It was approved for use by patients age 5 and older by the U.S. Food and Drug Administration (FDA) on July 7, 2017, making Endari the first approved pediatric treatment for sickle cell disease, and the first new treatment for adults in almost 20 years.
Glutamine, an amino acid, plays various and fundamental roles in cell metabolism, including protein synthesis, chemical energy production, and anti-oxidant formation. The most abundant amino acid in the body, glutamine is naturally produced (largely in the lungs), and usually in sufficient amounts for our needs. But is often used as a supplement to counter infection, injury, stress, and to treat certain diseases.
How Endari works
Patients with sickle cell disease have an altered form of the hemoglobin protein (which carries oxygen, via the blood, to tissues) that renders red blood cells susceptible to oxidation damage.
High oxidative stress has been associated with an increased stiffness in these red blood cells, leading to their sickle-like shape. Less flexible than healthy (and round) red blood cells, these abnormal cells often stick to vessel walls, blocking or slowing blood flow and oxygen transport.
Endari increases the amount of free glutamine circulating in the blood, which is taken up by the sickle cells and used to generate anti-oxidant molecules as a product of glutamine degradation.
These new antioxidants help neutralize the oxidative stress in sickle red blood cells, allowing them to regain the flexibility needed to travel through blood vessels and capillaries, carrying oxygen to tissues throughout the body.
Studies with Endari
Emmaus has completed three clinical trials that assessed the effectiveness of Endari in treating sickle cell anemia and sickle cell thalassemia.
The first, which ended in 2008, was a Phase 2 double-blind and placebo-controlled study (NCT00125788) evaluating the number of sickle cell crises experienced by about 80 enrolled patients during 48 weeks of treatment.
A second Phase 2 study (NCT00586209) that ended in 2009 evaluated the effectiveness of Endari, versus placebo, in 18 sickle cell anemia patients. Its focus was improvements in exercise endurance and breath, and the number of disease crises — as measured by pain levels and narcotics use, changes in energy and appetite, and hospital and emergency room visits over 28 days.
A Phase 3 randomized, double-blind and placebo-controlled study (NCT01179217) evaluated the effects of Endari on the red blood cells of 230 adult and pediatric patients (ages 5 and older) with sickle cell anemia or sickle thalassemia. The U.S.-based trial, which concluded in 2014, compared 48 weeks of treatment with oral Endari or with maltodextrin, a food additive, for changes in sickle cell crises, hospitalizations and emergency room or medical visits, hematological parameters, and for adverse reactions.
Trial results were favorable, showing that treatment with Endari led to a statistically significant 25 percent reduction in the median frequency of disease crises, and a significant 33 percent median decrease in hospitalization rates. Improvements were seen in both treated adults and children, Emmaus reported. The treatment was also seen to be safe and well-tolerated.
Based on these results, Emmaus submitted a New Drug Application to the U.S. Food and Drug Administration (FDA), seeking approval for Endari to treat sickle cell disease. The application was accepted in November 2016.
The FDA’s Oncologic Drugs Advisory Committee recommended, in a 10–3 vote, that Endari be approved to treat sickle cell disease in both adults and children on May 24, 2017. The FDA announced its favorable decision less than two months later.
Endari was designated an orphan drug in both the U.S. and in Europe, and placed on fast track development by the FDA.
Known side effects of Endari use can include constipation, nausea, headache, cough, abdominal pain, and pain in the extremities, back and chest.
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