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KEYSTONE, COLO. – Sublingual immunotherapy is finally coming.
Allergy therapy using rapidly dissolving oral tablets instead of subcutaneous injections has been approved in Europe for years. With Food and Drug Administration approval of sublingual immunotherapy tablets for the treatment of grass and ragweed allergies considered highly likely later this spring, the expectation is that patients, their referring physicians, and allergists will have many questions about this game-changing therapeutic innovation.
Dr. Harold S. Nelson, who closely follows developments in the field, provided answers at a meeting on allergy and respiratory diseases sponsored by National Jewish Health.
Among his key points:
• The effectiveness of sublingual immunotherapy (SLIT) for allergic rhinitis and allergic asthma is now thoroughly established. So are the optimal dosing regimens: SLIT tablets are dosed once daily at 30 times the optimal subcutaneous immunotherapy (SCIT) once-monthly maintenance dose. In other words, over the course of a month, a patient on SLIT will take a roughly 30 times greater dose of grass or ragweed allergen than will a patient on SCIT.
• SLIT for grass allergy will be approved for patients aged 5-65, while SLIT for ragweed will receive an indication for 18- to 65-year-olds.
• SLIT, like conventional subcutaneous immunotherapy, is disease-modifying therapy, which prevents new sensitization and progression to asthma.
• The optimal duration of SLIT is 3-4 years, which typically produces 7-8 years of persisting benefit before retreatment is needed.
• SCIT results in faster clinical improvement than does SLIT. And at least through the first 12-15 months, SCIT also appears to be significantly more effective.
• The use of SLIT in combination with mixes of other readily available pollen extracts is not supported by any evidence of efficacy.
• The big advantages SLIT offers over SCIT are convenience and safety. Although in U.S. clinical trials 1 in every 200-300 SLIT-treated patients experienced mild systemic reactions – typically with the first dose no fatal or near-fatal anaphylactic reactions have occurred. That’s why SLIT will be approved for at-home use after a first in-office observed dose. However, the FDA will mandate that SLIT prescriptions be accompanied by coprescription of an epinephrine autoinjector, according to Dr. Nelson of National Jewish Health in Denver and professor of medicine at the University of Colorado at Denver.
Once SLIT products win FDA approval, the therapy will get a CPT code and become, for the first time, a billable treatment – a most welcome development. But Dr. Nelson emphasized that SLIT’s approval will also create a new dilemma for physicians and their many patients with multiple allergies, say, to trees, dogs, and molds in addition to grasses or ragweed.
"Something everybody’s going to have to decide is where to position this treatment," Dr. Nelson said. "Most of the companies have no plans to take SLIT beyond the standardized extracts, which means grass, ragweed, house dust mite, and cat. You’re probably never going to have SLIT for cottonwood or juniper. And it seems unlikely that anyone is going to put a patient on tablets and injections at the same time. So it’s a decision that will have to be made for every patient: whether the ability to treat grass and ragweed, and later, house dust mite and cat, is sufficient for that patient. Because if it’s not, then probably the patient is still a candidate for SCIT."
The strategy of the companies developing SLIT is not that oral therapy is supposed to be a replacement for SCIT, but rather that it provides an immunotherapy option for patients who currently don’t receive it because they balk at the inconvenience of monthly in-office injections, he continued.
"The idea is that if these people are told, ‘You can just take a tablet at home,’ they’ll opt to get at least their allergies to grass and ragweed treated," Dr. Nelson explained.
Compliance and treatment persistence are going to be issues with SLIT, as documented in a Dutch retrospective study of 3,690 patients placed on SLIT and 2,796 who received SCIT. Only 23% of patients on SCIT stayed on treatment for the recommended 3 years. While that’s hardly a stellar adherence rate, it was actually more than three times better than with SLIT, where the rate was just 7%. The median duration of adherence with SCIT was 1.7 years, compared with 0.6 years for SLIT. The main reason patients stopped SCIT was the inconvenience, while the No. 1 reason people gave up on SLIT was ineffectiveness (J. Allergy Clin. Immunol. 2013;132:353-60).
To be fair, the Dutch study is a worst-case scenario for SLIT, according to Dr. Nelson. There are data showing adherence to SLIT is best when patients are routinely seen in the office every 3 months, apparently not the case in the Dutch study.
In a soon-to-be-published report, Dr. Nelson has reviewed 11 randomized head-to-head-comparison studies of SLIT versus SCIT and found them consistently uninformative. Most often, the deck was stacked against SLIT because it was given only three times per week and/or in too-low doses. In his view, there is only one enlightening comparative study, a recent randomized trial in which 40 Danish patients allergic to grass pollen received optimally dosed SLIT, SCIT, or neither for 15 months, with the same company’s standardized injectable and tablet Timothy grass preparations being used.
After 15 months, both treatments were effective, clinically as well as immunologically, compared with the no-treatment controls, with the benefits becoming significant in the first 1-3 months. However, the improvements in IgG4, IgE-blocking factor, facilitated antigen presentation, and the basal activation test were generally twice as great in the SCIT group. Moreover, the symptomatic response to nasal challenge – the only measure of clinical response utilized in the study was significantly better than in controls only with SCIT (Clin. Exp. Allergy 2014;44:417-28).
"This is the best comparative study we have, and it may be the best we’ll get. Here both treatments are being given optimally, and it’s very clear that at least in the first year, SCIT beats SLIT. It looks as though SLIT is trying to catch up late but doesn’t quite get there through 15 months. The investigators have stored frozen cells, so we can look forward to data on changes in regulatory T cells and suppression of Th2 cells in further publications," Dr. Nelson said.
Of note, an analysis of seven phase III clinical trials totaling nearly 2,700 adults and children showed that roughly half of them experienced transient local adverse reactions to grass SLIT. The reactions usually began on day 1, lasted 30-60 minutes, and recurred with the first seven or so daily doses. The reactions predominantly involved itching of the mouth or throat. About 10% of patients reported a sensation of swelling in the mouth that wasn’t visible to observers and tended to last longer than a week.
"Some people are surprised at the high incidence of these local, transient adverse reactions," he commented.
A common practice among American allergists is off-label sublingual administration of mixtures of eight or more pollen extracts. But a randomized, double-blind, placebo-controlled clinical trial in which Dr. Nelson was senior coinvestigator suggested this may be counterproductive when such mixtures are given in conjunction with Timothy pollen extract. A SLIT combination of Timothy pollen and nine additional pollen allergen extracts performed significantly worse than Timothy alone at the same dose; in fact, it failed to outdistance placebo in most endpoints (J. Allergy Clin. Immunol. 2009;124:150-6).
"This was a small, 56-patient study that clearly needs to be replicated, but there’s no financial backing for it. This is rather critical, since many people doing off-label sublingual immunotherapy using multiple allergen extracts think that they know what they’re doing. I hope I’ve made the point that they don’t know what dose to use, and there’s no evidence that multiple allergen mixes are really effective," Dr. Nelson said.
Grass allergies are the most common seasonal allergies in the United States. The three standardized SLIT products under FDA review, all of which have been approved in Europe for years, are Grastek, a Timothy grass extract, and Ragwitek, both developed by Merck in partnership with ALK of Denmark, and Oralair, a five-grass product developed by the French company Stallergenes. Oralair, to be marketed in the United States by Greer, contains Timothy grass allergen as well as extracts of four other temperate pasture grasses. Of note, Bermuda and Bahia grasses, common causes of seasonal allergy, aren’t included in Oralair or Grastek.
The companies have pursued different dosing strategies. ALK recommends taking Grastek continuously year-round. Stallergenes recommends starting Oralair a few months before the start of grass allergy season and stopping when the pollen season is over. In one 3-year study, 633 grass-allergic patients were randomized to Oralair or placebo starting 2 or 4 months prior to the pollen season. The reduction in adjusted symptom scores was similar with 2 vs. 4 months of therapy in advance of the allergy season (J. Allergy Clin. Immunol. 2011;128:559-66). That’s an important finding because it means preseasonally treated patients can purchase 8 weeks fewer tablets, the allergist noted.
Dr. Nelson’s prediction that these three SLIT products are headed for FDA approval this spring stems from enthusiastic endorsements by the agency’s Allergenic Products Advisory Committee. The SLIT grass allergy products were recommended unanimously, and the ragweed SLIT also received a strongly favorable vote.
He reported serving as a consultant to Merck, Pearl Therapeutic, and Circassia.
KEYSTONE, COLO. – Sublingual immunotherapy is finally coming.
Allergy therapy using rapidly dissolving oral tablets instead of subcutaneous injections has been approved in Europe for years. With Food and Drug Administration approval of sublingual immunotherapy tablets for the treatment of grass and ragweed allergies considered highly likely later this spring, the expectation is that patients, their referring physicians, and allergists will have many questions about this game-changing therapeutic innovation.
Dr. Harold S. Nelson, who closely follows developments in the field, provided answers at a meeting on allergy and respiratory diseases sponsored by National Jewish Health.
Among his key points:
• The effectiveness of sublingual immunotherapy (SLIT) for allergic rhinitis and allergic asthma is now thoroughly established. So are the optimal dosing regimens: SLIT tablets are dosed once daily at 30 times the optimal subcutaneous immunotherapy (SCIT) once-monthly maintenance dose. In other words, over the course of a month, a patient on SLIT will take a roughly 30 times greater dose of grass or ragweed allergen than will a patient on SCIT.
• SLIT for grass allergy will be approved for patients aged 5-65, while SLIT for ragweed will receive an indication for 18- to 65-year-olds.
• SLIT, like conventional subcutaneous immunotherapy, is disease-modifying therapy, which prevents new sensitization and progression to asthma.
• The optimal duration of SLIT is 3-4 years, which typically produces 7-8 years of persisting benefit before retreatment is needed.
• SCIT results in faster clinical improvement than does SLIT. And at least through the first 12-15 months, SCIT also appears to be significantly more effective.
• The use of SLIT in combination with mixes of other readily available pollen extracts is not supported by any evidence of efficacy.
• The big advantages SLIT offers over SCIT are convenience and safety. Although in U.S. clinical trials 1 in every 200-300 SLIT-treated patients experienced mild systemic reactions – typically with the first dose no fatal or near-fatal anaphylactic reactions have occurred. That’s why SLIT will be approved for at-home use after a first in-office observed dose. However, the FDA will mandate that SLIT prescriptions be accompanied by coprescription of an epinephrine autoinjector, according to Dr. Nelson of National Jewish Health in Denver and professor of medicine at the University of Colorado at Denver.
Once SLIT products win FDA approval, the therapy will get a CPT code and become, for the first time, a billable treatment – a most welcome development. But Dr. Nelson emphasized that SLIT’s approval will also create a new dilemma for physicians and their many patients with multiple allergies, say, to trees, dogs, and molds in addition to grasses or ragweed.
"Something everybody’s going to have to decide is where to position this treatment," Dr. Nelson said. "Most of the companies have no plans to take SLIT beyond the standardized extracts, which means grass, ragweed, house dust mite, and cat. You’re probably never going to have SLIT for cottonwood or juniper. And it seems unlikely that anyone is going to put a patient on tablets and injections at the same time. So it’s a decision that will have to be made for every patient: whether the ability to treat grass and ragweed, and later, house dust mite and cat, is sufficient for that patient. Because if it’s not, then probably the patient is still a candidate for SCIT."
The strategy of the companies developing SLIT is not that oral therapy is supposed to be a replacement for SCIT, but rather that it provides an immunotherapy option for patients who currently don’t receive it because they balk at the inconvenience of monthly in-office injections, he continued.
"The idea is that if these people are told, ‘You can just take a tablet at home,’ they’ll opt to get at least their allergies to grass and ragweed treated," Dr. Nelson explained.
Compliance and treatment persistence are going to be issues with SLIT, as documented in a Dutch retrospective study of 3,690 patients placed on SLIT and 2,796 who received SCIT. Only 23% of patients on SCIT stayed on treatment for the recommended 3 years. While that’s hardly a stellar adherence rate, it was actually more than three times better than with SLIT, where the rate was just 7%. The median duration of adherence with SCIT was 1.7 years, compared with 0.6 years for SLIT. The main reason patients stopped SCIT was the inconvenience, while the No. 1 reason people gave up on SLIT was ineffectiveness (J. Allergy Clin. Immunol. 2013;132:353-60).
To be fair, the Dutch study is a worst-case scenario for SLIT, according to Dr. Nelson. There are data showing adherence to SLIT is best when patients are routinely seen in the office every 3 months, apparently not the case in the Dutch study.
In a soon-to-be-published report, Dr. Nelson has reviewed 11 randomized head-to-head-comparison studies of SLIT versus SCIT and found them consistently uninformative. Most often, the deck was stacked against SLIT because it was given only three times per week and/or in too-low doses. In his view, there is only one enlightening comparative study, a recent randomized trial in which 40 Danish patients allergic to grass pollen received optimally dosed SLIT, SCIT, or neither for 15 months, with the same company’s standardized injectable and tablet Timothy grass preparations being used.
After 15 months, both treatments were effective, clinically as well as immunologically, compared with the no-treatment controls, with the benefits becoming significant in the first 1-3 months. However, the improvements in IgG4, IgE-blocking factor, facilitated antigen presentation, and the basal activation test were generally twice as great in the SCIT group. Moreover, the symptomatic response to nasal challenge – the only measure of clinical response utilized in the study was significantly better than in controls only with SCIT (Clin. Exp. Allergy 2014;44:417-28).
"This is the best comparative study we have, and it may be the best we’ll get. Here both treatments are being given optimally, and it’s very clear that at least in the first year, SCIT beats SLIT. It looks as though SLIT is trying to catch up late but doesn’t quite get there through 15 months. The investigators have stored frozen cells, so we can look forward to data on changes in regulatory T cells and suppression of Th2 cells in further publications," Dr. Nelson said.
Of note, an analysis of seven phase III clinical trials totaling nearly 2,700 adults and children showed that roughly half of them experienced transient local adverse reactions to grass SLIT. The reactions usually began on day 1, lasted 30-60 minutes, and recurred with the first seven or so daily doses. The reactions predominantly involved itching of the mouth or throat. About 10% of patients reported a sensation of swelling in the mouth that wasn’t visible to observers and tended to last longer than a week.
"Some people are surprised at the high incidence of these local, transient adverse reactions," he commented.
A common practice among American allergists is off-label sublingual administration of mixtures of eight or more pollen extracts. But a randomized, double-blind, placebo-controlled clinical trial in which Dr. Nelson was senior coinvestigator suggested this may be counterproductive when such mixtures are given in conjunction with Timothy pollen extract. A SLIT combination of Timothy pollen and nine additional pollen allergen extracts performed significantly worse than Timothy alone at the same dose; in fact, it failed to outdistance placebo in most endpoints (J. Allergy Clin. Immunol. 2009;124:150-6).
"This was a small, 56-patient study that clearly needs to be replicated, but there’s no financial backing for it. This is rather critical, since many people doing off-label sublingual immunotherapy using multiple allergen extracts think that they know what they’re doing. I hope I’ve made the point that they don’t know what dose to use, and there’s no evidence that multiple allergen mixes are really effective," Dr. Nelson said.
Grass allergies are the most common seasonal allergies in the United States. The three standardized SLIT products under FDA review, all of which have been approved in Europe for years, are Grastek, a Timothy grass extract, and Ragwitek, both developed by Merck in partnership with ALK of Denmark, and Oralair, a five-grass product developed by the French company Stallergenes. Oralair, to be marketed in the United States by Greer, contains Timothy grass allergen as well as extracts of four other temperate pasture grasses. Of note, Bermuda and Bahia grasses, common causes of seasonal allergy, aren’t included in Oralair or Grastek.
The companies have pursued different dosing strategies. ALK recommends taking Grastek continuously year-round. Stallergenes recommends starting Oralair a few months before the start of grass allergy season and stopping when the pollen season is over. In one 3-year study, 633 grass-allergic patients were randomized to Oralair or placebo starting 2 or 4 months prior to the pollen season. The reduction in adjusted symptom scores was similar with 2 vs. 4 months of therapy in advance of the allergy season (J. Allergy Clin. Immunol. 2011;128:559-66). That’s an important finding because it means preseasonally treated patients can purchase 8 weeks fewer tablets, the allergist noted.
Dr. Nelson’s prediction that these three SLIT products are headed for FDA approval this spring stems from enthusiastic endorsements by the agency’s Allergenic Products Advisory Committee. The SLIT grass allergy products were recommended unanimously, and the ragweed SLIT also received a strongly favorable vote.
He reported serving as a consultant to Merck, Pearl Therapeutic, and Circassia.
KEYSTONE, COLO. – Sublingual immunotherapy is finally coming.
Allergy therapy using rapidly dissolving oral tablets instead of subcutaneous injections has been approved in Europe for years. With Food and Drug Administration approval of sublingual immunotherapy tablets for the treatment of grass and ragweed allergies considered highly likely later this spring, the expectation is that patients, their referring physicians, and allergists will have many questions about this game-changing therapeutic innovation.
Dr. Harold S. Nelson, who closely follows developments in the field, provided answers at a meeting on allergy and respiratory diseases sponsored by National Jewish Health.
Among his key points:
• The effectiveness of sublingual immunotherapy (SLIT) for allergic rhinitis and allergic asthma is now thoroughly established. So are the optimal dosing regimens: SLIT tablets are dosed once daily at 30 times the optimal subcutaneous immunotherapy (SCIT) once-monthly maintenance dose. In other words, over the course of a month, a patient on SLIT will take a roughly 30 times greater dose of grass or ragweed allergen than will a patient on SCIT.
• SLIT for grass allergy will be approved for patients aged 5-65, while SLIT for ragweed will receive an indication for 18- to 65-year-olds.
• SLIT, like conventional subcutaneous immunotherapy, is disease-modifying therapy, which prevents new sensitization and progression to asthma.
• The optimal duration of SLIT is 3-4 years, which typically produces 7-8 years of persisting benefit before retreatment is needed.
• SCIT results in faster clinical improvement than does SLIT. And at least through the first 12-15 months, SCIT also appears to be significantly more effective.
• The use of SLIT in combination with mixes of other readily available pollen extracts is not supported by any evidence of efficacy.
• The big advantages SLIT offers over SCIT are convenience and safety. Although in U.S. clinical trials 1 in every 200-300 SLIT-treated patients experienced mild systemic reactions – typically with the first dose no fatal or near-fatal anaphylactic reactions have occurred. That’s why SLIT will be approved for at-home use after a first in-office observed dose. However, the FDA will mandate that SLIT prescriptions be accompanied by coprescription of an epinephrine autoinjector, according to Dr. Nelson of National Jewish Health in Denver and professor of medicine at the University of Colorado at Denver.
Once SLIT products win FDA approval, the therapy will get a CPT code and become, for the first time, a billable treatment – a most welcome development. But Dr. Nelson emphasized that SLIT’s approval will also create a new dilemma for physicians and their many patients with multiple allergies, say, to trees, dogs, and molds in addition to grasses or ragweed.
"Something everybody’s going to have to decide is where to position this treatment," Dr. Nelson said. "Most of the companies have no plans to take SLIT beyond the standardized extracts, which means grass, ragweed, house dust mite, and cat. You’re probably never going to have SLIT for cottonwood or juniper. And it seems unlikely that anyone is going to put a patient on tablets and injections at the same time. So it’s a decision that will have to be made for every patient: whether the ability to treat grass and ragweed, and later, house dust mite and cat, is sufficient for that patient. Because if it’s not, then probably the patient is still a candidate for SCIT."
The strategy of the companies developing SLIT is not that oral therapy is supposed to be a replacement for SCIT, but rather that it provides an immunotherapy option for patients who currently don’t receive it because they balk at the inconvenience of monthly in-office injections, he continued.
"The idea is that if these people are told, ‘You can just take a tablet at home,’ they’ll opt to get at least their allergies to grass and ragweed treated," Dr. Nelson explained.
Compliance and treatment persistence are going to be issues with SLIT, as documented in a Dutch retrospective study of 3,690 patients placed on SLIT and 2,796 who received SCIT. Only 23% of patients on SCIT stayed on treatment for the recommended 3 years. While that’s hardly a stellar adherence rate, it was actually more than three times better than with SLIT, where the rate was just 7%. The median duration of adherence with SCIT was 1.7 years, compared with 0.6 years for SLIT. The main reason patients stopped SCIT was the inconvenience, while the No. 1 reason people gave up on SLIT was ineffectiveness (J. Allergy Clin. Immunol. 2013;132:353-60).
To be fair, the Dutch study is a worst-case scenario for SLIT, according to Dr. Nelson. There are data showing adherence to SLIT is best when patients are routinely seen in the office every 3 months, apparently not the case in the Dutch study.
In a soon-to-be-published report, Dr. Nelson has reviewed 11 randomized head-to-head-comparison studies of SLIT versus SCIT and found them consistently uninformative. Most often, the deck was stacked against SLIT because it was given only three times per week and/or in too-low doses. In his view, there is only one enlightening comparative study, a recent randomized trial in which 40 Danish patients allergic to grass pollen received optimally dosed SLIT, SCIT, or neither for 15 months, with the same company’s standardized injectable and tablet Timothy grass preparations being used.
After 15 months, both treatments were effective, clinically as well as immunologically, compared with the no-treatment controls, with the benefits becoming significant in the first 1-3 months. However, the improvements in IgG4, IgE-blocking factor, facilitated antigen presentation, and the basal activation test were generally twice as great in the SCIT group. Moreover, the symptomatic response to nasal challenge – the only measure of clinical response utilized in the study was significantly better than in controls only with SCIT (Clin. Exp. Allergy 2014;44:417-28).
"This is the best comparative study we have, and it may be the best we’ll get. Here both treatments are being given optimally, and it’s very clear that at least in the first year, SCIT beats SLIT. It looks as though SLIT is trying to catch up late but doesn’t quite get there through 15 months. The investigators have stored frozen cells, so we can look forward to data on changes in regulatory T cells and suppression of Th2 cells in further publications," Dr. Nelson said.
Of note, an analysis of seven phase III clinical trials totaling nearly 2,700 adults and children showed that roughly half of them experienced transient local adverse reactions to grass SLIT. The reactions usually began on day 1, lasted 30-60 minutes, and recurred with the first seven or so daily doses. The reactions predominantly involved itching of the mouth or throat. About 10% of patients reported a sensation of swelling in the mouth that wasn’t visible to observers and tended to last longer than a week.
"Some people are surprised at the high incidence of these local, transient adverse reactions," he commented.
A common practice among American allergists is off-label sublingual administration of mixtures of eight or more pollen extracts. But a randomized, double-blind, placebo-controlled clinical trial in which Dr. Nelson was senior coinvestigator suggested this may be counterproductive when such mixtures are given in conjunction with Timothy pollen extract. A SLIT combination of Timothy pollen and nine additional pollen allergen extracts performed significantly worse than Timothy alone at the same dose; in fact, it failed to outdistance placebo in most endpoints (J. Allergy Clin. Immunol. 2009;124:150-6).
"This was a small, 56-patient study that clearly needs to be replicated, but there’s no financial backing for it. This is rather critical, since many people doing off-label sublingual immunotherapy using multiple allergen extracts think that they know what they’re doing. I hope I’ve made the point that they don’t know what dose to use, and there’s no evidence that multiple allergen mixes are really effective," Dr. Nelson said.
Grass allergies are the most common seasonal allergies in the United States. The three standardized SLIT products under FDA review, all of which have been approved in Europe for years, are Grastek, a Timothy grass extract, and Ragwitek, both developed by Merck in partnership with ALK of Denmark, and Oralair, a five-grass product developed by the French company Stallergenes. Oralair, to be marketed in the United States by Greer, contains Timothy grass allergen as well as extracts of four other temperate pasture grasses. Of note, Bermuda and Bahia grasses, common causes of seasonal allergy, aren’t included in Oralair or Grastek.
The companies have pursued different dosing strategies. ALK recommends taking Grastek continuously year-round. Stallergenes recommends starting Oralair a few months before the start of grass allergy season and stopping when the pollen season is over. In one 3-year study, 633 grass-allergic patients were randomized to Oralair or placebo starting 2 or 4 months prior to the pollen season. The reduction in adjusted symptom scores was similar with 2 vs. 4 months of therapy in advance of the allergy season (J. Allergy Clin. Immunol. 2011;128:559-66). That’s an important finding because it means preseasonally treated patients can purchase 8 weeks fewer tablets, the allergist noted.
Dr. Nelson’s prediction that these three SLIT products are headed for FDA approval this spring stems from enthusiastic endorsements by the agency’s Allergenic Products Advisory Committee. The SLIT grass allergy products were recommended unanimously, and the ragweed SLIT also received a strongly favorable vote.
He reported serving as a consultant to Merck, Pearl Therapeutic, and Circassia.
EXPERT ANALYSIS FROM THE PULMONARY AND ALLERGY UPDATE
