. The European Medicines Agency (EMA) has cited that although there are no evident safety concerns with the treatment, a lack of conclusive evidence for efficacy of Xyndari™ (patent filed under this name in Europe) is not reassuring.³ The EMA quotes that “the main study did not show that Xyndari was effective at reducing the number of sickle cell crises or hospital visits.”⁴ Following this negative sentiment, Emmaus Medical Europe Ltd. withdrew their application for EMA approval. 

References

1. FDA approves new treatment for sickle cell disease. News release. US Food and Drug Administration; July 7, 2017.

2. Endari. Package insert. Emmaus Medical, Inc.; 2017. Accessed November 9, 2021.

3. Endari (L-glutamine) for sickle cell disease. Sickle Cell Disease News. Updated February 8, 2021. Accessed November 9, 2021.

4. Xyndari: withdrawal of the marketing authorisation application. European Medicines Agency. October 18, 2019. Accessed November 9, 2021.

Reviewed by Debjyoti Talukdar, MD, on 11/9/2021.

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Kyle Habet, MD

Kyle Habet, MD, is a physician at Belize International Institute of Neuroscience where he is a member of a multidisciplinary group of healthcare professionals involved in the care of patients with an array of neurological and psychiatric diseases. He is a published author, researcher and instructor of neuroscience and clinical medicine at Washington University of Health and Science.