FDA News

FDA advisory committee expresses support for L-glutamine for sickle cell disease

An FDA panel today expressed its support for the approval of L-glutamine powder in the treatment of sickle cell disease.

The Oncologic Drugs Advisory Committee (ODAC) voted 10-3 in favor of Emmaus Medical’s new drug application for oral L-glutamine powder for chronic use in adults and children age 5 years and older with sickle cell disease.

Brian I. Rini

The FDA previously granted L-glutamine orphan drug designation in 2001 and fast track designation in 2005. The panel discussed whether the drug’s benefits outweighed its risks.

“My ‘yes,’ like many of the [votes], was difficult,” Brian I. Rini, MD, FACP, acting chairperson of ODAC and a HemOnc Today Editorial Board member, said during the meeting. “This could have gone either way. This is clearly a bad disease — worse than cancer in many ways, mostly from a stigma standpoint — and to complete two randomized studies is a major accomplishment. Our job, however, is to recommend approval of drugs not based on desperate need, but based on good data. The data were all there and I think it might be helpful in how we apply this drug clinically if it is FDA approved.”

Sickle cell disease (SCD) is a hereditary disorder caused by a single point mutation in the hemoglobin chain and affects nearly 100,000 Americans, 95% of whom are black.

A phase 3 multicenter, double blind, placebo controlled study (GLUSCC09-01) included 229 patients aged 5 years and older (mean age, 21.9 years; 22.3% 12 years or younger; 54.1% female; 94.3% black) with SCD or sickle ß0 thalassemia who had at least two painful episodes within 12 months prior to screening.

Researchers randomly assigned patients to receive oral L-glutamine (0.3 mg/kg per day, n = 151) or placebo (n = 78) for 48 weeks, followed by a 3-week tapering period. Most patients (90.4%) had sickle cell anemia.

The primary efficacy analysis compared frequency of sickle cell crises — defined as a visit to an ED or medical facility for SCD–related pain treated with a parenterally administered narcotic or ketorolac — through 48 weeks. Researchers also considered acute chest syndrome, priapism and splenic sequestration sickle cell crises, even if the symptoms did not require narcotics.

A median of three sickle cell crisis events occurred for patients in the L-glutamine arm compared with four in the placebo group (P = .0052).

Premature discontinuation occurred in 36% of the L-glutamine group and 24% of the placebo group.

However, further exploration by the FDA showed a trend favoring L-glutamine with a range of reduction in crises per 48 weeks from 0.4 to 0.9. A similar phase 2 study also showed a trend in favor of L-glutamine over placebo, although the primary efficacy endpoint did not reach statistical significance.

Researchers evaluated safety data from patients pooled from the phase 3 and phase 2 trials.

Yutaka Niihara

Most patients experienced a treatment-related serious adverse event, the most common of which were sickle cell anemia with crisis (L-glutamine, 66.3%; placebo, 72.1%) and acute chest syndrome (7% vs. 18.9).

Treatment-related adverse events led to 2.7% of L-glutamine patients and 0.9% of placebo patients withdrawing from the study.

The most common adverse reactions overall included constipation, nausea, headache, cough, pain in extremity, back pain, chest pain and abdominal pain.

“Had this been a very toxic product, I don’t think this committee would have voted for approval,” Rini said. “But, in essence, it’s a natural product with low risk.”

Patients receiving L-glutamine had a 56% delay in time to first crisis, a 67% decrease in acute chest syndrome, a 33% decrease in hospital visits, and a 39% decrease in simple blood transfusions compared with the placebo arm, lead researcher Yutaka Niihara, MD, MPH, CEO of Emmaus Medical, said during his presentation.

“The decreased adhesion [triggered by L-glutamine] is an indication that sickle red blood cells have smoother transit through small vasculature, which helps prevent sickle cell crisis,” Niihara said.

The physical, emotional and financial demands placed on patients with SCD are “extreme” and FDA approval of L-glutamine would address those demands, Wally R. Smith, MD, professor of internal medicine at Virginia Commonwealth University, told the panel.

“The demands of living with sickle cell disease are interrupted every time a patient has a single crisis, and having one fewer of those would be welcomed by my patients and by their families and by their employers,” Smith said. “In the event L-glutamine helps them, I’m all for having this drug approved.”

The FDA often follows the guidance of ODAC when making its final decision about an agent’s approval, but the agency is not obligated to do so. – by Chuck Gormley

An FDA panel today expressed its support for the approval of L-glutamine powder in the treatment of sickle cell disease.

The Oncologic Drugs Advisory Committee (ODAC) voted 10-3 in favor of Emmaus Medical’s new drug application for oral L-glutamine powder for chronic use in adults and children age 5 years and older with sickle cell disease.

Brian I. Rini

The FDA previously granted L-glutamine orphan drug designation in 2001 and fast track designation in 2005. The panel discussed whether the drug’s benefits outweighed its risks.

“My ‘yes,’ like many of the [votes], was difficult,” Brian I. Rini, MD, FACP, acting chairperson of ODAC and a HemOnc Today Editorial Board member, said during the meeting. “This could have gone either way. This is clearly a bad disease — worse than cancer in many ways, mostly from a stigma standpoint — and to complete two randomized studies is a major accomplishment. Our job, however, is to recommend approval of drugs not based on desperate need, but based on good data. The data were all there and I think it might be helpful in how we apply this drug clinically if it is FDA approved.”

Sickle cell disease (SCD) is a hereditary disorder caused by a single point mutation in the hemoglobin chain and affects nearly 100,000 Americans, 95% of whom are black.

A phase 3 multicenter, double blind, placebo controlled study (GLUSCC09-01) included 229 patients aged 5 years and older (mean age, 21.9 years; 22.3% 12 years or younger; 54.1% female; 94.3% black) with SCD or sickle ß0 thalassemia who had at least two painful episodes within 12 months prior to screening.

Researchers randomly assigned patients to receive oral L-glutamine (0.3 mg/kg per day, n = 151) or placebo (n = 78) for 48 weeks, followed by a 3-week tapering period. Most patients (90.4%) had sickle cell anemia.

The primary efficacy analysis compared frequency of sickle cell crises — defined as a visit to an ED or medical facility for SCD–related pain treated with a parenterally administered narcotic or ketorolac — through 48 weeks. Researchers also considered acute chest syndrome, priapism and splenic sequestration sickle cell crises, even if the symptoms did not require narcotics.

A median of three sickle cell crisis events occurred for patients in the L-glutamine arm compared with four in the placebo group (P = .0052).

Premature discontinuation occurred in 36% of the L-glutamine group and 24% of the placebo group.

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However, further exploration by the FDA showed a trend favoring L-glutamine with a range of reduction in crises per 48 weeks from 0.4 to 0.9. A similar phase 2 study also showed a trend in favor of L-glutamine over placebo, although the primary efficacy endpoint did not reach statistical significance.

Researchers evaluated safety data from patients pooled from the phase 3 and phase 2 trials.

Yutaka Niihara

Most patients experienced a treatment-related serious adverse event, the most common of which were sickle cell anemia with crisis (L-glutamine, 66.3%; placebo, 72.1%) and acute chest syndrome (7% vs. 18.9).

Treatment-related adverse events led to 2.7% of L-glutamine patients and 0.9% of placebo patients withdrawing from the study.

The most common adverse reactions overall included constipation, nausea, headache, cough, pain in extremity, back pain, chest pain and abdominal pain.

“Had this been a very toxic product, I don’t think this committee would have voted for approval,” Rini said. “But, in essence, it’s a natural product with low risk.”

Patients receiving L-glutamine had a 56% delay in time to first crisis, a 67% decrease in acute chest syndrome, a 33% decrease in hospital visits, and a 39% decrease in simple blood transfusions compared with the placebo arm, lead researcher Yutaka Niihara, MD, MPH, CEO of Emmaus Medical, said during his presentation.

“The decreased adhesion [triggered by L-glutamine] is an indication that sickle red blood cells have smoother transit through small vasculature, which helps prevent sickle cell crisis,” Niihara said.

The physical, emotional and financial demands placed on patients with SCD are “extreme” and FDA approval of L-glutamine would address those demands, Wally R. Smith, MD, professor of internal medicine at Virginia Commonwealth University, told the panel.

“The demands of living with sickle cell disease are interrupted every time a patient has a single crisis, and having one fewer of those would be welcomed by my patients and by their families and by their employers,” Smith said. “In the event L-glutamine helps them, I’m all for having this drug approved.”

The FDA often follows the guidance of ODAC when making its final decision about an agent’s approval, but the agency is not obligated to do so. – by Chuck Gormley