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The available data on the use of L-glutamine powder for treating sickle cell disease is favorable in terms of the agent’s overall benefit-risk profile, a majority of the Food and Drug Administration’s Oncologic Drugs Advisory Committee agreed during a meeting May 24.
L-glutamine powder, which is used as an oral solution for treating sickle cell disease, showed moderate benefit in a phase III study and a smaller phase II study, and if approved by the FDA – which usually follows the recommendations of its advisory committees – would be only the second treatment approved for the debilitating and sometimes deadly disease. The first, hydroxyurea, was approved for use in adults in 1998.
The committee voted 10-3 in favor of L-glutamate, after hearing from representatives of the new drug marketing applicant, Emmaus Medical, about the efficacy and safety data, as well as from FDA representatives who analyzed the data, physicians who treat sickle cell patients, patient advocates, and patients and their family members who gave emotional testimony in favor of approving this treatment.
“This is clearly a bad disease. It’s worse than cancer in many ways. I think probably mostly from a stigma standpoint it has a desperate need [for treatments],” said acting committee chair Brian I. Rini, MD, who voted in favor of the agent.
While there were some concerns about the data, including questions about methodologies, differential dropout rates between study arms, baseline characteristics that may have affected outcomes, and discrepancies between the Emmaus Medical data and the FDA’s analyses of the data, “all seemed to come down in favor of the agent,” Dr. Rini said, citing its “modest but consistent benefit” and low risk.
“I think one thing that’s strikingly clear is that even any sort of modest benefit in this community, given the sequelae of crises, is significant; it doesn’t take much to produce a clinical impact, and that should be motivation to study more drugs in this disease,” he said.
Another focus among those who voted “yes” was on the overwhelming need for treatment for sickle cell patients, who spend “a hugely disproportionate part of their life in the health care system, and who have had a tremendous burden imposed on them by their disease,” according to Harold J. Burstein, MD, PhD, of Dana-Farber Cancer Institute in Boston, who said he was swayed by the low risk of toxicity and the corroborating evidence in the phase II and III trials.
“What I took away was that one fewer hospital visit per year was a clinically compelling benefit for any individual or family or hospital that might be caring for patients with sickle cell disease,” he said, referencing a finding that treated patients had three visits, compared with four visits among patients in the placebo group, in the phase III study.
The data presented to the committee during the meeting by Yutaka Niihara, MD, of Emmaus Medical, included findings from a phase III randomized, placebo-controlled multicenter study (GLUSCC09-01) involving patients aged 5 years and older with sickle cell disease or beta-0 thalassemia who had at least two episodes of painful crises within the 12 months prior to screening. A total of 152 patients were randomized to receive oral L-glutamine at a dose of 0.3 mg/kg per day for 48 weeks followed by a 3-week tapering period, and 78 received placebo.
The Emmaus Medical analysis demonstrated a significant decrease in crisis events (median of 3 vs. 4) among treatment vs. placebo group patients, and the time to second crisis was delayed by 79 days in the treatment group (hazard ratio 0.68). The analysis, however, was complicated by the differential dropout rates (36% vs. 24% in the treatment and placebo arms, respectively), necessitating the use of imputation methods. Various methods were used to handle the missing data, and the findings with each of them favored L-glutamine, but each had important limitations, and while the FDA’s analysis of the various approaches showed that each favored L-glutamine over placebo with a range of reduction in the rates of crises from 0.4 to 0.9, this contributed to the decision by some panel member to vote against the agent.
The phase II study (Study 10478), which had a similar design, failed to meet its specified significance level for primary efficacy analysis, but showed a trend in favor of L-glutamine vs. placebo, Dr. Niihara said.
As for safety, Dr. Niihara reported that a safety population of 187 patients treated with L-glutamine and 111 treated with placebo in the phase II and III studies showed that most patients experienced a treatment-emergent adverse event – most often sickle cell anemia with crisis (66% and 72% in the groups, respectively) and acute chest syndrome (7% and 19%, respectively). Treatment-emergent adverse events led to withdrawal in 2.7% and 0.9% of patients, respectively. The most common adverse reactions were constipation, nausea, headache, cough, pain in the extremities, back pain, chest pain, and abdominal pain.
Bernard F. Cole, PhD, who was among the “no” votes, said he had concerns about “the limitations resulting from differential dropout” rates, which may have artificially shifted the risk profile.
“As a result of those limitations, it’s not clear whether patients at higher risk of a [sickle cell crisis] event might have disproportionately dropped out of the L-glutamine arm,” he explained. “My hope is that the sponsors can more thoroughly address the limitations of this pivotal trial with the FDA,” said Dr. Cole, a professor in the department of mathematics and statistics at the University of Vermont, Burlington.
Dr. Rini, despite his “yes” vote, agreed with the need for more data, noting that additional data analysis could help when it comes to clinical application of L-glutamine.
Specifically, more data regarding duration of therapy and quality data collection that “borrows from the cancer world ... in terms of rigor or data collection,” is needed, he said.
The committee members had no relevant conflicts of interests to disclose.
The available data on the use of L-glutamine powder for treating sickle cell disease is favorable in terms of the agent’s overall benefit-risk profile, a majority of the Food and Drug Administration’s Oncologic Drugs Advisory Committee agreed during a meeting May 24.
L-glutamine powder, which is used as an oral solution for treating sickle cell disease, showed moderate benefit in a phase III study and a smaller phase II study, and if approved by the FDA – which usually follows the recommendations of its advisory committees – would be only the second treatment approved for the debilitating and sometimes deadly disease. The first, hydroxyurea, was approved for use in adults in 1998.
The committee voted 10-3 in favor of L-glutamate, after hearing from representatives of the new drug marketing applicant, Emmaus Medical, about the efficacy and safety data, as well as from FDA representatives who analyzed the data, physicians who treat sickle cell patients, patient advocates, and patients and their family members who gave emotional testimony in favor of approving this treatment.
“This is clearly a bad disease. It’s worse than cancer in many ways. I think probably mostly from a stigma standpoint it has a desperate need [for treatments],” said acting committee chair Brian I. Rini, MD, who voted in favor of the agent.
While there were some concerns about the data, including questions about methodologies, differential dropout rates between study arms, baseline characteristics that may have affected outcomes, and discrepancies between the Emmaus Medical data and the FDA’s analyses of the data, “all seemed to come down in favor of the agent,” Dr. Rini said, citing its “modest but consistent benefit” and low risk.
“I think one thing that’s strikingly clear is that even any sort of modest benefit in this community, given the sequelae of crises, is significant; it doesn’t take much to produce a clinical impact, and that should be motivation to study more drugs in this disease,” he said.
Another focus among those who voted “yes” was on the overwhelming need for treatment for sickle cell patients, who spend “a hugely disproportionate part of their life in the health care system, and who have had a tremendous burden imposed on them by their disease,” according to Harold J. Burstein, MD, PhD, of Dana-Farber Cancer Institute in Boston, who said he was swayed by the low risk of toxicity and the corroborating evidence in the phase II and III trials.
“What I took away was that one fewer hospital visit per year was a clinically compelling benefit for any individual or family or hospital that might be caring for patients with sickle cell disease,” he said, referencing a finding that treated patients had three visits, compared with four visits among patients in the placebo group, in the phase III study.
The data presented to the committee during the meeting by Yutaka Niihara, MD, of Emmaus Medical, included findings from a phase III randomized, placebo-controlled multicenter study (GLUSCC09-01) involving patients aged 5 years and older with sickle cell disease or beta-0 thalassemia who had at least two episodes of painful crises within the 12 months prior to screening. A total of 152 patients were randomized to receive oral L-glutamine at a dose of 0.3 mg/kg per day for 48 weeks followed by a 3-week tapering period, and 78 received placebo.
The Emmaus Medical analysis demonstrated a significant decrease in crisis events (median of 3 vs. 4) among treatment vs. placebo group patients, and the time to second crisis was delayed by 79 days in the treatment group (hazard ratio 0.68). The analysis, however, was complicated by the differential dropout rates (36% vs. 24% in the treatment and placebo arms, respectively), necessitating the use of imputation methods. Various methods were used to handle the missing data, and the findings with each of them favored L-glutamine, but each had important limitations, and while the FDA’s analysis of the various approaches showed that each favored L-glutamine over placebo with a range of reduction in the rates of crises from 0.4 to 0.9, this contributed to the decision by some panel member to vote against the agent.
The phase II study (Study 10478), which had a similar design, failed to meet its specified significance level for primary efficacy analysis, but showed a trend in favor of L-glutamine vs. placebo, Dr. Niihara said.
As for safety, Dr. Niihara reported that a safety population of 187 patients treated with L-glutamine and 111 treated with placebo in the phase II and III studies showed that most patients experienced a treatment-emergent adverse event – most often sickle cell anemia with crisis (66% and 72% in the groups, respectively) and acute chest syndrome (7% and 19%, respectively). Treatment-emergent adverse events led to withdrawal in 2.7% and 0.9% of patients, respectively. The most common adverse reactions were constipation, nausea, headache, cough, pain in the extremities, back pain, chest pain, and abdominal pain.
Bernard F. Cole, PhD, who was among the “no” votes, said he had concerns about “the limitations resulting from differential dropout” rates, which may have artificially shifted the risk profile.
“As a result of those limitations, it’s not clear whether patients at higher risk of a [sickle cell crisis] event might have disproportionately dropped out of the L-glutamine arm,” he explained. “My hope is that the sponsors can more thoroughly address the limitations of this pivotal trial with the FDA,” said Dr. Cole, a professor in the department of mathematics and statistics at the University of Vermont, Burlington.
Dr. Rini, despite his “yes” vote, agreed with the need for more data, noting that additional data analysis could help when it comes to clinical application of L-glutamine.
Specifically, more data regarding duration of therapy and quality data collection that “borrows from the cancer world ... in terms of rigor or data collection,” is needed, he said.
The committee members had no relevant conflicts of interests to disclose.
The available data on the use of L-glutamine powder for treating sickle cell disease is favorable in terms of the agent’s overall benefit-risk profile, a majority of the Food and Drug Administration’s Oncologic Drugs Advisory Committee agreed during a meeting May 24.
L-glutamine powder, which is used as an oral solution for treating sickle cell disease, showed moderate benefit in a phase III study and a smaller phase II study, and if approved by the FDA – which usually follows the recommendations of its advisory committees – would be only the second treatment approved for the debilitating and sometimes deadly disease. The first, hydroxyurea, was approved for use in adults in 1998.
The committee voted 10-3 in favor of L-glutamate, after hearing from representatives of the new drug marketing applicant, Emmaus Medical, about the efficacy and safety data, as well as from FDA representatives who analyzed the data, physicians who treat sickle cell patients, patient advocates, and patients and their family members who gave emotional testimony in favor of approving this treatment.
“This is clearly a bad disease. It’s worse than cancer in many ways. I think probably mostly from a stigma standpoint it has a desperate need [for treatments],” said acting committee chair Brian I. Rini, MD, who voted in favor of the agent.
While there were some concerns about the data, including questions about methodologies, differential dropout rates between study arms, baseline characteristics that may have affected outcomes, and discrepancies between the Emmaus Medical data and the FDA’s analyses of the data, “all seemed to come down in favor of the agent,” Dr. Rini said, citing its “modest but consistent benefit” and low risk.
“I think one thing that’s strikingly clear is that even any sort of modest benefit in this community, given the sequelae of crises, is significant; it doesn’t take much to produce a clinical impact, and that should be motivation to study more drugs in this disease,” he said.
Another focus among those who voted “yes” was on the overwhelming need for treatment for sickle cell patients, who spend “a hugely disproportionate part of their life in the health care system, and who have had a tremendous burden imposed on them by their disease,” according to Harold J. Burstein, MD, PhD, of Dana-Farber Cancer Institute in Boston, who said he was swayed by the low risk of toxicity and the corroborating evidence in the phase II and III trials.
“What I took away was that one fewer hospital visit per year was a clinically compelling benefit for any individual or family or hospital that might be caring for patients with sickle cell disease,” he said, referencing a finding that treated patients had three visits, compared with four visits among patients in the placebo group, in the phase III study.
The data presented to the committee during the meeting by Yutaka Niihara, MD, of Emmaus Medical, included findings from a phase III randomized, placebo-controlled multicenter study (GLUSCC09-01) involving patients aged 5 years and older with sickle cell disease or beta-0 thalassemia who had at least two episodes of painful crises within the 12 months prior to screening. A total of 152 patients were randomized to receive oral L-glutamine at a dose of 0.3 mg/kg per day for 48 weeks followed by a 3-week tapering period, and 78 received placebo.
The Emmaus Medical analysis demonstrated a significant decrease in crisis events (median of 3 vs. 4) among treatment vs. placebo group patients, and the time to second crisis was delayed by 79 days in the treatment group (hazard ratio 0.68). The analysis, however, was complicated by the differential dropout rates (36% vs. 24% in the treatment and placebo arms, respectively), necessitating the use of imputation methods. Various methods were used to handle the missing data, and the findings with each of them favored L-glutamine, but each had important limitations, and while the FDA’s analysis of the various approaches showed that each favored L-glutamine over placebo with a range of reduction in the rates of crises from 0.4 to 0.9, this contributed to the decision by some panel member to vote against the agent.
The phase II study (Study 10478), which had a similar design, failed to meet its specified significance level for primary efficacy analysis, but showed a trend in favor of L-glutamine vs. placebo, Dr. Niihara said.
As for safety, Dr. Niihara reported that a safety population of 187 patients treated with L-glutamine and 111 treated with placebo in the phase II and III studies showed that most patients experienced a treatment-emergent adverse event – most often sickle cell anemia with crisis (66% and 72% in the groups, respectively) and acute chest syndrome (7% and 19%, respectively). Treatment-emergent adverse events led to withdrawal in 2.7% and 0.9% of patients, respectively. The most common adverse reactions were constipation, nausea, headache, cough, pain in the extremities, back pain, chest pain, and abdominal pain.
Bernard F. Cole, PhD, who was among the “no” votes, said he had concerns about “the limitations resulting from differential dropout” rates, which may have artificially shifted the risk profile.
“As a result of those limitations, it’s not clear whether patients at higher risk of a [sickle cell crisis] event might have disproportionately dropped out of the L-glutamine arm,” he explained. “My hope is that the sponsors can more thoroughly address the limitations of this pivotal trial with the FDA,” said Dr. Cole, a professor in the department of mathematics and statistics at the University of Vermont, Burlington.
Dr. Rini, despite his “yes” vote, agreed with the need for more data, noting that additional data analysis could help when it comes to clinical application of L-glutamine.
Specifically, more data regarding duration of therapy and quality data collection that “borrows from the cancer world ... in terms of rigor or data collection,” is needed, he said.
The committee members had no relevant conflicts of interests to disclose.
Key clinical point:
Major finding: In a phase III study, there was a significant decrease in crisis events (median of 3 vs. 4) among treatment vs. placebo group patients.
Data source: A total of 152 patients were randomized to receive oral L-glutamine at a dose of 0.3 mg/kg per day for 48 weeks followed by a 3-week tapering period, and 78 received placebo.
Disclosures: The committee members had no relevant conflicts of interests to disclose.