The approval was based on placebo-controlled phase II and phase III trials suggesting that L-glutamate offered moderate benefit to patients with this rare, serious, and potentially fatal blood disorder.
L-glutamine oral powder will be marketed under the brand name Endari by Emmaus Medical. The FDA granted the approval through its orphan drug pathway, which is reserved for treatments of rare diseases or conditions. The National Institutes of Health estimates that sickle cell disorder affects approximately 100,000 individuals in the United States. Previously, the only drug approved for treating sickle cell disorder was hydroxyurea, which the FDA green-lighted in 1998.
The randomized, placebo-controlled, phase III trial on which the approval of L-glutamine was based (GLUSCC09-01) comprised patients aged 5-58 years with sickle cell disease or beta-0 thalassemia who had at least two episodes of painful crises during the 12 months before screening. A total of 152 patients were randomly assigned to receive oral L-glutamine (0.3 mg/kg per day) for 48 weeks followed by a 3-week tapering period, while 78 patients received placebo. Patients who received L-glutamine averaged three hospital visits for painful crises for which they received parenteral narcotics or ketorolac, while the placebo group averaged four such hospital visits. Additionally, the time to second crisis was delayed by 79 days in the treatment group, compared with the placebo group (hazard ratio, 0.68).
L-glutamine also was associated with fewer hospital days (median 6.5 vs. 11 days) and fewer occurrences of potentially life-threatening acute chest syndrome (8.6% vs. 23.1%), investigators reported to the FDA’s Oncologic Drugs Advisory Committee during a meeting on May 24.
Safety studies of L-glutamine included phase II and phase III data from 187 patients who received L-glutamine and 111 patients who received placebo, the investigators reported. Based on these analyses, rates of sickle cell anemia with crisis were 66% in the treatment population and 72% in placebo recipients. Rates of acute chest syndrome were 7% and 19%, respectively. Treatment-emergent adverse events led patients to drop out of the studies in 2.7% and 0.9% of cases. The most common adverse events of L-glutamine therapy were constipation, nausea, headache, cough, pain in the extremities, back pain, chest pain, and abdominal pain.
The FDA advisory committee voted 10-3 in favor of approving L-glutamate after hearing from industry and FDA representatives, physicians who treat patients with sickle cell disorder, and patients and their family members at the May 24 meeting. “No” voters expressed concerns about differing drop-out rates between the study groups, but other committee members emphasized the severe impact of sickle cell disorder on quality of life and the crucial need for more treatments.
The FDA Orphan Products Grants Program provided some of the funding to develop the drug. The FDA committee members had no relevant conflicts of interests.