Pill May Be an Alternative to Injections for Ragweed Immunotherapy

ORLANDO – Immunotherapy with a pill formulated from ragweed pollen safely and effectively reduced symptoms and the need for therapy to manage symptoms in patients with ragweed allergy.

The findings were noted in two pivotal, placebo-controlled trials that together enrolled 1,349 patients in North America and Europe. The company that is developing the oral formulation, Merck, plans to use the results as the basis for a licensing application to the Food and Drug Administration next year, Dr. Hendrick Nolte, the company’s senior director for research in Kenilworth, N.J., said at the meeting.

Mitchel L. Zoler/IMNG Medical Media

But the studies only assessed the pill’s efficacy for ragweed desensitization while patients were on treatment, and only during the first year of treatment. Thus, both studies failed to address the ability of the new formulation to modify disease, a hallmark effect of standard pollen desensitization by serial injections.

"Immunotherapy based on injections is disease modifying when used for 3-5 years. You can stop [the injections] and see continued benefit," said Dr. Peter S. Creticos, lead investigator for one of the two Merck studies (J. Allergy Clin. Immunol. 2012 [doi:10.1016/j.jaci.2011.12.481]). Both ragweed pollen trials "were only single-season studies, so they can’t answer" whether disease was modified, he said in an interview during a poster presentation at the meeting.

However, a European study that used the same formulation examined the impact of 3 consecutive years of oral desensitization to ragweed followed by 2 years when patients received no immunotherapy. The results showed long-lasting tolerance that persisted during both follow-up years, said Dr. Creticos, an allergy and immunology physician at Johns Hopkins Hospital in Baltimore.

Reductions in symptoms and the need for symptom-controlling medications during ragweed-pollen season ranged from 21%-27%, compared with placebo, depending on the dosage. These differences were "clinically meaningful" and similar in efficacy to conventional, injection-based desensitization against ragweed, added Dr. Creticos. Unlike injections, the oral formulation did not cause any systemic reactions.

If the oral ragweed pill eventually receives U.S. marketing approval, it is likely to appeal to some patients, but may also have some downsides.

"A small percentage of patients won’t get injections because they are afraid of injections, they are afraid of systemic reactions, or they don’t want to have to regularly go to a doctor’s office," he said. "A daily pill is more convenient and easier, and it may be safer and just as effective." The main drawback is less reliable compliance. "A patient must be willing to take the pill daily, starting 16 weeks before the (allergy) season starts."

The study he presented randomized 565 North American adults with allergic rhinoconjunctivitis to ragweed to treatment with a pill containing 6 Amb a 1-U ragweed pollen, 12 Amb a 1-U, or placebo. Treatment began approximately 16 weeks before the start of each patient’s local ragweed pollen season, and continued for 52 weeks. Patients in all three arms could freely use symptom-controlling medications as needed: an oral antihistamine, antihistamine eyedrops, a nasal steroid, and an oral steroid.

The study’s primary efficacy end point was the patient’s total combined score – their rhinoconjunctivitis daily symptom score and daily medication-use score – during the peak of the ragweed season. For this measure, patients receiving the higher-dose ragweed pill had an average 27% reduction in their combined score, compared with the average among the placebo patients, and patients who received the lower-dose pill had an average 21% reduction, compared with placebo, both statistically significant differences. Both treatment groups showed similar improvements, compared with placebo, for secondary end points of total score throughout the entire ragweed season, symptom score during both the season’s peak and the entire season, and medication-use score during the season’s peak and the entire season.

The daily, oral pill was well tolerated at both dosages, with no deaths, systemic allergic reactions, or life-threatening events. The most common, treatment-related adverse events occurred early, and were transient and self-limited. Throat irritation occurred in 26%-29% of the active pill recipients, depending on the dosage. Other side effects included oral pruritus, in 19%; a swollen tongue, in 12%-19%; ear pruritus; tongue pruritus; oral paresthesia; and several other effects that occurred in less than 10% of treated patients. The majority of the adverse effects were mild or moderate, and none were serious. Two patients received epinephrine during the study. One patient had to a concomitant food-allergy reaction and the second was treated for local swelling and nervousness, so epinephrine treatment was not really needed.

"In routine practice, desensitization injections produce systemic reactions in 2%-6% of patients. I think we didn’t see that with the pill because the uptake is slower," Dr. Creticos said.

Results from the second trial, reported in a poster by Dr. Nolte, came from a study with a similar design that randomized 784 patients at sites in both North America and Europe (J. Allergy Clin. Immunol. 2012 [doi:10.1016/j.jaci.2011.12.482]). This 52-week treatment study added a third active-treatment arm in which patients receive a daily pill containing 1.5 Amb a 1-U ragweed pollen. This low-dose pill did not produce a statistically-significant improvement in efficacy, compared with placebo. The 6 Amb a 1-U and 12 Amb a 1-U dosages resulted in a 19% and 24% average reduction in the total combined score during the peak ragweed season, statistically significant benefits for the study’s primary end point. The safety profile of the two highest doses also mimicked the first study, with no serious adverse effects and no systemic allergic reactions, anaphylaxis, or life-threatening effects. The type and severity of the treatment-related adverse effects were very similar to the first study. One patient in the second study received epinephrine, for a concomitant food-allergy reaction.

Both trials were sponsored by Merck, which is developing the oral ragweed-pollen desensitization pill. Dr. Creticos said that he has received research support from and has been a consultant to Merck as well as to several other drug companies. Dr. Nolte is an employee of Merck.

ORLANDO – Immunotherapy with a pill formulated from ragweed pollen safely and effectively reduced symptoms and the need for therapy to manage symptoms in patients with ragweed allergy.

The findings were noted in two pivotal, placebo-controlled trials that together enrolled 1,349 patients in North America and Europe. The company that is developing the oral formulation, Merck, plans to use the results as the basis for a licensing application to the Food and Drug Administration next year, Dr. Hendrick Nolte, the company’s senior director for research in Kenilworth, N.J., said at the meeting.

Mitchel L. Zoler/IMNG Medical Media

But the studies only assessed the pill’s efficacy for ragweed desensitization while patients were on treatment, and only during the first year of treatment. Thus, both studies failed to address the ability of the new formulation to modify disease, a hallmark effect of standard pollen desensitization by serial injections.

"Immunotherapy based on injections is disease modifying when used for 3-5 years. You can stop [the injections] and see continued benefit," said Dr. Peter S. Creticos, lead investigator for one of the two Merck studies (J. Allergy Clin. Immunol. 2012 [doi:10.1016/j.jaci.2011.12.481]). Both ragweed pollen trials "were only single-season studies, so they can’t answer" whether disease was modified, he said in an interview during a poster presentation at the meeting.

However, a European study that used the same formulation examined the impact of 3 consecutive years of oral desensitization to ragweed followed by 2 years when patients received no immunotherapy. The results showed long-lasting tolerance that persisted during both follow-up years, said Dr. Creticos, an allergy and immunology physician at Johns Hopkins Hospital in Baltimore.

Reductions in symptoms and the need for symptom-controlling medications during ragweed-pollen season ranged from 21%-27%, compared with placebo, depending on the dosage. These differences were "clinically meaningful" and similar in efficacy to conventional, injection-based desensitization against ragweed, added Dr. Creticos. Unlike injections, the oral formulation did not cause any systemic reactions.

If the oral ragweed pill eventually receives U.S. marketing approval, it is likely to appeal to some patients, but may also have some downsides.

"A small percentage of patients won’t get injections because they are afraid of injections, they are afraid of systemic reactions, or they don’t want to have to regularly go to a doctor’s office," he said. "A daily pill is more convenient and easier, and it may be safer and just as effective." The main drawback is less reliable compliance. "A patient must be willing to take the pill daily, starting 16 weeks before the (allergy) season starts."

The study he presented randomized 565 North American adults with allergic rhinoconjunctivitis to ragweed to treatment with a pill containing 6 Amb a 1-U ragweed pollen, 12 Amb a 1-U, or placebo. Treatment began approximately 16 weeks before the start of each patient’s local ragweed pollen season, and continued for 52 weeks. Patients in all three arms could freely use symptom-controlling medications as needed: an oral antihistamine, antihistamine eyedrops, a nasal steroid, and an oral steroid.

The study’s primary efficacy end point was the patient’s total combined score – their rhinoconjunctivitis daily symptom score and daily medication-use score – during the peak of the ragweed season. For this measure, patients receiving the higher-dose ragweed pill had an average 27% reduction in their combined score, compared with the average among the placebo patients, and patients who received the lower-dose pill had an average 21% reduction, compared with placebo, both statistically significant differences. Both treatment groups showed similar improvements, compared with placebo, for secondary end points of total score throughout the entire ragweed season, symptom score during both the season’s peak and the entire season, and medication-use score during the season’s peak and the entire season.

The daily, oral pill was well tolerated at both dosages, with no deaths, systemic allergic reactions, or life-threatening events. The most common, treatment-related adverse events occurred early, and were transient and self-limited. Throat irritation occurred in 26%-29% of the active pill recipients, depending on the dosage. Other side effects included oral pruritus, in 19%; a swollen tongue, in 12%-19%; ear pruritus; tongue pruritus; oral paresthesia; and several other effects that occurred in less than 10% of treated patients. The majority of the adverse effects were mild or moderate, and none were serious. Two patients received epinephrine during the study. One patient had to a concomitant food-allergy reaction and the second was treated for local swelling and nervousness, so epinephrine treatment was not really needed.

"In routine practice, desensitization injections produce systemic reactions in 2%-6% of patients. I think we didn’t see that with the pill because the uptake is slower," Dr. Creticos said.

Results from the second trial, reported in a poster by Dr. Nolte, came from a study with a similar design that randomized 784 patients at sites in both North America and Europe (J. Allergy Clin. Immunol. 2012 [doi:10.1016/j.jaci.2011.12.482]). This 52-week treatment study added a third active-treatment arm in which patients receive a daily pill containing 1.5 Amb a 1-U ragweed pollen. This low-dose pill did not produce a statistically-significant improvement in efficacy, compared with placebo. The 6 Amb a 1-U and 12 Amb a 1-U dosages resulted in a 19% and 24% average reduction in the total combined score during the peak ragweed season, statistically significant benefits for the study’s primary end point. The safety profile of the two highest doses also mimicked the first study, with no serious adverse effects and no systemic allergic reactions, anaphylaxis, or life-threatening effects. The type and severity of the treatment-related adverse effects were very similar to the first study. One patient in the second study received epinephrine, for a concomitant food-allergy reaction.

Both trials were sponsored by Merck, which is developing the oral ragweed-pollen desensitization pill. Dr. Creticos said that he has received research support from and has been a consultant to Merck as well as to several other drug companies. Dr. Nolte is an employee of Merck.

ORLANDO – Immunotherapy with a pill formulated from ragweed pollen safely and effectively reduced symptoms and the need for therapy to manage symptoms in patients with ragweed allergy.

The findings were noted in two pivotal, placebo-controlled trials that together enrolled 1,349 patients in North America and Europe. The company that is developing the oral formulation, Merck, plans to use the results as the basis for a licensing application to the Food and Drug Administration next year, Dr. Hendrick Nolte, the company’s senior director for research in Kenilworth, N.J., said at the meeting.

Mitchel L. Zoler/IMNG Medical Media

But the studies only assessed the pill’s efficacy for ragweed desensitization while patients were on treatment, and only during the first year of treatment. Thus, both studies failed to address the ability of the new formulation to modify disease, a hallmark effect of standard pollen desensitization by serial injections.

"Immunotherapy based on injections is disease modifying when used for 3-5 years. You can stop [the injections] and see continued benefit," said Dr. Peter S. Creticos, lead investigator for one of the two Merck studies (J. Allergy Clin. Immunol. 2012 [doi:10.1016/j.jaci.2011.12.481]). Both ragweed pollen trials "were only single-season studies, so they can’t answer" whether disease was modified, he said in an interview during a poster presentation at the meeting.

However, a European study that used the same formulation examined the impact of 3 consecutive years of oral desensitization to ragweed followed by 2 years when patients received no immunotherapy. The results showed long-lasting tolerance that persisted during both follow-up years, said Dr. Creticos, an allergy and immunology physician at Johns Hopkins Hospital in Baltimore.

Reductions in symptoms and the need for symptom-controlling medications during ragweed-pollen season ranged from 21%-27%, compared with placebo, depending on the dosage. These differences were "clinically meaningful" and similar in efficacy to conventional, injection-based desensitization against ragweed, added Dr. Creticos. Unlike injections, the oral formulation did not cause any systemic reactions.

If the oral ragweed pill eventually receives U.S. marketing approval, it is likely to appeal to some patients, but may also have some downsides.

"A small percentage of patients won’t get injections because they are afraid of injections, they are afraid of systemic reactions, or they don’t want to have to regularly go to a doctor’s office," he said. "A daily pill is more convenient and easier, and it may be safer and just as effective." The main drawback is less reliable compliance. "A patient must be willing to take the pill daily, starting 16 weeks before the (allergy) season starts."

The study he presented randomized 565 North American adults with allergic rhinoconjunctivitis to ragweed to treatment with a pill containing 6 Amb a 1-U ragweed pollen, 12 Amb a 1-U, or placebo. Treatment began approximately 16 weeks before the start of each patient’s local ragweed pollen season, and continued for 52 weeks. Patients in all three arms could freely use symptom-controlling medications as needed: an oral antihistamine, antihistamine eyedrops, a nasal steroid, and an oral steroid.

The study’s primary efficacy end point was the patient’s total combined score – their rhinoconjunctivitis daily symptom score and daily medication-use score – during the peak of the ragweed season. For this measure, patients receiving the higher-dose ragweed pill had an average 27% reduction in their combined score, compared with the average among the placebo patients, and patients who received the lower-dose pill had an average 21% reduction, compared with placebo, both statistically significant differences. Both treatment groups showed similar improvements, compared with placebo, for secondary end points of total score throughout the entire ragweed season, symptom score during both the season’s peak and the entire season, and medication-use score during the season’s peak and the entire season.

The daily, oral pill was well tolerated at both dosages, with no deaths, systemic allergic reactions, or life-threatening events. The most common, treatment-related adverse events occurred early, and were transient and self-limited. Throat irritation occurred in 26%-29% of the active pill recipients, depending on the dosage. Other side effects included oral pruritus, in 19%; a swollen tongue, in 12%-19%; ear pruritus; tongue pruritus; oral paresthesia; and several other effects that occurred in less than 10% of treated patients. The majority of the adverse effects were mild or moderate, and none were serious. Two patients received epinephrine during the study. One patient had to a concomitant food-allergy reaction and the second was treated for local swelling and nervousness, so epinephrine treatment was not really needed.

"In routine practice, desensitization injections produce systemic reactions in 2%-6% of patients. I think we didn’t see that with the pill because the uptake is slower," Dr. Creticos said.

Results from the second trial, reported in a poster by Dr. Nolte, came from a study with a similar design that randomized 784 patients at sites in both North America and Europe (J. Allergy Clin. Immunol. 2012 [doi:10.1016/j.jaci.2011.12.482]). This 52-week treatment study added a third active-treatment arm in which patients receive a daily pill containing 1.5 Amb a 1-U ragweed pollen. This low-dose pill did not produce a statistically-significant improvement in efficacy, compared with placebo. The 6 Amb a 1-U and 12 Amb a 1-U dosages resulted in a 19% and 24% average reduction in the total combined score during the peak ragweed season, statistically significant benefits for the study’s primary end point. The safety profile of the two highest doses also mimicked the first study, with no serious adverse effects and no systemic allergic reactions, anaphylaxis, or life-threatening effects. The type and severity of the treatment-related adverse effects were very similar to the first study. One patient in the second study received epinephrine, for a concomitant food-allergy reaction.

Both trials were sponsored by Merck, which is developing the oral ragweed-pollen desensitization pill. Dr. Creticos said that he has received research support from and has been a consultant to Merck as well as to several other drug companies. Dr. Nolte is an employee of Merck.