FDA medical oncologists discuss the July 7, 2017, approval of l-glutamine to reduce the acute complications of sickle cell disease.
Sanjeeve Bala: Welcome back to the DISCO. Today’s Drug Information Soundcast in Clinical Oncology from FDA’s Oncology Center of Excellence discusses the recent approval of L-glutamine, marketed as Endari.
Abhi Nair: Sickle cell disease is an inherited hemoglobinopathy in which sickled RBC’s become lodged in small vessels leading to ischemia. The resulting vaso-occlusion causes painful crises and tissue damage that cripple the quality of life of these patients and often lead to hospitalizations. Vaso-occlusion can lead to sequelae like strokes, acute chest syndrome, hepatic crisis, and bone infarction. Until the recent approval of L-glutamine, hydroxyurea was the only approved drug for treatment of sickle cell disease. Hydroxyurea reduces the frequency of crises and reduces the need for blood transfusions. However, some patients do not respond to hydroxyurea, and it has serious safety concerns as well, so there is a huge unmet need in this disease for new therapies. Hi, I’m Abhi Nair.
SB: And I’m Sanjeeve Bala. Today at the DISCO, we’ll discuss the recent approval of L-glutamine indicated to reduce the acute complications of sickle cell disease in adult and pediatric patients 5 years of age and older.
AN: Sanjeeve, tell us a bit about the mechanism of action of L-glutamine.
SB: Abhi, we’ll need to go back to biochemistry basics. L-glutamine is a naturally occurring amino acid. Although the mechanism of action for L-glutamine is not fully understood, its use in sickle cell disease is based on its antioxidant activity. It increases NAD redox potential in sickle red blood cells through increasing the availability of reduced glutathione. This may lessen oxidative damage in sickle red blood cells.
AN: That sounds interesting. Tell us about the FDA approval pathway for L-glutamine for sickle cell disease.
SB: This is the second FDA-approved indication for L-glutamine. It was approved as a product called NutreStore in 2004 for use in treating short bowel syndrome. The application for sickle cell disease was a 505(b) 2 application referencing NutreStore.
AN: So a prior approval was used in the current application. How does that work?
SB: Abhi, the 505(b)(2) pathway is intended to minimize unnecessary duplication of animal studies and clinical trials, and make approvals more efficient. Products that are based on previously approved, called reference listed products in regulatory jargon, can use some data and other information from those older products.
AN: So this application relied in part on information collected at the time of the first approval for L-glutamine.
SB: That’s right, which reduced the amount of data required, making the process more efficient.
AN: Can you summarize the primary clinical data and endpoints that led to the approval in Sickle cell disease?
SB: Sure, Abhi. The application relied on results of a randomized, double-blind, placebo-controlled, multi-center trial in 230 sickle cell patients who were 5 to 58 years old. These patients either had sickle cell anemia or sickle beta-zero thalassemia and two or more painful crises within the 12 months before entering the study. About two-thirds of patients also were receiving stable doses of hydroxyurea at study entry and continued this drug during the study. Patients were randomized to receive either L-glutamine or placebo for 48 weeks followed by a three week taper.
AN: What was the primary endpoint of the trial, Sanjeeve? How was it defined?
SB: The primary endpoint was the number of crises during the first 48 weeks on study treatment. A sickle cell crisis was defined as a visit to a medical facility for sickle cell disease-related pain that required treatment with a parenteral narcotic or parenteral ketorolac.
AN: The occurrence of chest syndrome, priapism, and splenic sequestration were therefore considered sickle cell crises. What were the results?
SB: The number of sickle cell crises among patients who received L-glutamine was reduced compared to those receiving placebo, with a median of 3 crises in the glutamine arm versus 4 in the placebo arm. Treatment with L-glutamine also resulted in fewer hospitalizations due to sickle cell pain, fewer cumulative hospital days, longer time to first crisis and a lower incidence of acute chest syndrome.
AN: The Oncologic Drugs Advisory Committee discussed L-glutamine at a meeting on May 24, 2017. Interpretation of the trial was complicated by large dropout rates and differential dropout rates between treatment arms, with a higher dropout rate among patients randomized to the glutamine arm. This necessitated multiple sensitivity analyses to examine impact of the imbalances. The advisory committee discussed the missing efficacy data and the analyses performed by the FDA. The committee voted in favor of L-glutamine and agreed that it has a favorable risk-benefit profile for patients with sickle cell anemia.
AN: Tell us about the safety findings for L-glutamine.
SB: The most common adverse reactions occurring in greater than 10% of patients treated with L-glutamine were constipation, nausea, headache, cough, and pain (in the abdomen, limb, back, or chest). Detailed safety information is available in the package insert.
AN: Give us some pearls regarding dosing of L-glutamine?
SB: The recommended dose of L-glutamine powder is 5 to 15 grams twice daily based on body weight.
AN: Give us the three take-home points from this DISCO.
SB: Sure Abhi…… In patients with sickle cell disease, L-glutamine reduced the number of debilitating sickle cell crises. The safety profile of L-glutamine was favorable and adverse reactions were manageable. L-glutamine is dosed based on weight, and prescribers should refer to the package insert for detailed information available on the web at Drugs@FDA.
SB: For a transcript with links to an in-depth look at the FDA analysis, and the multidisciplinary team of FDA experts who conducted the review, visit the FDA Oncology Center of Excellence DISCO website at fda.gov/DISCO.
AN: Leave us your questions and comments on Twitter @FDAOncology and as always, we welcome your feedback. I’m Abhi Nair, and thank you for tuning in.
SB: And until next time at the DISCO, I’m Sanjeeve Bala.
This Drug Information Soundcast in Clinical Oncology was developed by Abhilasha Nair, Sanjeeve Bala, Kathy M. Robie Suh, Ann T. Farrell, Kirsten B. Goldberg, and Richard Pazdur, of the Oncology Center of Excellence and the Office of Hematology and Oncology Products. Steven Jackson of the Division of Drug Information was the sound producer.
Members of the Multi-Disciplinary Review and Evaluation team for this product application were:
Biometrics Reviewer: Che L. Smith
Biopharmaceutics Reviewer: Jing Li
Clinical Reviewer: Rosanna W. Setse
Clinical Pharmacology Reviewer: Yuhong Chen
Marketing and Advertising Professional Reviewer: Robert L. Nguyen
Non-Clinical Reviewer: Shwu Luan Lee
Pharmacovigilance Reviewer: Saharat Patanavanich
MA-Professional Secondary Reviewer: Susannah O’Donnell
Regulatory Project Manager: Michael V. Gwathmey