Omalizumab shows efficacy for refractory chronic idiopathic urticaria

SAN ANTONIO – Omalizumab diminished the signs and symptoms of chronic idiopathic urticaria in a dose-dependent fashion in a phase III study of 323 patients who failed to respond adequately to H1-antihistamines.

After 12 weeks of treatment with the recombinant humanized monoclonal antibody, improvements from baseline in weekly itch-severity scores were significantly greater in patients randomized to receive three doses of either 300 mg or 150 mg every 4 weeks, compared with placebo (score change of -9.8 and -8.1 vs. -5.1, respectively). The itch-severity score in patients randomized to receive a 75-mg dose changed by -5.9 points, but this did not differ significantly from the change in the placebo group, according to Dr. Marcus Maurer of Charite-Universitatsmedizin, Berlin. The report was published online on Feb. 24 in the New England Journal of Medicine.

The findings from this international double-blind trial were reported simultaneously at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

In addition to meeting the primary 12-week response endpoint of change in weekly itch-severity score, patients receiving the 300-mg and 150-mg doses of omalizumab also experienced significant improvements, compared with patients given placebo, on all but one secondary endpoint, including change in the 7-day urticaria activity score (UAS7), change in the score for the weekly number of hives, time until a reduction from baseline of at least 5 points in the weekly itch-severity score (the MID), the proportions of patients with a UAS7 of 6 or less, the number of patients with a weekly MID response in the itch-severity score, the change from baseline in the score for the size of the largest hive, and change from baseline in the overall score on the Dermatology Life Quality Index. Those receiving 300 mg, but not those receiving 150 mg, also experienced significant improvement in the proportion of angioedema-free days from weeks 4-12 (N. Engl. J. Med. 2013 Feb. 24 [doi:10.1056/NEJMoa1215372]).

In a post hoc analysis at 12 weeks, 53%, 23%, 18%, and 10%, of those in the 300-mg, 150-mg, 75-mg, and placebo groups, respectively, were completely free of hives, and 44%, 22%, 16%, and 5%, respectively, were free of both hives and itching.

Of note, many patients experienced extremely rapid improvement, raising questions about a potential, as-yet unidentified and fundamental characteristic of this disease, study coauthors Dr. Thomas B. Casale, professor of medicine and medical microbiology and immunology and chief of allergy/immunology at Creighton University Medical Center, Omaha, Neb., and Dr. Allen P. Kaplan, clinical professor of medicine at the Medical University of South Carolina, Charleston, reported during a press briefing at AAAAI.

They explained that omalizumab, currently approved as an add-on therapy for moderate to severe persistent allergic asthma, is known to bind the allergic antibody immunoglobulin E (IgE). Many patients with chronic urticaria have an antibody that binds to a protein on the surface of histamine-containing cells, and that protein binds IgE.

"Just one injection drops one’s IgE level pretty close to zero ... and we learned that when we drop IgE to rock bottom, the protein on the cell to which it is attached also drops – and that’s the protein that the circulating antibody interacts with. The thinking was that if we drop the surface protein low enough, there’s nothing for the antibody to react with, and the hives would improve," he said.

This was, in fact, the case, as demonstrated in a phase I study of 12 patients, in which 7 patients responded dramatically, 4 responded partially, and 1 had no response. These findings led to the current phase III study, which is one of three such studies that investigators hope will lead to the drug’s approval for chronic idiopathic urticaria, because the high cost of the drug is prohibitive with respect to off-label use.

The same effect was seen in the current study.

This effect, however, takes a couple weeks to become apparent, so the rapid responses that occur in numerous patients suggest there is something more at play.

"This is working even faster than we thought, and probably there is a function of the allergic antibody that we do not yet understand," Dr. Kaplan said. "So this is going to be not only a terrific therapy for the disorder, but will lead to research in the future that probably – we hope – will elucidate the underlying abnormality of chronic urticaria beyond our current understanding of it. It’s very exciting, because it might elucidate some fundamental analogy that we don’t appreciate, and would have implications for allergic disease across the board."

The current study comprised patients aged 12-75 years who had a 6-month or longer history of chronic idiopathic urticaria, the presence of hives associated with itching for at least 8 consecutive weeks at any time prior to enrollment (despite H1-antihistamine use), a UAS7 of 16 or more during a 7-day period, a weekly itch-severity score of at least 8, a score of at least 4 on the UAS on at least one of the screening-visit days, and receipt of a licensed dose of a second-generation H1-antihistamine for at least 3 consecutive days immediately prior to the screening visit. Those with a clearly defined underlying cause for their symptoms were excluded. The doses evaluated in this study were based on a prior dose-ranging study, which showed no additional benefit with doses over 300 mg, the investigators said.

Patients continued to receive stable doses of H1-antihistamines throughout the 12-week treatment period, and were permitted to use diphenhydramine as a rescue medication.

Omalizumab was well tolerated in this study, with a similar number of adverse events occurring across the treatment groups. Serious adverse events occurred more often in the 300-mg group, with 6% of patients in that group experiencing a serious adverse event, compared with 3% of patients in the placebo group, and 1% of patients in the 150-mg and 75-mg groups, but the events were not considered to be related to the study drug.

The duration of response, however, was limited, as noted during a 16-week observation period following the initial 12-week treatment period.

Although the weekly itch-severity scores did not return to baseline during follow-up, they did increase to the levels seen in the placebo group.

The findings are nonetheless encouraging, Dr. Kaplan said, noting that this disease, which can have dramatic adverse effects on quality of life, is not uncommon, and can be difficult to treat, with about half of all patients failing to respond to standard therapy with high dose antihistamines. Alternate treatments used to treat the disease, including steroids and cyclosporine, can be effective, but can be highly toxic, he said.

"For refractory patients we have nothing that matches (omalizumab’s) combination of this kind of efficacy with low side effects, so many of us in the field kind of view this as a game changer for the patients," he said.

This study was sponsored by Genentech and Novartis Pharma. Several study authors made disclosures. A complete list of these disclosures is available with the full text of the article at NEJM.org.

fpnews@elsevier.com

SAN ANTONIO – Omalizumab diminished the signs and symptoms of chronic idiopathic urticaria in a dose-dependent fashion in a phase III study of 323 patients who failed to respond adequately to H1-antihistamines.

After 12 weeks of treatment with the recombinant humanized monoclonal antibody, improvements from baseline in weekly itch-severity scores were significantly greater in patients randomized to receive three doses of either 300 mg or 150 mg every 4 weeks, compared with placebo (score change of -9.8 and -8.1 vs. -5.1, respectively). The itch-severity score in patients randomized to receive a 75-mg dose changed by -5.9 points, but this did not differ significantly from the change in the placebo group, according to Dr. Marcus Maurer of Charite-Universitatsmedizin, Berlin. The report was published online on Feb. 24 in the New England Journal of Medicine.

The findings from this international double-blind trial were reported simultaneously at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

In addition to meeting the primary 12-week response endpoint of change in weekly itch-severity score, patients receiving the 300-mg and 150-mg doses of omalizumab also experienced significant improvements, compared with patients given placebo, on all but one secondary endpoint, including change in the 7-day urticaria activity score (UAS7), change in the score for the weekly number of hives, time until a reduction from baseline of at least 5 points in the weekly itch-severity score (the MID), the proportions of patients with a UAS7 of 6 or less, the number of patients with a weekly MID response in the itch-severity score, the change from baseline in the score for the size of the largest hive, and change from baseline in the overall score on the Dermatology Life Quality Index. Those receiving 300 mg, but not those receiving 150 mg, also experienced significant improvement in the proportion of angioedema-free days from weeks 4-12 (N. Engl. J. Med. 2013 Feb. 24 [doi:10.1056/NEJMoa1215372]).

In a post hoc analysis at 12 weeks, 53%, 23%, 18%, and 10%, of those in the 300-mg, 150-mg, 75-mg, and placebo groups, respectively, were completely free of hives, and 44%, 22%, 16%, and 5%, respectively, were free of both hives and itching.

Of note, many patients experienced extremely rapid improvement, raising questions about a potential, as-yet unidentified and fundamental characteristic of this disease, study coauthors Dr. Thomas B. Casale, professor of medicine and medical microbiology and immunology and chief of allergy/immunology at Creighton University Medical Center, Omaha, Neb., and Dr. Allen P. Kaplan, clinical professor of medicine at the Medical University of South Carolina, Charleston, reported during a press briefing at AAAAI.

They explained that omalizumab, currently approved as an add-on therapy for moderate to severe persistent allergic asthma, is known to bind the allergic antibody immunoglobulin E (IgE). Many patients with chronic urticaria have an antibody that binds to a protein on the surface of histamine-containing cells, and that protein binds IgE.

"Just one injection drops one’s IgE level pretty close to zero ... and we learned that when we drop IgE to rock bottom, the protein on the cell to which it is attached also drops – and that’s the protein that the circulating antibody interacts with. The thinking was that if we drop the surface protein low enough, there’s nothing for the antibody to react with, and the hives would improve," he said.

This was, in fact, the case, as demonstrated in a phase I study of 12 patients, in which 7 patients responded dramatically, 4 responded partially, and 1 had no response. These findings led to the current phase III study, which is one of three such studies that investigators hope will lead to the drug’s approval for chronic idiopathic urticaria, because the high cost of the drug is prohibitive with respect to off-label use.

The same effect was seen in the current study.

This effect, however, takes a couple weeks to become apparent, so the rapid responses that occur in numerous patients suggest there is something more at play.

"This is working even faster than we thought, and probably there is a function of the allergic antibody that we do not yet understand," Dr. Kaplan said. "So this is going to be not only a terrific therapy for the disorder, but will lead to research in the future that probably – we hope – will elucidate the underlying abnormality of chronic urticaria beyond our current understanding of it. It’s very exciting, because it might elucidate some fundamental analogy that we don’t appreciate, and would have implications for allergic disease across the board."

The current study comprised patients aged 12-75 years who had a 6-month or longer history of chronic idiopathic urticaria, the presence of hives associated with itching for at least 8 consecutive weeks at any time prior to enrollment (despite H1-antihistamine use), a UAS7 of 16 or more during a 7-day period, a weekly itch-severity score of at least 8, a score of at least 4 on the UAS on at least one of the screening-visit days, and receipt of a licensed dose of a second-generation H1-antihistamine for at least 3 consecutive days immediately prior to the screening visit. Those with a clearly defined underlying cause for their symptoms were excluded. The doses evaluated in this study were based on a prior dose-ranging study, which showed no additional benefit with doses over 300 mg, the investigators said.

Patients continued to receive stable doses of H1-antihistamines throughout the 12-week treatment period, and were permitted to use diphenhydramine as a rescue medication.

Omalizumab was well tolerated in this study, with a similar number of adverse events occurring across the treatment groups. Serious adverse events occurred more often in the 300-mg group, with 6% of patients in that group experiencing a serious adverse event, compared with 3% of patients in the placebo group, and 1% of patients in the 150-mg and 75-mg groups, but the events were not considered to be related to the study drug.

The duration of response, however, was limited, as noted during a 16-week observation period following the initial 12-week treatment period.

Although the weekly itch-severity scores did not return to baseline during follow-up, they did increase to the levels seen in the placebo group.

The findings are nonetheless encouraging, Dr. Kaplan said, noting that this disease, which can have dramatic adverse effects on quality of life, is not uncommon, and can be difficult to treat, with about half of all patients failing to respond to standard therapy with high dose antihistamines. Alternate treatments used to treat the disease, including steroids and cyclosporine, can be effective, but can be highly toxic, he said.

"For refractory patients we have nothing that matches (omalizumab’s) combination of this kind of efficacy with low side effects, so many of us in the field kind of view this as a game changer for the patients," he said.

This study was sponsored by Genentech and Novartis Pharma. Several study authors made disclosures. A complete list of these disclosures is available with the full text of the article at NEJM.org.

fpnews@elsevier.com

SAN ANTONIO – Omalizumab diminished the signs and symptoms of chronic idiopathic urticaria in a dose-dependent fashion in a phase III study of 323 patients who failed to respond adequately to H1-antihistamines.

After 12 weeks of treatment with the recombinant humanized monoclonal antibody, improvements from baseline in weekly itch-severity scores were significantly greater in patients randomized to receive three doses of either 300 mg or 150 mg every 4 weeks, compared with placebo (score change of -9.8 and -8.1 vs. -5.1, respectively). The itch-severity score in patients randomized to receive a 75-mg dose changed by -5.9 points, but this did not differ significantly from the change in the placebo group, according to Dr. Marcus Maurer of Charite-Universitatsmedizin, Berlin. The report was published online on Feb. 24 in the New England Journal of Medicine.

The findings from this international double-blind trial were reported simultaneously at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

In addition to meeting the primary 12-week response endpoint of change in weekly itch-severity score, patients receiving the 300-mg and 150-mg doses of omalizumab also experienced significant improvements, compared with patients given placebo, on all but one secondary endpoint, including change in the 7-day urticaria activity score (UAS7), change in the score for the weekly number of hives, time until a reduction from baseline of at least 5 points in the weekly itch-severity score (the MID), the proportions of patients with a UAS7 of 6 or less, the number of patients with a weekly MID response in the itch-severity score, the change from baseline in the score for the size of the largest hive, and change from baseline in the overall score on the Dermatology Life Quality Index. Those receiving 300 mg, but not those receiving 150 mg, also experienced significant improvement in the proportion of angioedema-free days from weeks 4-12 (N. Engl. J. Med. 2013 Feb. 24 [doi:10.1056/NEJMoa1215372]).

In a post hoc analysis at 12 weeks, 53%, 23%, 18%, and 10%, of those in the 300-mg, 150-mg, 75-mg, and placebo groups, respectively, were completely free of hives, and 44%, 22%, 16%, and 5%, respectively, were free of both hives and itching.

Of note, many patients experienced extremely rapid improvement, raising questions about a potential, as-yet unidentified and fundamental characteristic of this disease, study coauthors Dr. Thomas B. Casale, professor of medicine and medical microbiology and immunology and chief of allergy/immunology at Creighton University Medical Center, Omaha, Neb., and Dr. Allen P. Kaplan, clinical professor of medicine at the Medical University of South Carolina, Charleston, reported during a press briefing at AAAAI.

They explained that omalizumab, currently approved as an add-on therapy for moderate to severe persistent allergic asthma, is known to bind the allergic antibody immunoglobulin E (IgE). Many patients with chronic urticaria have an antibody that binds to a protein on the surface of histamine-containing cells, and that protein binds IgE.

"Just one injection drops one’s IgE level pretty close to zero ... and we learned that when we drop IgE to rock bottom, the protein on the cell to which it is attached also drops – and that’s the protein that the circulating antibody interacts with. The thinking was that if we drop the surface protein low enough, there’s nothing for the antibody to react with, and the hives would improve," he said.

This was, in fact, the case, as demonstrated in a phase I study of 12 patients, in which 7 patients responded dramatically, 4 responded partially, and 1 had no response. These findings led to the current phase III study, which is one of three such studies that investigators hope will lead to the drug’s approval for chronic idiopathic urticaria, because the high cost of the drug is prohibitive with respect to off-label use.

The same effect was seen in the current study.

This effect, however, takes a couple weeks to become apparent, so the rapid responses that occur in numerous patients suggest there is something more at play.

"This is working even faster than we thought, and probably there is a function of the allergic antibody that we do not yet understand," Dr. Kaplan said. "So this is going to be not only a terrific therapy for the disorder, but will lead to research in the future that probably – we hope – will elucidate the underlying abnormality of chronic urticaria beyond our current understanding of it. It’s very exciting, because it might elucidate some fundamental analogy that we don’t appreciate, and would have implications for allergic disease across the board."

The current study comprised patients aged 12-75 years who had a 6-month or longer history of chronic idiopathic urticaria, the presence of hives associated with itching for at least 8 consecutive weeks at any time prior to enrollment (despite H1-antihistamine use), a UAS7 of 16 or more during a 7-day period, a weekly itch-severity score of at least 8, a score of at least 4 on the UAS on at least one of the screening-visit days, and receipt of a licensed dose of a second-generation H1-antihistamine for at least 3 consecutive days immediately prior to the screening visit. Those with a clearly defined underlying cause for their symptoms were excluded. The doses evaluated in this study were based on a prior dose-ranging study, which showed no additional benefit with doses over 300 mg, the investigators said.

Patients continued to receive stable doses of H1-antihistamines throughout the 12-week treatment period, and were permitted to use diphenhydramine as a rescue medication.

Omalizumab was well tolerated in this study, with a similar number of adverse events occurring across the treatment groups. Serious adverse events occurred more often in the 300-mg group, with 6% of patients in that group experiencing a serious adverse event, compared with 3% of patients in the placebo group, and 1% of patients in the 150-mg and 75-mg groups, but the events were not considered to be related to the study drug.

The duration of response, however, was limited, as noted during a 16-week observation period following the initial 12-week treatment period.

Although the weekly itch-severity scores did not return to baseline during follow-up, they did increase to the levels seen in the placebo group.

The findings are nonetheless encouraging, Dr. Kaplan said, noting that this disease, which can have dramatic adverse effects on quality of life, is not uncommon, and can be difficult to treat, with about half of all patients failing to respond to standard therapy with high dose antihistamines. Alternate treatments used to treat the disease, including steroids and cyclosporine, can be effective, but can be highly toxic, he said.

"For refractory patients we have nothing that matches (omalizumab’s) combination of this kind of efficacy with low side effects, so many of us in the field kind of view this as a game changer for the patients," he said.

This study was sponsored by Genentech and Novartis Pharma. Several study authors made disclosures. A complete list of these disclosures is available with the full text of the article at NEJM.org.

fpnews@elsevier.com