From Inhaled DHE Offers Rapid and Sustained Efficacy for Acute Migraine
Daniel M. Keller, PhD
Medscape
September 16, 2009 (Philadelphia, Pennsylvania) — In a phase 3 trial of a novel, orally inhaled formulation of dihydroergotamine (DHE; Levadex, MAP Pharmaceuticals) for the treatment of acute migraine, the drug showed rapid and sustained efficacy, was well tolerated with minimal adverse effects, and produced a low incidence of triptan-like sensations. It also appeared effective in patients generally thought to be treatment-resistant.
Lead investigator Stephen Silberstein, MD, told the audience here at the 14th International Headache Conference that the interesting concept with this strategy is the delivery of drugs to the lungs through a device that takes advantage of the widespread absorptive capacity in the pulmonary circuit. The device, a small inhaler, delivers 2-μ particles to the lungs at low speed and is triggered when a patient inhales. Dr. Silberstein is professor of neurology and director of the Headache Center at Jefferson Medical College in Philadelphia, and a member of the Medscape Neurology Advisory Board.
The multicenter, randomized, double-blind, placebo-controlled phase 3 trial, FREEDOM-301, had a run-in period of at least 28 days, followed by double-blind treatment with active drug or placebo, followed in turn by open-label treatment for safety evaluation. Primary endpoints were relief of pain, phonophobia, and photophobia, and freedom from nausea at 2 hours. The study was funded by MAP Pharmaceuticals.
Topline results were released in May of this year and were reported on at that time by Medscape Neurology.
Early Relief
The placebo (n = 453) and active treatment (n = 450) groups were well matched, with mean ages of 40 and 41 years, respectively (range, 18 – 65), and were 91% to 92% women. Each group had a mean Headache Impact Test score of 66 at baseline. At the time of treatment, just more than half of each group rated their headaches as moderate, and just less than half rated them as severe.
"Statistically speaking, we saw pain relief as early as 30 minutes," Dr. Silberstein reported. "At the primary endpoint of 2 hours, 59% of the active group compared to 35% in the placebo group had pain relief." The difference between the active and control groups at 2 hours was significant at the P <.0001 level. Inhaled DHE was superior to placebo for sustaining pain relief between 2 to 24 hours and 2 to 48 hours (44% vs 20% and 36% vs 17%, respectively; P <.0001 for both).
For the more rigorous criterion of being pain-free at 2 hours, 10% of the placebo group achieved this endpoint compared with 28% of the DHE group (P <.0001). By 24 and 48 hours, 23% and 18% of the DHE group was still pain free (P = .0024 and P <.0001 vs placebo at each time point). Statistically significantly greater proportions of the active treatment group were free of phonophobia, photophobia, and nausea at 2 hours compared with the placebo group.
During the double-blind phase, the major difference in adverse events was the occurrence of complaints about the taste of the inhaled product (6.4% for DHE vs 1.7% for placebo), as would be expected for a DHE product. There was more nausea with the active drug (4.5%) than with placebo (2.0%), but Dr. Silberstein noted that with injectable DHE, nausea is always a problem and anti-emetics are indicated, although they were not used in this study.
Triptan-like sensitivities such as chest discomfort or pain and paresthesia were rare in either group. Dr. Silberstein said he was surprised by the number of upper respiratory infections during the run-in period; they persisted about equally for the 2 groups during the double-blind period.
When the researchers looked at predictors of response to the drug, treating earlier was better, but even if treatment occurred later than 8 hours, 50% of patients responded. Patients with Headache Impact Test scores of less than 60, indicating less disability, responded slightly better than those with scores greater than 60 (about 68% vs 58%, respectively). The presence or absence of allodynia did not appear to have an effect on response rates. Dr. Silberstein concluded that orally inhaled DHE was effective in a broad spectrum of migraine patients, including those thought to be generally treatment-resistant.
DHE delivered by oral inhalation produces fewer adverse effects than injectable DHE because of the pharmacokinetics of each. The Tmax is short with the inhaled form, and its Cmax is lower because of the delivery system. "Therefore, you don't have the sudden increase in dihydroergotamine level, [and] that results in a much better tolerability profile," Dr. Silberstein explained.
New Routes of Administration
Session cochair Todd Schwedt, MD, assistant professor of neurology and director of the headache center at Washington University School of Medicine in St. Louis, Missouri, told Medscape Neurology that the results look "quite promising" because there is a lot of interest in finding new routes of administration for medications to abort acute migraines.
"There's quite a bit of evidence that there's relative gastric stasis that occurs during migraine," Dr. Schwedt said, "meaning that the absorption of orally administered medications is oftentimes poor."
Given the frequent adverse effects of nausea and chest pain with intravenous DHE, he said this new delivery system may allow DHE to be used more often on an outpatient basis or earlier in a migraine attack. But Dr. Schwedt questioned how inhaled DHE compares with the currently available nasal formulation (Migranal, Valeant), and he considers the present study to be an early one.
Session co-chair Elizabeth Loder, MD, MPH, chief of the division of headache and pain at Brigham and Women's Hospital in Boston, Massachusetts, told Medscape Neurology that she thinks at present, DHE "is a great drug when used in the right patient," but that it is underused because it has to be given parenterally or intranasally.
"I've always wondered a bit about absorption," she said. "It seems to me that it's somewhat erratic, and that has tempered my enthusiasm for using it in that way." So added that she thinks inhaled DHE could be a useful advance.
"Certainly it was encouraging to see the relatively low side effect profile compared to what you'd experience if you gave it parenterally, so I'm encouraged by that," she said.
The study was funded by MAP Pharmaceuticals.
14th International Headache Congress: Abstract LBOR 04. Presented September 12, 2009.
Daniel M. Keller, PhD
Medscape
September 16, 2009 (Philadelphia, Pennsylvania) — In a phase 3 trial of a novel, orally inhaled formulation of dihydroergotamine (DHE; Levadex, MAP Pharmaceuticals) for the treatment of acute migraine, the drug showed rapid and sustained efficacy, was well tolerated with minimal adverse effects, and produced a low incidence of triptan-like sensations. It also appeared effective in patients generally thought to be treatment-resistant.
Lead investigator Stephen Silberstein, MD, told the audience here at the 14th International Headache Conference that the interesting concept with this strategy is the delivery of drugs to the lungs through a device that takes advantage of the widespread absorptive capacity in the pulmonary circuit. The device, a small inhaler, delivers 2-μ particles to the lungs at low speed and is triggered when a patient inhales. Dr. Silberstein is professor of neurology and director of the Headache Center at Jefferson Medical College in Philadelphia, and a member of the Medscape Neurology Advisory Board.
The multicenter, randomized, double-blind, placebo-controlled phase 3 trial, FREEDOM-301, had a run-in period of at least 28 days, followed by double-blind treatment with active drug or placebo, followed in turn by open-label treatment for safety evaluation. Primary endpoints were relief of pain, phonophobia, and photophobia, and freedom from nausea at 2 hours. The study was funded by MAP Pharmaceuticals.
Topline results were released in May of this year and were reported on at that time by Medscape Neurology.
Early Relief
The placebo (n = 453) and active treatment (n = 450) groups were well matched, with mean ages of 40 and 41 years, respectively (range, 18 – 65), and were 91% to 92% women. Each group had a mean Headache Impact Test score of 66 at baseline. At the time of treatment, just more than half of each group rated their headaches as moderate, and just less than half rated them as severe.
"Statistically speaking, we saw pain relief as early as 30 minutes," Dr. Silberstein reported. "At the primary endpoint of 2 hours, 59% of the active group compared to 35% in the placebo group had pain relief." The difference between the active and control groups at 2 hours was significant at the P <.0001 level. Inhaled DHE was superior to placebo for sustaining pain relief between 2 to 24 hours and 2 to 48 hours (44% vs 20% and 36% vs 17%, respectively; P <.0001 for both).
For the more rigorous criterion of being pain-free at 2 hours, 10% of the placebo group achieved this endpoint compared with 28% of the DHE group (P <.0001). By 24 and 48 hours, 23% and 18% of the DHE group was still pain free (P = .0024 and P <.0001 vs placebo at each time point). Statistically significantly greater proportions of the active treatment group were free of phonophobia, photophobia, and nausea at 2 hours compared with the placebo group.
During the double-blind phase, the major difference in adverse events was the occurrence of complaints about the taste of the inhaled product (6.4% for DHE vs 1.7% for placebo), as would be expected for a DHE product. There was more nausea with the active drug (4.5%) than with placebo (2.0%), but Dr. Silberstein noted that with injectable DHE, nausea is always a problem and anti-emetics are indicated, although they were not used in this study.
Triptan-like sensitivities such as chest discomfort or pain and paresthesia were rare in either group. Dr. Silberstein said he was surprised by the number of upper respiratory infections during the run-in period; they persisted about equally for the 2 groups during the double-blind period.
When the researchers looked at predictors of response to the drug, treating earlier was better, but even if treatment occurred later than 8 hours, 50% of patients responded. Patients with Headache Impact Test scores of less than 60, indicating less disability, responded slightly better than those with scores greater than 60 (about 68% vs 58%, respectively). The presence or absence of allodynia did not appear to have an effect on response rates. Dr. Silberstein concluded that orally inhaled DHE was effective in a broad spectrum of migraine patients, including those thought to be generally treatment-resistant.
DHE delivered by oral inhalation produces fewer adverse effects than injectable DHE because of the pharmacokinetics of each. The Tmax is short with the inhaled form, and its Cmax is lower because of the delivery system. "Therefore, you don't have the sudden increase in dihydroergotamine level, [and] that results in a much better tolerability profile," Dr. Silberstein explained.
New Routes of Administration
Session cochair Todd Schwedt, MD, assistant professor of neurology and director of the headache center at Washington University School of Medicine in St. Louis, Missouri, told Medscape Neurology that the results look "quite promising" because there is a lot of interest in finding new routes of administration for medications to abort acute migraines.
"There's quite a bit of evidence that there's relative gastric stasis that occurs during migraine," Dr. Schwedt said, "meaning that the absorption of orally administered medications is oftentimes poor."
Given the frequent adverse effects of nausea and chest pain with intravenous DHE, he said this new delivery system may allow DHE to be used more often on an outpatient basis or earlier in a migraine attack. But Dr. Schwedt questioned how inhaled DHE compares with the currently available nasal formulation (Migranal, Valeant), and he considers the present study to be an early one.
Session co-chair Elizabeth Loder, MD, MPH, chief of the division of headache and pain at Brigham and Women's Hospital in Boston, Massachusetts, told Medscape Neurology that she thinks at present, DHE "is a great drug when used in the right patient," but that it is underused because it has to be given parenterally or intranasally.
"I've always wondered a bit about absorption," she said. "It seems to me that it's somewhat erratic, and that has tempered my enthusiasm for using it in that way." So added that she thinks inhaled DHE could be a useful advance.
"Certainly it was encouraging to see the relatively low side effect profile compared to what you'd experience if you gave it parenterally, so I'm encouraged by that," she said.
The study was funded by MAP Pharmaceuticals.
14th International Headache Congress: Abstract LBOR 04. Presented September 12, 2009.
