The New England Journal of Medicine has published the 48-week phase 3 clinical trial results that supported the FDA approval of L-glutamine oral powder for the reduction of acute complications of sickle cell disease in adult and pediatric patients.
Approved by the US Food and Drug Administration (FDA) in July 2017 to reduce the acute vaso-occlusive pain complications of sickle cell disease, L-glutamine oral powder (Endari) was the first drug approved for the rare blood disease in in the 20 years since the approval of hydroxyurea.
Now, the New England Journal of Medicine (NEJM) has published the 48-week phase 3 clinical trial results that supported the FDA approval. From the data acquired in the phase 3 trial, investigators concluded that the median number of pain crises in children and adults with sickle cell disease was lower among those who received oral therapy with l-glutamine, administered alone, or with hydroxyurea, compared with those who received placebo, with or without hydroxyurea.
“The idea that this [publication] comes a year after [approval] really reflects the vigor of the review process and shows NEJM really did its job of assuring the public interest that L-glutamine, along with the findings of the study, are real and significant,” Darrell W. Harrington, MD, MACP, chief medical officer at Emmaus Life Sciences, told Rare Disease Report® .
“For Dr Niihara [the lead investigator] and the results of this trial of L-glutamine to be chosen for publication in the NEJM is in itself a big statement,” he added. “On one hand, it says something about the nature and quality of the science. On the other hand, it says this is something that is important for the population; particularly, for a population for which there hasn’t been much written about, much discovery, or much new, available material for the treatment of sickle cell disease.”
A multicenter, randomized, placebo-controlled, double-blind, phase 3 trial was used to evaluate the efficacy of pharmaceutical-grade l-glutamine in reducing the incidence of pain crises among patients with sickle cell anemia or sickle β0-thalassemia with a history of 2 or more pain crises during the previous year.
For the trial, 230 participants were randomly assigned in a 2:1 ratio to receive either L-glutamine or placebo. L-glutamine powder or placebo powder was orally administered twice-daily at 0.3 g per kilogram of body weight per dose (10g, 20g, or 30g [maximum dose] per day); this was followed by a tapering period of 3 weeks and an observation period of 2 weeks. Patients who were receiving hydroxyurea at a dose that had been stable for at least 3 months prior to screening continued the therapy through the 48-week treatment period.
A total of 156 patients were reported to have completed the trial; ninety-seven of the 152 patients (63.8%) who received L-glutamine and 59 of the 78 patients (75.6%) who received placebo. The reported data show that those who received L-glutamine oral powder experienced significantly fewer sickle cell crises compared with those who received the placebo—25% less; p=0.005 (median 3 vs. median 4); they also experienced significantly fewer hospitalizations—33% less; p=0.005 (median 2 vs. median 3)—compared with those who receive placebo.
Additionally, investigators report significantly fewer hospitalizations for those who were given L-glutamine compared with those who received placebo (p=0.02; median 6.5 days vs. median 11 days). Those who received L-glutamine experienced a significantly lower incidence of acute chest syndrome (ACS) by more than 60%; p=0.003 (13 of 152 patients [8.6%] in the L-glutamine group had at least 1 episode of ACS compared with 18 of 78 in the placebo group [23.1%]. Constipation, nausea, headache, abdominal pain, cough, pain in extremity, back pain, and chest pain were listed as the most common adverse reactions experienced, and they occurred over 10% of patients.
“The results are pretty impactful,” added Dr Harrington to Rare Disease ReportÒ. “The most impactful finding that is associated with life and death in patients with sickle cell disease is that the study also showed a 60% reduction in acute chest syndrome, which is one of the most severe acute complications that can lead to death in sickle cell disease. These are all really important meaningful clinical outcomes.”
Dr Harrington also went on to explain that approximately two-thirds of patients in the study, spanning both groups, were also on hydroxyurea treatment. The study demonstrated L-glutamine provided better benefit than hydroxyurea in that there were less treatment-associated side effects. However, it was found that whether patients were on hydroxyurea or not, they experienced similar positive results; this is especially important for patients who have failed hydroxyurea therapy in the past or are unable to take hydroxyurea due to its level of toxicity and side effects, as it offers another treatment option.
In an editorial note also published in NEJM, Caterina P. Minniti, MD, added how the results from the phase 3 trial show that there is still a need for better monitoring of toxic effects for treatments and a greater representation of the entire sickle cell disease population, such as those with more severe disease. Three deaths occurred in 2 randomized trials of L-glutamine involving patients with sickle cell disease.
“Because L-glutamine has a putatively different mechanism (or mechanisms) of action and toxicity profile than hydroxyurea, concomitant use is possible and most likely advantageous,” Dr Minniti writes. “In the era of personalized medicine, there is a need to identify subgroups of patients within the population of patients with sickle cell disease who are most likely to benefit from such therapy.”
Dr Minniti also noted that “no simple and reproducible biomarker of oxidative stress exists that can guide clinicians in identifying patients who are most likely to have a response and in monitoring adherence and effectiveness.” As oxidative stress is hallmark of sickle cell disease, tracking, reducing, and preventing it would be of great benefit for patients.
While the challenges still exist for patients with sickle cell disease, looking forward, Dr Harrington emphasized that L-glutamine has opened the door for other treatment options with its approval and success.
“In some ways, the L-glutamine FDA approval and NEJM publication is opening up a pathway for newer therapies that may have, otherwise, been harder to get through for a disease that hasn’t gotten much attention at all,” he said. “There are a lot of really profound and indirect effects of this publication.”